wikidoc - User contributions [en]

User:AED

2025-09-28T15:22:10Z

Alara E. Dagsali: /* Pages Authored/Co-authored/Collaborated */

==Alara Ece Dagsali==
'''Alara Ece Dagsali'''
 '''Contact:'''
email: alaraecedagsai99@gmail.com; +905313614710

==Medical Education==
*School of Medicine (M.D.):
Istanbul Medipol University 2021- 2024
Demiroglu Bilim University 2018-2021

==Pages Authored/Co-authored/Collaborated==

#[[Diclofenac Patch]]
#[[Cortisone Acetate]]
#[[Scorpion]]
#[[Clocortolone Pivalate]]
#[[Lodoxamide]]
#[[Isosulfan Blue]]
#[[Ibuprofen Lysine]]
#[[Prussian blue]]
#[[Botulism Antitoxin]]
#[[Trastuzumab emtansine]]
#[[Adagrasib]]
#[[Tranexamic]]
#[[Reni Syndrome]]
#[[Norelgestromin]]
#[[2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes: Developed by the task force on the management of cardiovascular disease in patients with diabetes of the European Society of Cardiology (ESC)]]
#[[Meningitis]]
#[[Acute Myocardial Infarction]]
#[[Bacterial Vaginosis]]
#[[Ceftobiprole medocaril sodium]]
#[[Danicopan]]
#[[Pegulicianine]]
#[[Vadadustat]]
#[[Givinostat Hydrochloride]]
#[[Nogapendekin alfa inbakicept-pmln]]
#[[Sotatercept-csrk]]
#[[Ansuvimab-zykl]]
#[[Berotralstat]]
#[[Margetuximab]]
#[[Naxitamab]]
#[[Relugolix]]
#[[Tirbanibulin]]
#[[Vibegron]]
#[[Atoltivimab, maftivimab, and odesivimab-ebgn]]
#[[Lonafarbin]]
#[[Lumasiran]]
#[[Pralsetinib]]
#[[Setmelanotide]]
#[[Clascoterone]]
#[[Cooper cu 64 dotatate injection]]
#[[Oliceridine]]
#[[Satralizumab]]
#[[Somapacitan-beco]]
#[[Viltolarsen]]
#[[Risdiplam]]
#[[Abametapir]]
#[[Decitabine and cedazuridine]]
#[[Fostemsavir]]
#[[Lurbinectedin]]
#[[Remimazolam]]
#[[Tafasitamab]]
#[[Triheptanoin]]
#[[Flortaucipir]]
#[[Fluoroestradiol]]
#[[Inebilizumab]]
#[[Opicapone]]
#[[Capmatinib]]
#[[Selpercatinib]]
#[[Pemigatinib]]
#[[Sacituzumab govitecan]]
#[[Tucatinib]]
#[[Selumetinib]]
#[[Osilodrostat]]
#[[Ozanimod]]
#[[Rimegepant]]
#[[ 2023 ESC Guidelines for the management of cardiovascular
disease in patients with diabetes: Developed by the task force on the management of cardiovascular disease in patients with diabetes of
the European Society of Cardiology]]

==Work Experience==
*Wikidoc - Associate Editor-In-Chief, 2023 - Current
*Yeditepe University Hospitals Cardiac Electrophysiology Lab, Istanbul TURKEY - Student Research Scientist, October 2021 - Current
*Istanbul Medipol University Science Club, Istanbul TURKEY - Research Intern, Istanbul TURKEY, April 2022 - July 2022
*TUBITAK (Scientific and Technological Research Council of Turkey),Istanbul TURKEY - Research Intern, November 2020 - April 2022
*Florance Nightingale Hospitals,Istanbul TURKEY - Translator of Articles, March 2020 - April 2020

==Clinical Experience==
*Harvard Medical School Teaching Hospital, Beth Israel Deaconess Medical Center (BIDMC),Boston , MA - Cardiac Electrophysiology Lab - Clinical Observership, June 2023
*Jackson Park Hospital, Chicago, IL - Internal Medicine, Department of Nephrology - Clinical Elective, August 2022
*DRK Kliniken Berlin, Berlin - Internal Medicine, Department of Gastroentrology, Hematology/Oncology and Addiction Diseases - Clinical Elective, August 2021
*The Universidade Estadual Paulista (UNESP) Faculdade de Medicina, São Paulo, Brasil - Department of Immunology, Genetics, and Pathology - Research Elective, August 2019

==Publications==
*Baysal E, Mutluer FO, Dagsali AE, Kumrulu UC, Huang HD, Aksu T. Improved health-related quality of life after cardioneuroablation in patients with vasovagal syncope [published online ahead of print, 2022 Nov 11]. J Interv Card Electrophysiol. 2022;10.1007/s10840-022-01420-9. doi:10.1007/s10840-022-01420-9
*38th National Cardiology Congress Turkish Society of Cardiology - Oral Presentation - Improved health-related quality of life after cardioneuroablation in patients with vasovagal syncope
*18th International Congress of Update in Cardiology and Cardiovascular Surgery - Oral Presentation - Improved health-related quality of life after cardioneuroablation in patients with vasovagal syncope

==Non-Profit Organizations & Activities==
*KACUV (Hope Foundation for Children with Cancer) - Infield Volunteer
*Down Syndrome Association - Volunteer
*International Liver Transplantation Society (ILTS), Istanbul 2022 Congress - Student Staff
*Turkish Medical Students' International Committee (TurkMSIC), Local Public Health Assistant (2019) / Local Public Health Officer (2020)

==Languages==
*Turkish - native - C2
*English - fluent - C1
*Italian - Beginner/Intermediate - B1
*German - Beginner/Intermediate - B1

==Members==
*American College of Cardiology
*American Academy of Neurology
*Turkish Medical Students' International Committee (TurkMSIC)
*European Medical Students' Association (EMSA)

Rimegepant

2025-05-13T20:12:48Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=rimegepant |aOrAn=an |drugClass=antagonist of the calcitonin gene-related peptide receptor |indicationType=treatment |indication='''Acute Treatment of Migraine''' NURTEC ODT is indicated for the acute treatment of migraine with or without aura in adults. '''Preventive Treatment of Episodic Migraine''' NURTEC ODT is indicated for the preventive treatment of episodic migraine in..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=rimegepant
|aOrAn=an
|drugClass=antagonist of the calcitonin gene-related peptide receptor
|indicationType=treatment
|indication='''Acute Treatment of Migraine'''
NURTEC ODT is indicated for the acute treatment of migraine with or without aura in adults.

'''Preventive Treatment of Episodic Migraine'''
NURTEC ODT is indicated for the preventive treatment of episodic migraine in adults.
|adverseReactions=The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

*Hypersensitivity Reactions

*Hypertension

*Raynaud’s Phenomenon
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult='''Acute Treatment of Migraine'''
NURTEC ODT is indicated for the acute treatment of migraine with or without aura in adults.

'''Preventive Treatment of Episodic Migraine'''
NURTEC ODT is indicated for the preventive treatment of episodic migraine in adults.

'''DOSAGE'''
The recommended dose of NURTEC ODT is 75 mg taken orally, as needed.

The maximum dose in a 24-hour period is 75 mg. The safety of using more than 18 doses in a 30-day period has not been established.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Rimegepant in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Rimegepant in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Rimegepant in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Rimegepant in pediatric patients.
|contraindications=NURTEC ODT is contraindicated in patients with a history of hypersensitivity reaction to rimegepant, NURTEC ODT, or any of its components. Delayed serious hypersensitivity has occurred
|warnings='''Hypersensitivity Reactions'''
Hypersensitivity reactions, including dyspnea and rash, have occurred with NURTEC ODT in clinical studies. Hypersensitivity reactions can occur days after administration, and delayed serious hypersensitivity has occurred. If a hypersensitivity reaction occurs, discontinue NURTEC ODT and initiate appropriate therapy.

'''Hypertension'''
Development of hypertension and worsening of pre-existing hypertension have been reported following the use of CGRP antagonists, including NURTEC ODT, in the postmarketing setting.

Some of the patients who developed new-onset hypertension had risk factors for hypertension. There were cases requiring initiation of pharmacological treatment for hypertension and, in some cases, hospitalization. Hypertension may occur at any time during treatment, but was most frequently reported within 7 days of therapy initiation. NURTEC ODT was discontinued in many of the reported cases.

Monitor patients treated with NURTEC ODT for new-onset hypertension or worsening of pre-existing hypertension, and consider whether discontinuation of NURTEC ODT is warranted if evaluation fails to establish an alternative etiology or blood pressure is inadequately controlled.

'''Raynaud’s Phenomenon'''
Development of Raynaud’s phenomenon and recurrence or worsening of pre-existing Raynaud’s phenomenon have been reported in the postmarketing setting following the use of CGRP antagonists, including NURTEC ODT.

In reported cases with small molecule CGRP antagonists, symptom onset occurred a median of 1.5 days following dosing. Many of the cases reported serious outcomes, including hospitalizations and disability, generally related to debilitating pain. In most reported cases, discontinuation of the CGRP antagonist resulted in resolution of symptoms.

NURTEC ODT should be discontinued if signs or symptoms of Raynaud’s phenomenon develop, and patients should be evaluated by a healthcare provider if symptoms do not resolve. Patients with a history of Raynaud’s phenomenon should be monitored for, and informed about the possibility of, worsening or recurrence of signs and symptoms.
|clinicalTrials='''Acute Treatment of Migraine''':
The safety of NURTEC ODT for the acute treatment of migraine in adults has been evaluated in a randomized, double-blind, placebo-controlled trial (Study 1) in 682 patients with migraine who received one 75 mg dose of NURTEC ODT. Approximately 85% were female, 74% were White, 21% were Black, and 17% were Hispanic or Latino. The mean age at study entry was 40 years (range 18-75 years of age).

Long-term safety was assessed in an open-label extension study using a different oral dosage form of rimegepant. That study evaluated 1,798 patients, dosing intermittently for up to one year, including 1,131 patients who were exposed to rimegepant 75 mg for at least 6 months, and 863 who were exposed for at least one year, all of whom treated an average of at least two migraine attacks per month.

The most common adverse reaction in Study 1 was nausea (2% in patients who received NURTEC ODT compared to 0.4% of patients who received placebo).

Hypersensitivity, including dyspnea and severe rash, occurred in less than 1% of patients treated with NURTEC ODT.
'''Preventive Treatment of Episodic Migraine'''
The safety of NURTEC ODT for the preventive treatment of episodic migraine in adults has been established in a randomized, double-blind, placebo-controlled trial with an open-label extension (Study 2) using a different oral dosage form of rimegepant. In the 12-week, double-blind treatment period, 370 patients with migraine received one 75 mg dose of rimegepant every other day. Approximately 81% were female, 80% were White, 17% were Black, and 28% were Hispanic or Latino. The mean age at study entry was 41 years (range 18-74 years of age). Long-term safety was assessed in an open-label extension study that included 603 patients who were treated for up to one year. Overall, 527 patients were exposed to rimegepant 75 mg for at least 6 months, and 311 were exposed for at least one year.

The most common adverse reactions (occurring in at least 2% of rimegepant-treated patients and at a frequency of at least 1% higher than placebo) in Study 2 were nausea (2.7% in patients who received rimegepant compared with 0.8% of patients who received placebo) and abdominal pain/dyspepsia (2.4% in patients who received rimegepant compared with 0.8% of patients who received placebo).
|postmarketing=The following adverse reactions have been identified during postapproval use of NURTEC ODT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Vascular Disorders: Hypertension
|drugInteractions='''CYP3A4 Inhibitors'''
Concomitant administration of NURTEC ODT with strong inhibitors of CYP3A4 results in a significant increase in rimegepant exposure. Avoid concomitant administration of NURTEC ODT with strong inhibitors of CYP3A4.

Concomitant administration of NURTEC ODT with moderate inhibitors of CYP3A4 may result in increased exposure of rimegepant. Avoid another dose of NURTEC ODT within 48 hours when it is concomitantly administered with moderate inhibitors of CYP3A4.

'''CYP3A Inducers'''
Concomitant administration of NURTEC ODT with strong or moderate inducers of CYP3A can result in a significant reduction in rimegepant exposure, which may lead to loss of efficacy of NURTEC ODT. Avoid concomitant administration of NURTEC ODT with strong or moderate inducers of CYP3A .

'''P-gp Inhibitors'''
Concomitant administration of NURTEC ODT with potent inhibitors of P-gp (e.g., amiodarone, cyclosporine, lapatinib, quinidine, ranolazine) may result in increased exposure of rimegepant. Avoid another dose of NURTEC ODT within 48 hours when it is concomitantly administered with potent inhibitors of P-gp
|useInLaborDelivery=There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to NURTEC ODT during pregnancy. For more information, healthcare providers or patients are encouraged to contact: 1-877-366-0324, email nurtecpregnancyregistry@ppd.com, or visit
|useInNursing=A lactation study was conducted, and the results have established a relative infant dose of less than 1% of the maternal weight-adjusted dose and the milk-to-plasma ratio of 0.20. These data support that transfer of rimegepant into breastmilk is low. There are no data on the effects of rimegepant on a breastfed infant or on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for NURTEC ODT and any potential adverse effects on the breastfed infant from NURTEC ODT or from the underlying maternal condition.
|useInPed=Safety and effectiveness in pediatric patients have not been established.
|useInGeri=In pharmacokinetic studies, no clinically significant pharmacokinetic differences were observed between elderly and younger subjects. Clinical studies of NURTEC ODT did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
|useInRenalImpair=No dosage adjustment of NURTEC ODT is required in patients with mild, moderate, or severe renal impairment. NURTEC ODT has not been studied in patients with end-stage renal disease and in patients on dialysis. Avoid use of NURTEC ODT in patients with end-stage renal disease (CLcr < 15 mL/min)
|useInHepaticImpair=No dosage adjustment of NURTEC ODT is required in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Plasma concentrations of rimegepant were significantly higher in subjects with severe (Child-Pugh C) hepatic impairment. Avoid use of NURTEC ODT in patients with severe hepatic impairment
|administration=*Use dry hands when opening the blister pack.

*Peel back the foil covering of one blister and gently remove the orally disintegrating tablet (ODT). Do not push the ODT through the foil.

*As soon as the blister is opened, remove the ODT and place on the tongue; alternatively, the ODT may be placed under the tongue.

*The ODT will disintegrate in saliva so that it can be swallowed without additional liquid.

*Take the ODT immediately after opening the blister pack. Do not store the ODT outside the blister pack for future us
|monitoring=*Monitor patients treated with NURTEC ODT for new-onset hypertension or worsening of pre-existing hypertension, and consider whether discontinuation of NURTEC ODT is warranted if evaluation fails to establish an alternative etiology or blood pressure is inadequately controlled.

*NURTEC ODT should be discontinued if signs or symptoms of Raynaud’s phenomenon develop, and patients should be evaluated by a healthcare provider if symptoms do not resolve. Patients with a history of Raynaud’s phenomenon should be monitored for, and informed about the possibility of, worsening or recurrence of signs and symptoms.

*There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to NURTEC ODT during pregnancy.

*
|overdose=There is limited clinical experience with NURTEC ODT overdosage. Treatment of an overdose of NURTEC ODT should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. No specific antidote for the treatment of rimegepant overdose is available. Rimegepant is unlikely to be significantly removed by dialysis because of high serum protein binding
|mechAction=Rimegepant is a calcitonin gene-related peptide receptor antagonist.
|PD=The relationship between pharmacodynamic activity and the mechanism(s) by which rimegepant exerts its clinical effects is unknown.

No clinically relevant differences in resting blood pressure were observed when rimegepant was concomitantly administered with sumatriptan (12 mg subcutaneous, given as two 6 mg doses separated by one hour) compared with sumatriptan alone to healthy volunteers.

'''Cardiac Electrophysiology'''

At a single dose 4 times the recommended dose, rimegepant does not prolong the QT interval to any clinically relevant extent.
|PK='''Absorption'''

Following oral administration of NURTEC ODT, rimegepant is absorbed with the maximum concentration at 1.5 hours. The absolute oral bioavailability of rimegepant is approximately 64%.

'''Effects of Food'''

Following administration of NURTEC ODT under fed conditions with a high-fat or low-fat meal, Tmax was delayed by approximately 1 to 1.5 hours. A high-fat meal reduced Cmax by 42 to 53% and AUC by 32 to 38%. A low-fat meal reduced Cmax by 36% and AUC by 28%. NURTEC ODT was administered without regard to food in clinical safety and efficacy studies. The impact of the reduction in rimegepant exposure because of administration with food on its efficacy is unknown.

'''Distribution'''

The steady state volume of distribution of rimegepant is 120 L. Plasma protein binding of rimegepant is approximately 96%.

'''Elimination'''

''Metabolism''

Rimegepant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9.

Rimegepant is the primary form (~77%) with no major metabolites (i.e., > 10%) detected in plasma.

'''Excretion'''

The elimination half-life of rimegepant is approximately 11 hours in healthy subjects. Following oral administration of [14C]-rimegepant to healthy male subjects, 78% of the total radioactivity was recovered in feces and 24% in urine. Unchanged rimegepant is the major single component in excreted feces (42%) and urine (51%).

'''Specific Populations'''

'''Renal Impairment'''

In a dedicated clinical study comparing the pharmacokinetics of rimegepant in subjects with mild (estimated creatinine clearance [CLcr] 60-89 mL/min), moderate (CLcr 30-59 mL/min), and severe (CLcr 15-29 mL/min) renal impairment to that with normal subjects (healthy matched control), the exposure of rimegepant following single 75 mg dose was approximately 40% higher in subjects with moderate renal impairment. However, there was no clinically meaningful difference in the exposure of rimegepant in subjects with severe renal impairment compared to subjects with normal renal function (CLcr >= 90 mL/min). NURTEC ODT has not been studied in patients with end-stage renal disease (CLcr < 15 mL/min).

'''Hepatic Impairment'''

In a dedicated clinical study comparing the pharmacokinetics of rimegepant in subjects with mild, moderate, and severe hepatic impairment to that with normal subjects (healthy matched control), the exposure of rimegepant (Cmax and AUC) following single 75 mg dose was approximately 2-fold higher in subjects with severe impairment (Child-Pugh class C). There were no clinically meaningful differences in the exposure of rimegepant in subjects with mild (Child-Pugh class A) and moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function.

'''Other Specific Populations'''

No clinically significant differences in the pharmacokinetics of rimegepant were observed based on age, sex, race/ethnicity, body weight, or CYP2C9 genotype.

'''Drug Interaction Studies'''

''In Vitro Studies''

'''Enzymes'''
Rimegepant is a substrate of CYP3A4 and CYP2C9 (see In Vivo Studies). Rimegepant is not an inhibitor of CYP1A2, 2B6, 2C9, 2C19, 2D6, or UGT1A1 at clinically relevant concentrations. However, rimegepant is a weak inhibitor of CYP3A4 with time-dependent inhibition. Rimegepant is not an inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations.

*Transporters
Rimegepant is a substrate of P-gp and BCRP (see In Vivo Studies).

Rimegepant is not a substrate of OATP1B1 or OATP1B3. Considering its low renal clearance, rimegepant was not evaluated as a substrate of the OAT1, OAT3, OCT2, MATE1, or MATE2-K.

Rimegepant is not an inhibitor of P-gp, BCRP, OAT1, or MATE2-K at clinically relevant concentrations. It is a weak inhibitor of OATP1B1 and OAT3. Rimegepant is an inhibitor of OATP1B3, OCT2, and MATE1. In a dedicated interaction study, concomitant administration of 75 mg rimegepant at steady state with metformin, a MATE1 transporter substrate, at steady state resulted in no clinically significant impact on either metformin pharmacokinetics or on glucose utilization. No clinical drug interactions are expected for NURTEC ODT with OATP1B3 or OCT2, at clinically relevant concentrations.

'''In Vivo Studies'''

'''CYP3A4 Inhibitors'''

In a dedicated drug interaction study, concomitant administration of 75 mg rimegepant (single dose) with itraconazole, a strong CYP3A4 inhibitor, at steady state resulted in increased exposures of rimegepant (AUC by 4-fold and Cmax by ~1.5-fold). No dedicated drug interaction study was conducted to assess the effect of concomitant administration of a weak inhibitor of CYP3A4 on the pharmacokinetics of rimegepant. The concomitant administration of rimegepant with a moderate inhibitor of CYP3A4 may increase rimegepant exposures (AUC) by less than 2-fold. Concomitant administration of rimegepant with a weak inhibitor of CYP3A4 is not expected to have a clinically significant impact on rimegepant exposures.

'''CYP3A Inducers'''

In a dedicated drug interaction study, concomitant administration of 75 mg rimegepant (single dose) with rifampin, a strong CYP3A4 inducer, at steady state resulted in decreased exposures of rimegepant (AUC by 80% and Cmax by 64%), which may lead to loss of efficacy. No dedicated drug interaction study was conducted to assess the effect of concomitant administration of a moderate or weak inducer of CYP3A4 on the pharmacokinetics of rimegepant. Since rimegepant is a moderately sensitive substrate for CYP3A4, drugs that are moderate inducers of CYP3A4 can also cause significant reduction in rimegepant exposure resulting in loss of efficacy. Clinically significant interaction is not expected with concomitant administration of weak inducers of CYP3A4 and rimegepant.

'''CYP2C9 Inhibitors'''

In a dedicated drug interaction study, concomitant administration of 75 mg rimegepant (single dose) with fluconazole, a combined moderate CYP3A4 and CYP2C9 inhibitor, resulted in increased exposures of rimegepant (AUC by 1.8-fold) with no relevant effect on Cmax. Rimegepant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9. Increase in the exposure of rimegepant can be attributed to combined inhibition of CYP2C9 and CYP3A4 with fluconazole administration suggesting a minor contribution from CYP2C9. Thus, CYP2C9 inhibition alone is not expected to significantly affect rimegepant exposures.

P-gp and BCRP Inhibitors

In a dedicated drug interaction study, concomitant administration of NURTEC ODT with cyclosporine (a potent P-gp and BCRP inhibitor) and with quinidine (a potent P-gp inhibitor) resulted in an increase of similar magnitude in rimegepant exposure (AUC and Cmax by 1.6 and 1.4 fold with cyclosporine, and by 1.6 and 1.7 fold with quinidine, respectively). Therefore, concomitant administration of NURTEC ODT with BCRP inhibitors is not expected to have a clinically significant impact on rimegepant exposures.

Other Drugs: No significant pharmacokinetic interactions were observed when rimegepant was concomitantly administered with oral contraceptives (norelgestromin, ethinyl estradiol), midazolam (a sensitive CYP3A4 substrate), metformin (a MATE1 substrate), or sumatriptan.
|nonClinToxic='''Carcinogenesis'''

Oral administration of rimegepant to Tg.rasH2 mice (0, 10, 100, or 300 mg/kg/day) for 26 weeks and to rats (0, 5, 20, or 45 mg/kg/day) for 91-100 weeks resulted in no evidence of drug-induced tumors in either species. In rats, the plasma exposure (AUC) at the highest dose tested (45 mg/kg/day) was approximately 30 times that at the maximum recommended human dose (MRHD) of 75 mg/day.

'''Mutagenesis'''

Rimegepant was negative in in vitro (bacterial reverse-mutation, chromosomal aberration in Chinese hamster ovary cells) and in vivo (rat micronucleus) assays.

'''Impairment of Fertility'''

Oral administration of rimegepant (0, 30, 60, or 150 mg/kg/day) to male and female rats prior to and during mating and continuing in females to gestation day (GD) 7 resulted in reduced fertility at the highest dose tested. In a second fertility study testing lower doses (0, 5, 15, or 25 mg/kg/day), no adverse effects on fertility, uterine histopathology, or early embryonic development were observed. The no-effect dose for impairment of fertility and early embryonic development in rats (60 mg/kg/day) was associated with plasma drug exposures (AUC) approximately 30 times that in humans at the MRHD.
|clinicalStudies='''Acute Treatment of Migraine'''
The efficacy of NURTEC ODT for the acute treatment of migraine with and without aura in adults was demonstrated in a randomized, double-blind, placebo-controlled trial: Study 1 (NCT03461757). Patients in the study were randomized to receive 75 mg of NURTEC ODT (N=732) or placebo (N=734). Patients were instructed to treat a migraine of moderate to severe headache pain intensity. Rescue medication (i.e., NSAIDs, acetaminophen, and/or an antiemetic) was allowed 2 hours after the initial treatment. Other forms of rescue medication such as triptans were not allowed within 48 hours of initial treatment. Approximately 14% of patients were taking preventive medications for migraine at baseline. None of the patients in Study 1 were on concomitant preventive medication that act on the CGRP pathway.

The primary efficacy analyses were conducted in patients who treated a migraine with moderate to severe pain. NURTEC ODT 75 mg demonstrated an effect on pain freedom and most bothersome symptom (MBS) freedom at two hours after dosing, compared to placebo. Pain freedom was defined as a reduction of moderate or severe headache pain to no headache pain, and MBS freedom was defined as the absence of the self-identified MBS (i.e., photophobia, phonophobia, or nausea). Among patients who selected an MBS, the most commonly selected symptom was photophobia (54%), followed by nausea (28%), and phonophobia (15%).

'''Preventive Treatment of Episodic Migraine'''
The efficacy of NURTEC ODT for the preventive treatment of episodic migraine in adults was demonstrated in one randomized, double-blind, placebo-controlled trial of a different oral dosage form of rimegepant (Study 2; NCT03732638).

Study 2 enrolled adult patients with at least a 1-year history of migraine (with or without aura). Patients experienced an average of 10.9 headache days during the 28-day observational period, which included an average of 10.2 migraine days, prior to randomization into the trial. Patients were randomized to receive every other day dosing of rimegepant 75 mg (N=373) or placebo (N=374) for 12 weeks. Patients were allowed to use acute headache treatments (i.e., triptans, NSAIDs, acetaminophen, antiemetics, muscle relaxants, and aspirin) as needed. Approximately 10% of patients were taking one preventive medication for migraine at baseline. The use of a concomitant medication that acts on the CGRP pathway was not permitted for either the acute or preventive treatment of migraine.

The study excluded patients with myocardial infarction, acute coronary syndrome, percutaneous coronary intervention, cardiac surgery, stroke, or transient ischemic attack within six months of screening.

The primary efficacy endpoint for Study 2 was the change from baseline in the mean number of monthly migraine days (MMDs) during Weeks 9 through 12 of the double-blind treatment phase.

The percentage of patients who achieved at least a 50% reduction from baseline in moderate to severe MMDs during Weeks 9 through 12 of the double-blind treatment phase compared to placebo was also evaluated.
|howSupplied=NURTEC ODT 75 mg orally disintegrating tablets are white to off-white, circular, debossed with the symbol Image, and supplied in cartons containing a blister pack of 8 orally disintegrating tablets. Each ODT contains 75 mg rimegepant.
|storage=Store NURTEC ODT at controlled room temperature, 20°C to 25°C (68°F to 77°F); with excursions permitted between 15°C to 30°C (59°F to 86°F)
|fdaPatientInfo='''Handling of Orally Disintegrating Tablets Packaging'''

Instruct patients not to remove the blister from the outer aluminum pouch until ready to use the orally disintegrating tablet inside.

'''Hypersensitivity Reactions'''

Inform patients about the signs and symptoms of hypersensitivity reactions and that these reactions can occur days after administration of NURTEC ODT. Advise patients to contact their healthcare provider immediately if signs or symptoms of hypersensitivity reactions occur.

'''Hypertension'''

Inform patients that hypertension can develop or pre-existing hypertension can worsen with NURTEC ODT, and that they should contact their healthcare provider if they experience elevation in their blood pressure.

'''Raynaud’s Phenomenon'''

Inform patients that Raynaud’s phenomenon can develop or worsen with NURTEC ODT. Advise patients to discontinue NURTEC ODT and contact their healthcare provider if they experience signs or symptoms of Raynaud’s phenomenon.

'''Pregnancy Registry'''

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to NURTEC ODT during pregnancy. Encourage participation and advise patients about how they may enroll in the registry.

This product’s labeling may have been updated. For the most recent Prescribing Information, please visit www.pfizer.com.
|alcohol=Alcohol-Rimegepant interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=Nurtec
}}

Isatuximab

2025-05-13T10:30:07Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=isatuximab |aOrAn=a |drugClass=monoclonal antibody |indicationType=treatment |indication=SARCLISA is indicated: *in combination with pomalidomide and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor. *in combination with carfilzomib and dexamethasone, for the t..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=isatuximab
|aOrAn=a
|drugClass=monoclonal antibody
|indicationType=treatment
|indication=SARCLISA is indicated:

*in combination with pomalidomide and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor.
*in combination with carfilzomib and dexamethasone, for the treatment of adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy.
*in combination with bortezomib, lenalidomide, and dexamethasone, for the treatment of adult patients with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplant (ASCT).
|adverseReactions=The following clinically significant adverse reactions from SARCLISA are also described in other sections of the labeling:

*Infusion-Related Reactions
*Infections
*Neutropenia
*Second Primary Malignancies
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=SARCLISA is indicated:

*in combination with pomalidomide and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor.
*in combination with carfilzomib and dexamethasone, for the treatment of adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy.
*in combination with bortezomib, lenalidomide, and dexamethasone, for the treatment of adult patients with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplant (ASCT).

'''DOSAGE'''
SARCLISA is a clear to slightly opalescent, colorless to slightly yellow solution, essentially free of visible particulates available as:

*Injection: 100 mg/5 mL (20 mg/mL) in a single-dose vial
*Injection: 500 mg/25 mL (20 mg/mL) in a single-dose vial
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Isatuximab in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Isatuximab in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Isatuximab in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Isatuximab in pediatric patients.
|contraindications=SARCLISA is contraindicated in patients with severe hypersensitivity to isatuximab-irfc or to any of its excipients
|warnings='''Infusion-Related Reactions'''
Serious infusion-related reactions including life-threatening anaphylactic reactions have occurred with SARCLISA treatment. Severe signs and symptoms included cardiac arrest, hypertension, hypotension, bronchospasm, dyspnea, angioedema, and swelling. In clinical trials (ICARIA-MM, IKEMA, and IMROZ), in patients treated with SARCLISA (N=592), infusion-related reactions occurred in 206 patients (35%). Among these 206 patients, 92% experienced infusion-related reactions during the first infusion and 12% after the first cycle. The most common symptoms (≥5%) of an infusion-related reaction included dyspnea and cough. Grade 1 infusion-related reactions were reported in 6% of patients, grade 2 in 28%, and grade 3 or 4 in 1.2%. Anaphylactic reactions occurred in less than 1% of patients. The total incidence of SARCLISA infusion interruptions was less than 1% and the incidence of patients with at least one SARCLISA infusion interruption due to infusion-related reactions was 26%. The median time to first SARCLISA infusion interruption was 61 minutes (range 4 to 240 minutes). SARCLISA was discontinued in 1% of patients due to infusion-related reactions.

To decrease the risk and severity of infusion-related reactions, premedicate patients prior to SARCLISA infusion with acetaminophen, H2 antagonists, diphenhydramine, or equivalent, and dexamethasone.

Monitor vital signs frequently during the entire SARCLISA infusion. For patients with grade ≥2 reactions, interrupt SARCLISA infusion and provide appropriate medical management. For patients with grade 2 or grade 3 reactions, if symptoms improve to grade ≤1, restart SARCLISA infusion at half of the initial infusion rate, with supportive care as needed, and closely monitor patients. If symptoms do not recur after 30 minutes, the infusion rate may be increased to the initial rate. In case symptoms do not improve to grade ≤1 after interruption of SARCLISA infusion, persist or worsen despite appropriate medications, or require hospitalization, permanently discontinue SARCLISA and institute appropriate management. Permanently discontinue SARCLISA if an anaphylactic reaction or life-threatening (grade 4) infusion-related reaction occurs and institute appropriate management.

'''Infections'''
SARCLISA can cause severe, life-threatening, or fatal infections. In patients who received SARCLISA at the recommended dose in ICARIA-MM, IKEMA, and IMROZ (N=592), serious infections, including opportunistic infections, occurred in 46% of patients, grade 3 or 4 infections occurred in 43%, and fatal infections occurred in 4.7%. The most common type of serious infection reported was pneumonia (32%).

Monitor patients for signs and symptoms of infection prior to and during treatment with SARCLISA and treat appropriately. Administer prophylactic antimicrobials according to guidelines.

'''Neutropenia'''
SARCLISA can cause neutropenia.

In clinical trials (ICARIA-MM, IKEMA, and IMROZ), in patients treated with SARCLISA (N=592), neutropenia based on laboratory values occurred in 81%, with grade 3 or 4 occurring in 52%. Neutropenic infections occurred in 12% of patients, with grade 3 or 4 in 4.9%, and febrile neutropenia in 4%.

Monitor complete blood cell counts periodically during treatment. If needed, use antibacterial and antiviral prophylaxis during treatment. Monitor patients with neutropenia for signs of infection. In case of grade 4 neutropenia delay SARCLISA dose until neutrophil count recovery to at least 1 × 109/L, and provide supportive care with growth factors, according to institutional guidelines. No dose reductions of SARCLISA are recommended.

'''Second Primary Malignancies'''
The incidence of second primary malignancies, during treatment and post-treatment, is increased in patients treated with SARCLISA-containing regimens. In clinical trials (ICARIA-MM, IKEMA, and IMROZ), in patients treated with SARCLISA (N=592), second primary malignancies occurred in 71 patients (12%).

In ICARIA-MM, at a median follow-up time of 52 months, second primary malignancies occurred in 7% of patients in the Isa-Pd arm and in 2% of patients in the Pd arm.

In IKEMA study, at a median follow-up time of 57 months, second primary malignancies occurred in 10% of patients in the Isa-Kd arm and in 8% of patients in the Kd arm.

In IMROZ study, at a median follow-up time of 60 months, second primary malignancies occurred in 16% of patients in the Isa-VRd arm and in 9% of patients in the VRd arm.

The most common (≥1%) second primary malignancies in ICARIA-MM, IKEMA, and IMROZ (N=592) included skin cancers (7% with SARCLISA-containing regimens and 3.1% with comparative regimens) and solid tumors other than skin cancer (4.6% with SARCLISA-containing regimens and 2.9% with comparative regimens). Patients with non-melanoma skin cancer continued treatment after resection of the skin cancer, except 2 patients on the Isa-VRd arm and 1 patient on the VRd arm of the IMROZ study.

Monitor patients for the development of second primary malignancies.

'''Laboratory Test Interference'''
Interference with Serological Testing (Indirect Antiglobulin Test)

SARCLISA binds to CD38 on red blood cells (RBCs) and may result in a false positive indirect antiglobulin test (indirect Coombs test). This interference with the indirect Coombs test may persist for approximately 6 months after the last infusion of SARCLISA. The indirect antiglobulin test was positive during Isa-Pd treatment in 68% of the tested patients, and during Isa-Kd treatment in 63% of patients. In patients with a positive indirect antiglobulin test, blood transfusions were administered without evidence of hemolysis. ABO/RhD typing was not affected by SARCLISA treatment.

Before the first SARCLISA infusion, conduct blood type and screen tests on SARCLISA-treated patients. Consider phenotyping prior to starting SARCLISA treatment. If treatment with SARCLISA has already started, inform the blood bank that the patient is receiving SARCLISA and SARCLISA interference with blood compatibility testing can be resolved using dithiothreitol-treated RBCs. If an emergency transfusion is required, non–cross-matched ABO/RhD-compatible RBCs can be given as per local blood bank practices.

Interference with Serum Protein Electrophoresis and Immunofixation Tests

SARCLISA is an IgG kappa monoclonal antibody that can be incidentally detected on both serum protein electrophoresis and immunofixation assays used for the clinical monitoring of endogenous M-protein. This interference can impact the accuracy of the determination of complete response in some patients with IgG kappa myeloma protein.

'''Embryo-Fetal Toxicity'''
Based on the mechanism of action, SARCLISA can cause fetal harm when administered to a pregnant woman. SARCLISA may cause fetal immune cell depletion and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use an effective method of contraception during treatment with SARCLISA and for 5 months after the last dose. The combination of SARCLISA with pomalidomide or lenalidomide is contraindicated in pregnant women because pomalidomide or lenalidomide may cause birth defects and death of the unborn child. Refer to the pomalidomide or lenalidomide prescribing information on use during pregnancy.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

'''Relapsed and/or Refractory Multiple Myeloma'''

Combination treatment with pomalidomide and dexamethasone (Isa-Pd)

The safety of SARCLISA was evaluated in ICARIA-MM, a randomized, open-label clinical trial in patients with previously treated multiple myeloma. Patients received SARCLISA 10 mg/kg intravenously, weekly in the first cycle and every two weeks thereafter, in combination with pomalidomide and dexamethasone (Isa-Pd) (n=152) or pomalidomide and dexamethasone (Pd) (n=149) [see Clinical Studies (14)]. Among patients receiving Isa-Pd, 66% were exposed to SARCLISA for 6 months or longer and 24% were exposed for greater than 12 months or longer.

Serious adverse reactions occurred in 62% of patients receiving Isa-Pd. Serious adverse reactions in >5% of patients who received Isa-Pd included pneumonia (26%), upper respiratory tract infections (7%), and febrile neutropenia (7%). Fatal adverse reactions occurred in 11% of patients (those that occurred in more than 1% of patients were pneumonia and other infections [3%]).

Permanent treatment discontinuation due to an adverse reaction (grades 1–4) occurred in 7% of patients who received Isa-Pd. The most frequent adverse reactions requiring permanent discontinuation in patients who received Isa-Pd were infections (2.6%). SARCLISA alone was discontinued in 3% of patients due to infusion-related reactions.

Dosage interruptions due to an adverse reaction occurred in 31% of patients who received SARCLISA. The most frequent adverse reaction requiring dosage interruption was infusion-related reaction (28%).

The most common adverse reactions (≥20%) were upper respiratory tract infection, infusion-related reactions, pneumonia, and diarrhea.

Combination treatment with carfilzomib and dexamethasone (Isa-Kd)

The safety of SARCLISA was evaluated in IKEMA, a randomized, open-label clinical trial in patients with previously treated multiple myeloma. Patients received SARCLISA 10 mg/kg intravenously weekly in the first cycle, and every two weeks thereafter, in combination with carfilzomib and dexamethasone (Isa-Kd) (n=177) or carfilzomib and dexamethasone (Kd) (n=122) [see Clinical Studies (14)]. Among patients receiving Isa-Kd, 68% were exposed to SARCLISA for 12 months or longer and 51% were exposed for greater than 18 months.

Serious adverse reactions occurred in 59% of patients receiving Isa-Kd. The most frequent serious adverse reactions in >5% of patients who received Isa-Kd were pneumonia (25%) and upper respiratory tract infections (9%). Adverse reactions with a fatal outcome during treatment were reported in 3.4% of patients in the Isa-Kd group (those occurring in more than 1% of patients were pneumonia occurring in 1.7% and cardiac failure in 1.1% of patients).

Permanent treatment discontinuation due to an adverse reaction (grades 1–4) occurred in 8% of patients who received Isa-Kd. The most frequent adverse reactions requiring permanent discontinuation in patients who received Isa-Kd were infections (2.8%). SARCLISA alone was discontinued in 0.6% of patients due to infusion-related reactions.

Dosage interruptions due to an adverse reaction occurred in 33% of patients who received SARCLISA. The most frequent adverse reaction requiring dosage interruption was infusion-related reaction (30%).

The most common adverse reactions (≥20%) were upper respiratory tract infection, infusion-related reactions, fatigue, hypertension, diarrhea, pneumonia, dyspnea, insomnia, bronchitis, cough, and back pain.

Newly Diagnosed Multiple Myeloma not Eligible for Autologous Stem Cell Transplant

Combination treatment with bortezomib, lenalidomide, and dexamethasone (Isa-VRd)

The safety of SARCLISA was evaluated in IMROZ, a randomized, open-label clinical trial in patients with newly diagnosed multiple myeloma. Patients received SARCLISA 10 mg/kg intravenously on day 1, 8, 15, 22, and 29 in the first 42-day cycle, followed by every two weeks from cycle 2 to 4 (42-day cycles), followed by every two weeks from cycle 5 to 17 (28-day cycles), and then on day 1 from cycle 18 and onwards (28-day cycles), in combination with bortezomib, lenalidomide, and dexamethasone (Isa-VRd) (n=263) or bortezomib, lenalidomide, and dexamethasone (VRd) (n= 181). In IMROZ, median duration of exposure to treatment was 53 (range: 0.5–69) months in patients treated with Isa-VRd and 31 (range 0.6–67) months in patients treated with VRd.

Serious adverse reactions occurred in 71% of patients receiving Isa-VRd. The serious adverse reaction in > 5% of patients who received Isa-VRd was pneumonia (30%). Fatal adverse reactions occurred in 11% of patients with Isa-VRd (those occurring in more than 1% of patients were pneumonia (5%).

Permanent discontinuation of treatment due to an adverse reaction occurred in 22.8% of patients treated with Isa-VRd. The most frequent adverse reactions requiring permanent discontinuation in patients who received Isa-VRd were infections (8%). SARCLISA alone was discontinued in 2.3% of patients.

Dosage interruptions due to an adverse reaction occurred in 21% of patients who received SARCLISA. The most frequent adverse reaction requiring dosage interruption was infusion related reaction (21%).

The most common adverse reactions (≥20%) were upper respiratory tract infections, diarrhea, fatigue, peripheral sensory neuropathy, pneumonia, musculoskeletal pain, cataract, constipation, peripheral edema, rash, infusion-related reaction, insomnia, and COVID-19. The most common hematologic laboratory abnormalities (≥80%) were decreased hemoglobin, decreased leukocytes, decreased lymphocytes, decreased platelets, and decreased neutrophils.

'''Description of Selected Adverse Reactions'''

'''Cardiac failure'''

In IKEMA, cardiac failure (including cardiac failure, cardiac failure congestive, cardiac failure acute, cardiac failure chronic, left ventricular failure, and pulmonary edema) was reported in 7% of patients with the Isa-Kd group (grade ≥3 in 4%) and in 7% of patients with the Kd group (grade ≥3 in 4.1%). Serious cardiac failure was observed in 4% of patients in the Isa-Kd group and in 3.3% of patients in the Kd group. See the current prescribing information for carfilzomib for more information.
|drugInteractions='''Laboratory Test Interference'''
'''Interference with Serological Testing'''

SARCLISA, an anti-CD38 antibody, may interfere with blood bank serologic tests with false positive reactions in indirect antiglobulin tests (indirect Coombs tests), antibody detection (screening) tests, antibody identification panels, and antihuman globulin crossmatches in patients treated with SARCLISA.

'''Interference with Serum Protein Electrophoresis and Immunofixation Tests'''

SARCLISA may be incidentally detected by serum protein electrophoresis and immunofixation assays used for the monitoring of M-protein and may interfere with accurate response classification based on International Myeloma Working Group (IMWG) criteria. In patients with persistent very good partial response, where interference is suspected, consider using an FDA-cleared isatuximab-irfc-specific IFE assay to distinguish isatuximab from any remaining endogenous M protein in the patient's serum to facilitate determination of a complete response.
|useInLaborDelivery=Risk Summary

SARCLISA can cause fetal harm when administered to a pregnant woman. The assessment of isatuximab-irfc-associated risks is based on the mechanism of action and data from target antigen CD38 knockout animal models (see Data). There are no available data on SARCLISA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction toxicity studies have not been conducted with isatuximab-irfc. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, miscarriage, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

The combination of SARCLISA and pomalidomide or lenalidomide is contraindicated in pregnant women because pomalidomide and lenalidomide may cause birth defects and death of the unborn child. Refer to the pomalidomide or lenalidomide prescribing information on use during pregnancy. Pomalidomide and lenalidomide are only available through a REMS program.
|useInNursing=There are no available data on the presence of isatuximab-irfc in human milk, milk production, or the effects on the breastfed child. Maternal immunoglobulin G is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to SARCLISA are unknown. Because of the potential for serious adverse reactions in the breastfed child from isatuximab-irfc administered in combination with pomalidomide or lenalidomide and dexamethasone, advise lactating women not to breastfeed during treatment with SARCLISA. Refer to pomalidomide or lenalidomide prescribing information for additional information.
|useInPed=The safety and effectiveness of SARCLISA in pediatric patients have not been established.

The safety and efficacy of SARCLISA in combination with chemotherapy were assessed, but not established, in an open-label study (ACT15378, ISAKIDS, NCT03860844) in 62 pediatric patients aged 1.4 years to < 17 years with relapsed or refractory T-acute lymphoblastic leukemia (T-ALL), B-acute lymphoblastic leukemia (B-ALL), or acute myeloid leukemia (AML). No new safety signals were observed in pediatric patients in this trial.

Body weight adjusted clearance at steady state and volume of distribution of isatuximab in pediatric patients were within the range of values that were observed in adults.
|useInGeri=Of the total number of patients with relapsed or refractory multiple myeloma in clinical studies of SARCLISA, 56% (n=586) were 65 years of age and older, while 16% (n=163) were 75 years of age and older. No overall differences in safety or effectiveness were observed between patients 65 years of age and older compared to younger patients, and other reported clinical experience has not identified differences in responses between the adults 65 years of age and older and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Of the total number of SARCLISA-treated patients with newly diagnosed multiple myeloma in IMROZ, 72% (n=319) were less than 75 years of age and 28% (n=125) were 75 years of age and older. The clinical trial did not enroll patients over age 80. Adverse reactions occurring at a higher frequency in the SARCLISA arm (≥5%) in patients 75 years of age and older included neutropenia. Adverse reactions leading to dose modifications in patients 75 years of age and older occurred at a higher frequency (≥5%) in the SARCLISA arm. The hazard ratio for overall survival (OS) in patients 75 years of age and older was 1.25 [95% CI: 0.68 to 2.3].
|useInGender=SARCLISA can cause fetal harm when administered to a pregnant woman.

'''Pregnancy Testing'''

With the combination of SARCLISA with pomalidomide or lenalidomide, refer to the pomalidomide or lenalidomide labeling for pregnancy testing requirements prior to initiating treatment in females of reproductive potential.

'''Contraception'''

''Females''

Advise female patients of reproductive potential to use effective contraception during treatment and for 5 months after the last dose of SARCLISA. Additionally, refer to the pomalidomide or lenalidomide labeling for contraception requirements prior to initiating treatment in females of reproductive potential.

''Males''

Refer to the pomalidomide or lenalidomide prescribing information.
|administration=SARCLISA is used in combination with pomalidomide and dexamethasone or in combination with carfilzomib and dexamethasone or in combination with bortezomib, lenalidomide, and dexamethasone. For dosing instructions of combination agents administered with SARCLIS.
|monitoring=Monitor vital signs frequently during the entire SARCLISA infusion. For patients with grade ≥2 reactions, interrupt SARCLISA infusion and provide appropriate medical management. For patients with grade 2 or grade 3 reactions, if symptoms improve to grade ≤1, restart SARCLISA infusion at half of the initial infusion rate, with supportive care as needed, and closely monitor patients. Monitor patients for signs and symptoms of infection prior to and during treatment with SARCLISA and treat appropriately. Administer prophylactic antimicrobials according to guidelines.
Monitor patients with neutropenia for signs of infection. In case of grade 4 neutropenia delay SARCLISA dose until neutrophil count recovery to at least 1 × 109/L, and provide supportive care with growth factors, according to institutional guidelines. No dose reductions of SARCLISA are recommended.
Monitor patients for the development of second primary malignancies.
|mechAction=Isatuximab-irfc is an IgG1-derived monoclonal antibody that binds to CD38 expressed on the surface of hematopoietic and tumor cells, including multiple myeloma cells. Isatuximab-irfc induces apoptosis of tumor cells and activation of immune effector mechanisms including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement dependent cytotoxicity (CDC). Isatuximab-irfc inhibits the ADP-ribosyl cyclase activity of CD38. Isatuximab-irfc can activate natural killer (NK) cells in the absence of CD38-positive target tumor cells and suppresses CD38-positive T-regulatory cells. The combination of isatuximab-irfc and pomalidomide enhanced ADCC activity and direct tumor cell killing compared to that of isatuximab-irfc alone in vitro, and enhanced antitumor activity compared to the activity of isatuximab-irfc or pomalidomide alone in a human multiple myeloma xenograft model.
|PD=In multiple myeloma patients treated with SARCLISA combined with pomalidomide and dexamethasone, a decrease in absolute counts of total NK cells (including inflammatory CD16+ low CD56+ bright and cytotoxic CD16+ bright CD56+ dim NK cells) and CD19+ B cells was observed in peripheral blood.

'''Cardiac Electrophysiology'''

Up to 2 times the approved recommended dose, SARCLISA does not prolong the QT interval to any clinically relevant extent.

A relationship between isatuximab-irfc exposure and overall response rate and progression-free survival was observed.

No apparent relationship was observed between an increase of isatuximab-irfc exposure and adverse reactions.
|PK=Following administration of isatuximab-irfc in combination with pomalidomide and dexamethasone at the recommended dose and schedule, the steady-state mean (CV%) predicted maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of isatuximab-irfc were 351 µg/mL (36.0%) and 72,600 µg∙h/mL (51.7%), respectively.

Following administration of isatuximab-irfc in combination with carfilzomib and dexamethasone at the recommended dose and schedule, the steady state mean (CV%) predicted Cmax and AUC of isatuximab-irfc were 655 µg/mL (30.8%) and 159,000 µg∙h/mL (37.1%), respectively.

The median time to reach steady state of isatuximab-irfc was 18 weeks with a 3.1-fold accumulation.

Following administration of isatuximab-irfc in combination with bortezomib, lenalidomide, and dexamethasone at the recommended dose and schedule, the mean (CV%) predicted Cmax and AUC of isatuximab-irfc after the dose on Week 21 were 496 µg/mL (25.6%) and 120,000 µg∙h/mL (28.9%), respectively. The geometric mean (CV%) of accumulation ratio between steady state AUC and AUC after the dose on Week 21 is predicted to be 1.4 (35.8%). Isatuximab-irfc AUC increases in a greater than dose proportional manner over a dosage range from 1 mg/kg to 20 mg/kg (0.1 to 2 times the approved recommended dosage) every 2 weeks. Isatuximab-irfc AUC increases proportionally over a dosage range from 5 mg/kg to 20 mg/kg (0.5 to 2 times the approved recommended dosage) every week for 4 weeks followed by every 2 weeks.

'''Distribution'''

The mean (CV%) predicted total volume of distribution of isatuximab-irfc is of 8.13 L (26.2%).

'''Metabolism'''

Isatuximab-irfc is expected to be metabolized into small peptides by catabolic pathways.

'''Elimination'''

Isatuximab-irfc total clearance decreased with increasing dose and with multiple doses. At steady state, the near elimination (≥99%) of isatuximab-irfc from plasma after the last dose is predicted to occur in approximately 2 months. The elimination of isatuximab-irfc was similar when given as a single agent or as combination therapy.

'''Specific Populations'''

The following factors have no clinically meaningful effect on the exposure of isatuximab-irfc: age (36 to 85 years, 70 patients were ≥75 years old), sex, renal impairment including patients with End-Stage Renal Disease (ESRD) or on dialysis (eGFR <90 mL/min/1.73 m2), and mild hepatic impairment (total bilirubin ≤ upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN, or total bilirubin >1 to 1.5 × ULN and any AST). The effect of moderate (total bilirubin >1.5 to 3 × ULN and any AST) and severe (total bilirubin >3 × ULN and any AST) hepatic impairment on isatuximab-irfc pharmacokinetics is unknown.

No dose adjustments are recommended in these specific patient populations.

'''Body weight'''

The clearance of isatuximab-irfc increased with increasing body weight.

'''Race'''

White (n=377, 79%) or Asian (n=25, 5%) race have no clinically meaningful effect on the exposure of isatuximab-irfc. The effect of Black (n=18, 4%) race on the exposure of isatuximab-irfc is unknown.

'''Immunogenicity'''
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of isatuximab-irfc or of other isatuximab products.

Overall, across 9 clinical studies in relapsed and/or refractory multiple myeloma (RRMM) with SARCLISA single-agent and combination therapies including ICARIA-MM and IKEMA (N=1023), the incidence of treatment emergent anti-drug antibodies (ADAs) was <2%. In ICARIA-MM and IKEMA, no patients with RRMM tested positive for ADA. Therefore, the neutralizing ADA status was not determined. In RRMM, no effect of ADAs was observed on the pharmacokinetics, safety, or efficacy of SARCLISA.

In IMROZ, out of the 263 patients with NDMM treated with SARCLISA in combination with bortezomib, lenalidomide, and dexamethasone, 253 were evaluable for the presence of ADA, 22 patients (8.7%) tested positive for treatment-emergent ADAs, with 21 patients considered to have a transient ADA response and 1 considered to have an indeterminate ADA response. Among these 22 ADA-positive patients, 13 (5.9%) had neutralizing antibodies. In IMROZ, a trend to lower exposure was observed in ADA-positive patients, which was considered not clinically relevant. In patients with ADA-positive status to SARCLISA, including those with neutralizing antibodies, no meaningful impact of ADAs on safety or efficacy of SARCLISA was observed.
|nonClinToxic=Carcinogenicity and genotoxicity studies have not been conducted with isatuximab-irfc. Fertility studies have not been conducted with isatuximab-irfc.
|clinicalStudies='''Relapsed and/or Refractory Multiple Myeloma'''

'''ICARIA-MM'''

The efficacy and safety of SARCLISA in combination with pomalidomide and dexamethasone (Isa-Pd) were evaluated in ICARIA-MM (NCT02990338), a multicenter, multinational, randomized, open-label, 2-arm, phase 3 study in patients with relapsed and/or refractory multiple myeloma. Patients had received at least two prior therapies including lenalidomide and a proteasome inhibitor. Patients were eligible for inclusion if they had an Eastern Cooperative Oncology Group (ECOG) status of 0–2, platelets ≥75,000 cells/mm3, absolute neutrophil count ≥1 × 109/L, creatinine clearance ≥30 mL/min/1.73 m2 (MDRD formula), AST ≤3 × ULN, and ALT ≤3 × ULN.

A total of 307 patients were randomized in a 1:1 ratio to receive either SARCLISA in combination with pomalidomide and dexamethasone (Isa-Pd, 154 patients) or pomalidomide and dexamethasone (Pd, 153 patients). Treatment was administered in both groups in 28-day cycles until disease progression or unacceptable toxicity. SARCLISA 10 mg/kg was administered as an intravenous infusion weekly in the first cycle and every two weeks thereafter. Pomalidomide 4 mg was taken orally once daily from day 1 to day 21 of each 28-day cycle. Dexamethasone (orally or intravenously) 40 mg (20 mg for patients ≥75 years of age) was given on days 1, 8, 15, and 22 for each 28-day cycle.

Overall, demographic and disease characteristics at baseline were similar between the two treatment groups. The median patient age was 67 years (range 36–86), 20% of patients were ≥75 years; 79% of patients were White, 12% Asian, and 1% Black or African American; 10% of patients entered the study with a history of COPD or asthma. The proportion of patients with renal impairment (creatinine clearance <60 mL/min/1.73 m2) was 34%. The International Staging System (ISS) stage at study entry was I in 37%, II in 36% and III in 25% of patients. Overall, 20% of patients had high-risk chromosomal abnormalities at study entry; del(17p), t(4;14) and t(14;16) were present in 12%, 8% and 2% of patients, respectively.

The median number of prior lines of therapy was 3 (range 2–11). All patients received a prior proteasome inhibitor, all patients received prior lenalidomide, and 56% of patients received prior stem cell transplantation; the majority of patients (93%) were refractory to lenalidomide, 76% to a proteasome inhibitor, and 73% to both an immunomodulator and a proteasome inhibitor.

The median duration of treatment was 41 weeks for Isa-Pd group compared to 24 weeks for Pd group.

The efficacy of SARCLISA was based upon progression-free survival (PFS). PFS results were assessed by an Independent Response Committee based on central laboratory data for M-protein and central radiologic imaging review using the International Myeloma Working Group (IMWG) criteria. The improvement in PFS represented a 40% reduction in the risk of disease progression or death in patients treated with Isa-Pd.

The median time to first response in responders was 35 days in the Isa-Pd group versus 58 days in the Pd group. The median duration of response was 13.3 months (95% CI: 10.6-NR) in the Isa-Pd group versus 11.1 months (95% CI: 8.5-NR) in the Pd group. At a median follow-up time of 52.4 months, final median overall survival was 24.6 months in the Isa-Pd group and 17.7 months in the Pd group (HR=0.776; 95% CI: 0.594 to 1.015).

'''IKEMA'''

The efficacy and safety of SARCLISA in combination with carfilzomib and dexamethasone were evaluated in IKEMA (NCT03275285), a multicenter, multinational, randomized, open-label, 2-arm, phase 3 study in patients with relapsed and/or refractory multiple myeloma. Patients had received one to three prior lines of therapy. Patients were eligible for inclusion if they had an ECOG status of 0–2, platelets ≥50,000 cells/mm3, absolute neutrophil count ≥1 × 109/L, creatinine clearance ≥15 mL/min/1.73 m2 (MDRD formula), AST ≤3 × ULN, and ALT ≤3 × ULN.

A total of 302 patients were randomized in a 3:2 ratio to receive either SARCLISA in combination with carfilzomib and dexamethasone (Isa-Kd, 179 patients) or carfilzomib and dexamethasone (Kd, 123 patients). Treatment was administered in both groups in 28-day cycles until disease progression or unacceptable toxicity. SARCLISA 10 mg/kg was administered as an intravenous infusion weekly in the first cycle and every two weeks thereafter. Carfilzomib was administered as an intravenous infusion at the dose of 20 mg/m2 on days 1 and 2; 56 mg/m2 on days 8, 9, 15, and 16 of cycle 1; and at the dose of 56 mg/m2 on days 1, 2, 8, 9, 15, and 16 for subsequent cycles of each 28-day cycle. Dexamethasone (intravenously on the days of isatuximab-irfc and/or carfilzomib infusions, and orally on the other days) 20 mg was given on days 1, 2, 8, 9, 15, 16, 22, and 23 for each 28-day cycle. On the days where both SARCLISA and carfilzomib were administered, dexamethasone was administered first, followed by SARCLISA infusion, then followed by carfilzomib infusion.

Overall, demographic and disease characteristics at baseline were similar between the two treatment groups. The median patient age was 64 years (range 33–90), 9% of patients were ≥75 years, 71% were White, 17% Asian, and 3% Black or African American. The proportion of patients with renal impairment (eGFR<60 mL/min/1.73 m2) was 24% in the Isa-Kd group versus 15% in the Kd group. The International Staging System (ISS) stage at study entry was I in 53%, II in 31%, and III in 15% of patients. Overall, 24% of patients had high-risk chromosomal abnormalities at study entry; del(17p), t(4;14), t(14;16) were present in 11%, 14%, and 2% of patients, respectively. In addition, gain(1q21) was present in 42% of patients.

The median number of prior lines of therapy was 2 (range 1–4) with 44% of patients who received 1 prior line of therapy. Overall, 90% of patients received prior proteasome inhibitors, 78% received prior immunomodulators (including 43% who received prior lenalidomide), and 61% received prior stem cell transplantation. Overall, 33% of patients were refractory to prior proteasome inhibitors, 45% were refractory to prior immunomodulators (including 33% refractory to lenalidomide), and 21% were refractory to both a proteasome inhibitor and an immunomodulator.

The median duration of treatment was 80 weeks for the Isa-Kd group compared to 61 weeks for the Kd group.

The efficacy of SARCLISA was based upon PFS. PFS results were assessed by an Independent Response Committee based on central laboratory data for M-protein and central radiologic imaging review using the IMWG criteria. The improvement in PFS represented a 45% reduction in the risk of disease progression or death in patients treated with Isa-Kd compared to patients treated with Kd.

Newly Diagnosed Multiple Myeloma

'''IMROZ'''

The efficacy of SARCLISA in combination with bortezomib, lenalidomide, and dexamethasone was evaluated in IMROZ (NCT03319667), a multicenter, international, randomized, open-label, 2-arm, phase 3 study in patients with newly diagnosed multiple myeloma who are not eligible for stem cell transplantation. Patients were eligible for inclusion if they had an Eastern Cooperative Oncology Group (ECOG) status of 0 or 1, platelets ≥70,000 cells/mm3, absolute neutrophil count ≥1 × 109/L, creatinine clearance ≥30 mL/min/1.73 m2 (MDRD formula), AST ≤3 × ULN, and ALT ≤3 × ULN.

A total of 446 patients were randomized in a 3:2 ratio to receive either SARCLISA in combination with bortezomib, lenalidomide, and dexamethasone (Isa-VRd, 265 patients) or bortezomib, lenalidomide, and dexamethasone (VRd, 181 patients). Treatment was administered in both groups during 4 cycles of 42-days each for the induction period. After completion of cycle 4, patients entered the continuous treatment period starting from cycle 5, in which 28-day cycles were administered up to disease progression or unacceptable toxicity. During the continuous treatment period, patients of the Isa-VRd group received SARCLISA in combination with lenalidomide, and dexamethasone (Isa-Rd), and patients in the VRd group received lenalidomide, and dexamethasone (Rd). During the induction period (cycle 1 to 4, 42-day cycles), SARCLISA 10 mg/kg was administered as an intravenous infusion on day 1, 8, 15, 22, and 29, in the first cycle and on day 1, 15, and 29, from cycle 2 to 4. Bortezomib was administered subcutaneously at the dose of 1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of each cycle. Lenalidomide was administered orally at the dose of 25 mg/day from day 1 to 14 and from day 22 to 35 of each cycle. Dexamethasone (intravenously on the days of SARCLISA infusions, and orally on the other days) 20 mg/day was given on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, and 33 of each cycle. During the continuous treatment period (from cycle 5, 28-day cycles), SARCLISA 10 mg/kg was administered as an IV infusion on day 1 and 15 from cycle 5 to 17, and on day 1 from cycle 18. Lenalidomide was administered orally at the dose of 25 mg/day from day 1 to 21 of each cycle. Dexamethasone (intravenously on the days of SARCLISA infusions, and orally on the other days) 20 mg/day was given on days 1, 8, 15, and 22 of each cycle.

The median patient age was 72 years (range 55–80), 28% of patients were ≥75 years; 72% of patients were White, 11% Asian, and 0.9% Black or African American. The proportion of patients with renal impairment (eGFR<60 mL/min/1.73m2) was 29%. The Revised International Staging System (R-ISS) stage at study entry was I in 23%, II in 64%, and III in 10% of patients. Overall, 17% of patients had high-risk chromosomal abnormalities at study entry; del(17p), t(4;14), and t(14;16) were present in 5%, 9% and 2% of patients, respectively. In addition, 1q21+ was present in 37% of patients.

The efficacy of SARCLISA was established based upon progression-free survival (PFS). PFS results were assessed by an Independent Response Committee based on central laboratory data for M-protein and central radiologic imaging review using the International Myeloma Working Group (IMWG) criteria. The improvement in PFS represented a 40% reduction in the risk of disease progression or death in patients treated with Isa-VRd.
|howSupplied=SARCLISA (isatuximab-irfc) injection is a clear to slightly opalescent, colorless to slightly yellow solution, essentially free of visible particulates, supplied as follows:

*One 100 mg/5 mL (20 mg/mL) single-dose vial in a carton: NDC 0024-0654-01
*One 500 mg/25 mL (20 mg/mL) single-dose vial in a carton: NDC 0024-0656-01
|storage=Store in a refrigerator at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light. Do not freeze. Do not shake.
|fdaPatientInfo='''Infusion-Related Reaction'''

Advise patients to seek immediate medical attention for any of the following signs and symptoms of infusion-related reactions: shortness of breath, wheezing or trouble breathing; swelling of the face, mouth, throat, or tongue; throat tightness; palpitations; dizziness, lightheadedness, or fainting; headache; cough; rash or itching; nausea; runny or stuffy nose; or chills [see Warnings and Precautions (5.1)].

'''Infections'''

Inform patients about the risk of developing infections during SARCLISA treatment, and to report immediately any fever or symptoms of infection to their healthcare provider .

'''Neutropenia'''

Inform patients about the risk of neutropenia and infection during SARCLISA treatment and the importance of reporting immediately any fever or symptoms of infection to their healthcare provider.

'''Second Primary Malignancies'''

Inform patients of the risk of developing second primary malignancies during treatment with SARCLISA when given with pomalidomide and dexamethasone or with carfilzomib and dexamethasone, or with bortezomib, lenalidomide, and dexamethasone.

'''Cardiac Toxicities'''

Inform patients about the risk of cardiac failure during treatment with SARCLISA when given with carfilzomib and dexamethasone, and the importance of reporting immediately any difficulty breathing, cough, or leg swelling to their healthcare provider.

'''Interference with Laboratory Tests'''

Advise patients to inform healthcare providers and transfusion center personnel that they are treated with SARCLISA in case a red blood cell transfusion is planned. Advise patients that SARCLISA may affect the results of blood tests to match their blood type for approximately 6 months after their last infusion of SARCLISA.

'''Embryo-Fetal Toxicity'''

Advise pregnant women and females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 5 months after the last dose of SARCLISA.

Advise patients that pomalidomide or lenalidomide have the potential to cause fetal harm and have specific requirements regarding contraception, pregnancy testing, blood and sperm donation, and transmission in sperm. Advise patients to report suspected or known pregnancies. Pomalidomide and lenalidomide are only available through a REMS program.
|alcohol=Alcohol-Isatuximab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=SARCLISA
}}

Osilodrostat

2025-05-12T22:08:43Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=osilodrostat |aOrAn=a |drugClass=inhibits 11beta-hydroxylase |indicationType=treatment |indication=of endogenous hypercortisolemia in adults with Cushing's syndrome for whom surgery is not an option or has not been curative. |adverseReactions=Clinically significant adverse reactions that appear in other sections of the labeling include: *Hypocortisolism *QT Prolongation *Eleva..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=osilodrostat
|aOrAn=a
|drugClass=inhibits 11beta-hydroxylase
|indicationType=treatment
|indication=of endogenous hypercortisolemia in adults with Cushing's syndrome for whom surgery is not an option or has not been curative.
|adverseReactions=Clinically significant adverse reactions that appear in other sections of the labeling include:

*Hypocortisolism
*QT Prolongation
*Elevations in Adrenal Hormone Precursors and Androgens
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=treatment of endogenous hypercortisolemia in adults with Cushing's syndrome for whom surgery is not an option or has not been curative.

'''DOSAGE'''
ISTURISA is available as:

*1 mg tablets: Pale yellow, unscored, round, biconvex with beveled edge tablet, debossed "1" on one side.
*5 mg tablets: Yellow, unscored, round, biconvex with beveled edge tablet, debossed "5" on one side.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Osilodrostat in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Osilodrostat in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Osilodrostat in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Osilodrostat in pediatric patients.
|contraindications=None
|warnings='''Hypocortisolism'''
ISTURISA lowers cortisol levels and can lead to hypocortisolism and sometimes life-threatening adrenal insufficiency. Lowering of cortisol can cause nausea, vomiting, fatigue, abdominal pain, loss of appetite, dizziness. Significant lowering of serum cortisol may result in hypotension, abnormal electrolyte levels, and hypoglycemia.

Hypocortisolism can occur at any time during ISTURISA treatment. Evaluate patients for precipitating causes of hypocortisolism (infection, physical stress, etc.). Monitor 24-hour urine free cortisol, serum or plasma cortisol, and patient's signs and symptoms periodically during ISTURISA treatment.

Decrease or temporarily discontinue ISTURISA if urine free cortisol levels fall below the target range, there is a rapid decrease in cortisol levels, and/or patients report symptoms of hypocortisolism. Stop ISTURISA and administer exogenous glucocorticoid replacement therapy if serum or plasma cortisol levels are below target range and patients have symptoms of adrenal insufficiency. Re-initiate ISTURISA at a lower dose when urine free cortisol, serum or plasma cortisol levels are within target range, and/or patient symptoms have resolved. After ISTURISA discontinuation, cortisol suppression may persist beyond the 4 hour half-life of ISTURISA.

Educate patients on the symptoms associated with hypocortisolism and advise them to contact a healthcare provider if they occur.

'''QTc Prolongation'''
ISTURISA is associated with a dose-dependent QT interval prolongation (maximum mean estimated QTcF increase of up to 5.3 ms at 30 mg), which may cause cardiac arrhythmias.

Perform an ECG to obtain a baseline QTc interval measurement prior to initiating therapy with ISTURISA and monitor for an effect on the QTc interval thereafter. Correct hypokalemia and/or hypomagnesemia prior to ISTURISA initiation and monitor periodically during treatment with ISTURISA. Correct electrolyte abnormalities if indicated. Consider temporary discontinuation of ISTURISA in the case of an increase in QTc interval > 480 ms.

Use caution in patients with risk factors for QT prolongation, (such as congenital long QT syndrome, congestive heart failure, bradyarrhythmias, uncorrected electrolyte abnormalities, and concomitant medications known to prolong the QT interval) and consider more frequent ECG monitoring.

'''Elevations in Adrenal Hormone Precursors and Androgens'''
ISTURISA blocks cortisol synthesis and may increase circulating levels of cortisol and aldosterone precursors (11-deoxy cortisol and 11-deoxycorticosterone) and androgens.

Elevated 11-deoxycorticosterone levels may activate mineralocorticoid receptors and cause hypokalemia, edema and hypertension [see Adverse Reactions (6)]. Hypokalemia should be corrected prior to initiating ISTURISA. Monitor patients treated with ISTURISA for hypokalemia, worsening of hypertension and edema. ISTURISA-induced hypokalemia should be treated with intravenous or oral potassium supplementation based on event severity. If hypokalemia persists despite potassium supplementation, consider adding mineralocorticoid antagonists. ISTURISA dose reduction or discontinuation may be necessary.

Accumulation of androgens may lead to hirsutism, hypertrichosis and acne (in females). Inform patients of the symptoms associated with hyperandrogenism and advise them to contact a healthcare provider if they occur.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.

A total of 137 Cushing's disease patients were exposed to ISTURISA in the study. The adverse reactions that occurred with frequency higher than 10% during the core 48-week period

Other notable adverse reactions which occurred with a frequency less than 10% were: hirsutism (9.5%), acne (8.8%), dyspepsia (8%), insomnia (8%), anxiety (7.3%), depression (7.3%), gastroenteritis (7.3%), malaise (6.6%), tachycardia (6.6%), alopecia (5.8%), transaminases increased (4.4%), electrocardiogram QT prolongation (3.6%), and syncope (1.5%).

'''Description of Selected Adverse Reactions'''

'''Gastrointestinal Disorders'''

Gastrointestinal disorders, predominantly nausea, vomiting, diarrhea and abdominal pain were reported in 69% of patients. In many cases, the episodes were of short duration (1-2 days) and the severity was mild to moderate.

'''Hypocortisolism'''

Hypocortisolism was reported at a rate of 31% up to 12 weeks, and 18% from Weeks 12 to 26. The majority of cases were manageable by reducing the dose of ISTURISA and/or adding low-dose, short-term glucocorticoid therapy.

'''Changes in Pituitary Tumor Volume'''

An increase in the pituitary corticotroph tumor volume by greater than 20% from baseline was observed in 21/137 (15%) patients, while a decrease in tumor volume by greater than 20% from baseline was observed in 24/137 (18%) patients at Week 48. Eight patients discontinued because of an increase in tumor volume. There was no correlation between tumor volume increase and increase in adrenocorticotrophic hormone (ACTH). There was no specific pattern of timing of the tumor volume increase and no relationship with the total and the last dose of ISTURISA used in the study.

'''QTc Interval Prolongation'''

Adverse reactions of QT prolongation and clinically relevant ECG findings were reported. Five (4%) patients had an event of QT prolongation, 3 (2%) patients had a QTcF increase of > 60ms from baseline, and 18 (13%) had a new QTcF value of > 450ms.

'''Accumulation of Adrenal Hormone Precursors'''

CYP11B1 inhibition by ISTURISA is associated with adrenal steroid precursor accumulation and testosterone increases [see Warnings and Precautions (5.3)]. The incidence of adverse reactions potentially related to accumulation of adrenal hormone precursors was 42%. Hypertension and hypokalemia were the most common adrenal hormone precursor-related adverse reactions and occurred in 14% of patients and 17% of patients, respectively; edema was reported in 7% of patients, elevated blood pressure in 15% of patients. All cases of hypokalemia responded to treatment with potassium supplementation and/or mineralocorticoid antagonist therapy (e.g., spironolactone). One patient discontinued the study because of hypokalemia. In male patients testosterone levels generally increased but remained within normal limits; all patients were asymptomatic with no values above upper limit of normal (ULN) at last available value. In female patients, mean testosterone levels increased above the normal range from baseline and reversed when treatment was interrupted. The testosterone increase was associated with mild to moderate cases of hirsutism (12%) or acne (11%) in a subset of female patients.

'''Other Abnormal Laboratory Findings'''

'''Decreased Absolute Neutrophil Count'''

Of the 137 patients from the 48-week study, 18 patients had at least one measured absolute neutrophil count below the normal limit, 2 patients had an adverse reaction of neutropenia. No concomitant infections and/or fever were reported in patients with decreased absolute neutrophil count.

'''Elevated Liver Function Tests'''

Liver enzyme elevations in patients treated with ISTURISA were infrequent, typically mild and reversed spontaneously or following dose adjustment. Most liver abnormal parameters occurred during the dose-titration period and no patients discontinued ISTURISA drug due to abnormal liver chemistry parameters. Five (4%) patients had ALT or AST > 3 × ULN during the 48-week clinical study.
|drugInteractions=*CYP3A4 Inhibitors: Concomitant use of ISTURISA with a strong CYP3A4 inhibitor (e.g., itraconazole, clarithromycin) may cause an increase in osilodrostat concentration and may increase the risk of ISTURISA-related adverse reactions
*CYP3A4 and CYP2B6 Inducers: Concomitant use of ISTURISA with strong CYP3A4 and/or CYP2B6 inducers (e.g., carbamazepine, rifampin, phenobarbital) may cause a decrease in osilodrostat concentration and may reduce the efficacy of ISTURISA
*Discontinuation of strong CYP3A4 and/or CYP2B6 inducers while using ISTURISA may cause an increase in osilodrostat concentration and may increase the risk of ISTURISA-related adverse reactions
|useInLaborDelivery=There are no available data on osilodrostat use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with active Cushing's Syndrome during pregnancy.

No adverse developmental outcomes were observed in reproduction studies in pregnant rats and rabbits when exposed to osilodrostat during organogenesis at doses that produced maternal exposures of 7 and 0.5-times the 30 mg twice daily maximum clinical dose, by AUC. In rabbits, exposures associated with maternal toxicity at 7-times the maximum clinical dose resulted in decreased fetal viability. No adverse developmental outcomes were observed in a pre- and postnatal development study with administration of osilodrostat to pregnant rats from organogenesis through lactation at 8-times the 30 mg twice daily maximum clinical dose.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.
|useInNursing=There are no available data on the presence of osilodrostat in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions (such as adrenal insufficiency) in the breastfed infant, advise patients that breastfeeding is not recommended during treatment with ISTURISA and for one week after the final dose.
|useInPed=The safety and effectiveness of ISTURISA in pediatric patients have not been established.
|useInGeri=Of the 167 patients in clinical trials with ISTURISA, 10 (6%) were 65 years and older. There were no patients above 75 years of age. Based on the available data on the use of ISTURISA in patients older than 65 years, no dosage adjustment is required
|useInRenalImpair=No dosage adjustment of ISTURISA in patients with impaired renal function is required. In patients with moderate to severe renal impairment, UFC levels should be interpreted with caution due to reduced UFC excretion.
|useInHepaticImpair=Dosage adjustment is not required in patients with mild hepatic impairment (Child-Pugh A) but is required for patients with moderately impaired hepatic function (Child-Pugh B) and for patients with severe hepatic impairment (Child-Pugh C). More frequent monitoring of adrenal function may be required during dose titration in all patients with hepatic impairment.
|administration=No dose adjustment is required for patients with renal impairment. Use caution in interpreting urine free cortisol levels in patients with moderate to severe renal impairment, due to reduced urine free cortisol excretion
|monitoring=*Initiate dosing at 2 mg orally twice daily, with or without food.
*Initially, titrate the dosage by 1 to 2 mg twice daily, no more frequently than every 2 weeks based on the rate of cortisol changes, individual tolerability and improvement in signs and symptoms of *Cushing's syndrome. If a patient tolerates ISTURISA dosage of 10 mg twice daily and continues to have elevated 24-hour urine free cortisol (UFC) levels above upper normal limit, the dosage can be titrated further by 5 mg twice daily every 2 weeks. Monitor cortisol levels from at least two 24-hour urine free cortisol collections every 1-2 weeks until adequate clinical response is maintained.
*The maintenance dosage of ISTURISA is individualized and determined by titration based on cortisol levels and patient's signs and symptoms.
*The maintenance dosage varied between 2 mg and 7 mg twice daily in clinical trials. The maximum recommended maintenance dosage of ISTURISA is 30 mg twice daily.
*Once the maintenance dosage is achieved, monitor cortisol levels at least every 1-2 months or as indicated.
|overdose=Overdosage may result in severe hypocortisolism. Signs and symptoms suggestive of hypocortisolism may include nausea, vomiting, fatigue, low blood pressure, abdominal pain, loss of appetite, dizziness, and syncope.

In case of suspected overdosage, ISTURISA should be temporarily discontinued, cortisol levels should be checked, and if necessary, corticosteroid supplementation should be initiated. Close surveillance may be necessary, including monitoring of the QT interval, blood pressure, glucose, fluid, and electrolyte until the patient's condition is stable.
|mechAction=Osilodrostat is a cortisol synthesis inhibitor. It inhibits 11beta-hydroxylase (CYP11B1), the enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland. In a Chinese hamster lung cell line V79-4 that overexpresses human CYP11B1, adrenodoxin and adrenodoxin reductase, osilodrostat inhibited the activity of human CYP11B1 dose-dependently with IC50 values of 2.5 ± 0.1 nM (n = 4).
|PD=A dose dependent increase was observed in 11-deoxycortisol, the cortisol precursor, and ACTH levels in patients with Cushing's disease.

'''Cardiac Electrophysiology'''

A thorough QT study in 86 male and female healthy volunteers showed a maximum mean placebo-corrected QTcF interval increase of 1.73 ms [90% confidence interval (CI): 0.15, 3.31] at a 10 mg dose, and 25.38 ms (90% CI: 23.53, 27.22) at a 150 mg dose (up to 2.5 times the maximum recommended dosage).

The predicted mean placebo-corrected QTcF change from baseline at the highest recommended dose in clinical practice (30 mg twice daily) was estimated as 5.3 ms (90% CI: 4.2, 6.5), based on an interpolation of the data from the thorough QT Study and population PK analysis
|PK='''Absorption'''

Osilodrostat is absorbed with a time of maximum observed concentration (Tmax) of approximately 1 hour. Exposure (AUCinf and Cmax) slightly increases over dose-proportionally within the therapeutic dose range of 1 mg to 30 mg.

'''Effect of Food'''

In a healthy volunteer study (N = 20), subjects administered with a single, 30 mg oral dose of ISTURISA film-coated tablets with a high-fat meal resulted in reduction of AUC by 11% and Cmax by 21%, respectively. The median Tmax was delayed from 1 to 2.5 hours. These changes are not considered to be clinically significant, therefore ISTURISA can be administered with or without food.

'''Distribution'''

The median apparent volume of distribution of osilodrostat is approximately 100 L. Protein binding is low (36.4%). The osilodrostat blood-to-plasma concentration ratio is 0.85.

'''Elimination'''

The elimination half-life of osilodrostat is approximately 4 hours.

In an absorption, distribution, metabolism, and excretion study, the majority of the radioactivity dose of osilodrostat is eliminated in the urine (mean: 90.6% of administered dose) with only a minor amount eliminated in the feces (1.58% of dose). The low percentage of the dose eliminated in the urine as unchanged osilodrostat (5.2%) indicates that metabolism is the major clearance pathway in humans.

'''Metabolism'''

Multiple CYP enzymes (i.e., CYP3A4, CYP2B6, and CYP2D6) and UDP-glucuronosyltransferases contribute to osilodrostat metabolism and no single enzyme contributes greater than 25% to the total clearance. The metabolites are not expected to contribute to the pharmacological effect of osilodrostat.

'''Specific Populations'''

Age and gender have no significant impact on osilodrostat exposure in adults.

'''Race/Ethnicity'''

The relative bioavailability in Asian patients is approximately 20% higher compared to that of non-Asian, along with higher Tmax and Cmax, compared to other ethnicities. However, the difference is not clinically significant.

'''Patients with Renal Impairment'''

Osilodrostat exposure was similar in the three renal function groups [normal, severe, and end stage renal disease (ESRD) groups] and thus a study was not conducted in mild and moderate renal impairment groups. The results showed that the PK of osilodrostat was not influenced by varying degrees of renal impairment to any clinically significant extent .

'''Patients with Hepatic Impairment'''

There was a trend of increasing AUCinf to osilodrostat in moderate and severe hepatic impaired subjects (geo-mean ratios are 1.44 and 2.66, respectively) as compared to normal subjects. Exposures (Cmax and AUC) of osilodrostat in the mild hepatic impairment group were similar to those in the normal group.

'''Drug Interaction'''

In a healthy volunteer study (N = 20) using a single dose of osilodrostat (50 mg) and a probe drugs cocktail, osilodrostat showed inhibition potential on CYP1A2, CYP2C19, CYP2D6, and CYP3A4/5 isozymes with 2.5-, 1.9-, 1.5- and 1.5-fold increase in caffeine, omeprazole, dextromethorphan, and midazolam exposure, respectively.

There was no significant impact of osilodrostat (30 mg twice daily for 12 days) on the exposure of oral contraceptives containing 0.03 mg estradiol and 0.15 mg levonorgestrel in healthy female subjects.
|nonClinToxic='''Carcinogenesis'''

Carcinogenicity studies were conducted in Wistar Han rats and CD1 mice. Hepatocellular adenomas and carcinomas occurred in male rats at ≥ 10 mg/kg and in females at 30 mg/kg (18- and 65-times the 30 mg twice daily maximum clinical dose, by AUC, respectively). Thyroid follicular adenoma/carcinoma was also observed in male rats at 30 mg/kg. Hepatocellular adenomas and carcinomas occurred in male mice at ≥ 10 mg kg (6 times the maximum clinical dose, by AUC) but not in female mice at any dose ≤ 30 mg/kg (31 times the maximum clinical dose, by AUC). These findings are likely rodent specific and considered not relevant to humans. Genetic profiling studies support activation of hepatic constitutive androstane receptors as the likely tumorigenic mechanism in rodents and is not a significant concern for human risk at clinical exposure to osilodrostat.

'''Genotoxicity'''

Genotoxicity assays conducted in vitro in bacterial systems and in vitro and in vivo in mammalian systems with and without metabolic activation indicate that there is no genotoxic risk in humans with osilodrostat.

'''Impairment of Fertility'''

In a fertility and early embryonic-development study in Wistar Han rats, doses of 50 mg/kg (118 times the 30 mg twice daily maximum clinical dose, by AUC) resulted in changes to estrous cyclicity and impaired female fertility and embryo viability. No effect on reproductive performance in females was observed at 5 mg/kg (8 times the maximum clinical dose). Fertility and reproductive performance were not affected in male rats up to 50 mg/kg (77 times the maximum clinical dose, by AUC).
|clinicalStudies=The safety and efficacy of ISTURISA was assessed in a 48-week, multicenter study (called the Core Period) that consisted of four study periods as follows:

*Period 1: 12-week, open-label, dose titration period
*Period 2: 12-week, open-label, maintenance treatment period
*Period 3: 8-week, double-blind, placebo-controlled, randomized withdrawal treatment period which provided the data for the primary efficacy endpoint
*Period 4: open-label treatment period of 14 to 24 weeks duration
The trial enrolled Cushing's disease patients with persistent or recurrent disease despite pituitary surgery or de novo patients for whom surgery was not indicated or who had refused surgery. The mean age at enrollment was 41 years; 77% of patients were female. There were 65% Caucasian, 28% Asian, 3% black, and 4% other race. Overall, 96% patients had received previous treatments for Cushing's disease prior to entering the study, of which 88% had undergone surgery. Persistence or recurrence of Cushing's disease was evidenced by the mean of three 24-hour UFC (mUFC) > 1.5× upper limit of normal (ULN). The mUFC (SD) at baseline was 1006 nmol/24 hr (1589), which corresponds to approximately 7 × ULN. The median mUFC at baseline was 476 nmol/24 hr, which corresponds to approximately 3.5 × ULN.

'''Period 1 (Week 1 to 12)'''

137 patients received a starting dose of 2 mg ISTURISA orally twice daily that could be titrated up to a maximum of 30 mg twice daily at no greater than 2-week intervals to achieve a mUFC within the normal range. Individual dose adjustments were based on mUFC. The dose was increased if mUFC was above ULN and was reduced if mUFC was below the lower limit of normal (LLN), or if the patient had symptoms consistent with hypocortisolism and mUFC was in the lower part of the normal range.

'''Period 2 (Week 13 to 24)'''

130 patients entered Period 2. The daily dose for patients that achieved a mUFC within the normal range in Period 1 was maintained during Period 2. Patients who did not require further dose increase, tolerated the drug, and had a mUFC ≤ ULN at Week 24 (end of Period 2) were to be considered responders and eligible to enter the Randomization Withdrawal phase (Period 3). Patients whose mUFC became elevated during Period 2 could have their dose increased further, if tolerated, up to 30 mg twice daily. These patients were considered non-responders and did not enter Period 3 but continued open-label treatment together with the patients who did not achieve normal mUFC at Week 12 and were followed for long-term safety and response to treatment.

'''Period 3 (Week 26 to 34)'''

At Week 26, 71 patients were considered responders and were randomized 1:1 to continue receiving ISTURISA (n = 36) or to switch to placebo (n = 35) for 8 weeks. Patients were stratified at randomization according to dose received at Week 24 (≤ 5 mg twice daily vs 5 mg twice daily) and history of pituitary irradiation (yes/no).

Patients were to remain on their assigned treatment and dose throughout Period 3 if mUFC were within the normal range. Blinded dose reduction or temporary discontinuation for safety or tolerability reasons were permitted. Dose increases were not permitted during Period 3. Patients with mUFC increase > 1.5 × ULN or who required a dose increase were considered non-responders and discontinued from Period 3 but allowed to receive open-label treatment during Period 4.

'''Period 4 (Week 26 or 34 to 48)'''

This period included patients who were not eligible for randomization (n = 47) at Week 26, patients who were considered non-responders during Period 3 (n = 29), and patients who were considered responders during Period 3 (n = 41). Open-label treatment with ISTURISA continued in these patients until Week 48 when patients who maintained clinical benefit on ISTURISA, as judged by the Investigator, had an option to enter an extension period.

'''Efficacy Assessment'''

The primary efficacy endpoint of the study was to compare the percentage of complete responders at the end of the 8-week randomized withdrawal period (Period 3) between patients randomized to continue ISTURISA versus the patients switched to placebo. A complete responder for the primary endpoint was defined as a patient who had mUFC ≤ ULN based on central laboratory result at the end of Period 3 (Week 34), and who neither discontinued randomized treatment or the study nor had any dose increase above their Week 26 dose.

The key secondary endpoint was to assess the complete responder rate at the end of Period 2 (Week 24). A complete responder for the key secondary endpoint was defined as a patient with mUFC ≤ ULN at Week 24 who did not require an increase in dose above the level established at the end of Period 1 (Week 12). Patients who were missing mUFC assessment at Week 24 were counted as non-responders for the key secondary endpoint.

'''Results'''

At the end of Period 3, the percentage of complete responders for the primary endpoint was 86% and 29% in the ISTURISA and placebo groups, respectively (Table 3). The difference in percentage of complete responders between ISTURISA and placebo groups was 57%, with 95% two-sided CI of (38, 76). The 95% CI were not presented by individual strata due to the small sample sizes of some of these strata.

The key secondary endpoint, complete responder rate after 24 weeks of treatment with ISTURISA was achieved by 72/137 patients (52.6%) with 95% two-sided CI of (43.9, 61.1). The lower bound of this 95% CI exceeded 30%, the pre-specified threshold for statistical significance and minimum threshold for clinical benefit.

At Week 48, 91/137 patients (66%) had normal mUFC levels.

Variable decreases from baseline for blood pressure, glucose parameters, weight and weight circumference were observed at Week 48. However, because the study allowed initiation of anti-hypertensive and anti-diabetic medications and dose increases in patients already receiving such medications and the absence of a control group, the individual contribution of ISTURISA or of anti-hypertensive and anti-diabetic medication adjustments cannot be clearly established.
|howSupplied=*1 mg:Pale yellow, unscored, round, biconvex with beveled edge tablet, debossed "1" on one side.
*5 mg: Yellow, unscored, round, biconvex with beveled edge tablet, debossed "5" on one side.

*Each carton contains 3 blister packs. Each blister pack contains 20 tablets.
|storage=Store at room temperature between 68°F to 77°F (20°C to 25°C); excursions permitted 15°C to 30°C (59°F to 86°F); protect from moisture.
|fdaPatientInfo=Advise patients to read the FDA-approved patient labeling (Patient Information).

'''Monitoring'''

Instruct patients on the importance of laboratory monitoring and adhering to their return visit schedule.

'''Hypocortisolism'''

Advise patients that ISTURISA is associated with hypocortisolism-related events. Advise patients to report symptoms of hypercortisolism to their healthcare provider.

'''QT Prolongation'''

Advise patients of the signs and symptoms of QT prolongation. Advise patients to contact their healthcare provider immediately for signs or symptoms of QT prolongation.

Advise patients that an ECG will be taken before treatment and periodically thereafter. Advise patients with cardiac disease and risk factors for QT prolongation that adjustments in cardiac medications may be made and electrolyte disturbances may require correction.

'''Adrenal Hormone Precursors/Androgens'''

Advise patients that elevation of adrenal hormone precursors may occur and lead to low potassium levels, worsening of hypertension, and edema. Advise patients to report the occurrence of these symptoms to their healthcare provider.

Advise patients that elevations of androgens may occur and may lead to hirsutism, hypertrichosis, and acne (in females). Advise patients to report the occurrence of these symptoms to their healthcare provider.

'''Lactation'''

Advise females not to breastfeed during treatment with ISTURISA and for at least one week after treatment.
|alcohol=Alcohol-Osilodrostat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=ISTURISA
}}

Ozanimod

2025-05-12T21:54:57Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=ozanimod |aOrAn=a |drugClass=potent S1PR modulator |indicationType=treatment |indication=*relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. *moderately to severely active ulcerative colitis (UC) in adults. |adverseReactions=*Infections *Progressive Multifocal Leu..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=ozanimod
|aOrAn=a
|drugClass=potent S1PR modulator
|indicationType=treatment
|indication=*relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

*moderately to severely active ulcerative colitis (UC) in adults.
|adverseReactions=*Infections
*Progressive Multifocal Leukoencephalopathy
*Bradyarrhythmia and Atrioventricular Conduction Delays
*Liver Injury
*Fetal Risk
*Increased Blood Pressure
*Respiratory Effects
*Macular Edema
*Cutaneous Malignancies
*Posterior Reversible Encephalopathy Syndrome
*Unintended Additive Immunosuppressive Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Drugs
*Severe Increase in Multiple Sclerosis Disability after Stopping ZEPOSIA
*Immune System Effects after Stopping ZEPOSIA
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=*relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

*moderately to severely active ulcerative colitis (UC) in adults.

'''DOSAGE'''
Capsules:

*0.23 mg ozanimod: light grey opaque body/light grey opaque cap imprinted with black ink "OZA" on the cap and "0.23 mg" on the body

*0.46 mg ozanimod: light grey opaque body/orange opaque cap imprinted with black ink "OZA" on the cap and "0.46 mg" on the body

*0.92 mg ozanimod: orange opaque body/orange opaque cap imprinted with black ink "OZA" on the cap and "0.92 mg" on the body
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Ozanimod in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Ozanimod in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Ozanimod in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Ozanimod in pediatric patients.
|contraindications=ZEPOSIA is contraindicated in patients who:

*In the last 6 months, have experienced a myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III or IV heart failure

*Have the presence of Mobitz type II second-degree or third degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker

*Have severe untreated sleep apnea

*Are taking a monoamine oxidase (MAO) inhibitor
|warnings='''Infections'''
Risk of Infections

ZEPOSIA causes a mean reduction in peripheral blood lymphocyte count to approximately 45% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. ZEPOSIA may therefore increase the susceptibility to infections, some serious in nature. Life-threatening and rare fatal infections have occurred in patients receiving ZEPOSIA.

Obtain a recent (i.e., within 6 months or after discontinuation of prior MS or UC therapy) complete blood count (CBC) including lymphocyte count before initiation of ZEPOSIA.

Delay initiation of ZEPOSIA in patients with an active infection until the infection is resolved.

In MS Study 1 and Study 2, the overall rate of infections and rate of serious infections in patients treated with ZEPOSIA were similar to that in patients who received interferon (IFN) beta-1a (35% vs. 34% and 1% vs. 0.8%, respectively). In UC Study 1 and Study 3, the overall rate of infections and rate of serious infections in patients treated with ZEPOSIA were similar to that in patients who received placebo (9.9% vs. 10.7% and 0.8% vs. 0.4%, respectively). In UC Study 2, the overall rate of infections in patients treated with ZEPOSIA was higher than in patients treated with placebo (23% vs. 12%) and the rate of serious infections was similar (0.9% vs. 1.8%).

ZEPOSIA increased the risk of viral upper respiratory tract infections, urinary tract infections, and herpes infections.

The proportion of patients treated with ZEPOSIA who experienced lymphocyte counts less than 0.2 × 109/L was 3.3% in MS Study 1 and Study 2. The proportion of patients treated with ZEPOSIA with lymphocyte counts less than 0.2 × 109/L was 2% in UC Study 1 and Study 3 and 2.3% in UC Study 2. These values generally returned to greater than 0.2 × 109/L while patients remained on treatment with ZEPOSIA. After discontinuing ZEPOSIA 0.92 mg, the median time for peripheral blood lymphocytes to return to the normal range was approximately 30 days, with approximately 80% to 90% of patients in the normal range within 3 months.

Consider interruption of treatment with ZEPOSIA if a patient develops a serious infection.

Because the elimination of ZEPOSIA after discontinuation may take up to 3 months, continue monitoring for infections throughout this period.

'''Herpes Viral Infection'''

Cases of localized herpes virus infection (e.g., herpes zoster and herpes simplex) were seen in clinical trials of ZEPOSIA.

In MS Study 1 and Study 2, herpes zoster was reported as an adverse reaction in 0.6% of patients treated with ZEPOSIA 0.92 mg and in 0.2% of patients who received IFN beta-1a.

In UC Study 1 and Study 3, herpes zoster was reported in 0.4% of patients who received ZEPOSIA and none in patients who received placebo. In UC Study 2, herpes zoster was reported in 2.2% of patients who received ZEPOSIA and 0.4% of patients who received placebo. None were serious or disseminated.

Herpes simplex encephalitis and varicella zoster meningitis have been reported with sphingosine 1-phosphate (S1P) receptor modulators. Patients without a healthcare professional-confirmed history of varicella (chickenpox), or without documentation of a full course of vaccination against varicella zoster virus (VZV), should be tested for antibodies to VZV before initiating ZEPOSIA (see Vaccinations below).

'''Cryptococcal Infection'''

Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with S1P receptor modulators. Physicians should be vigilant for clinical symptoms or signs of CM. Patients with symptoms or signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment. ZEPOSIA treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.

Prior and Concomitant Treatment with Anti-Neoplastic, Non-Corticosteroid Immunosuppressive, or Immune-modulating Therapies

In the MS and UC clinical studies, patients who received ZEPOSIA were not to receive concomitant treatment with anti-neoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies used for the treatment of MS and UC. Concomitant use of ZEPOSIA with any of these therapies would be expected to increase the risk of immunosuppression. In UC studies, concomitant use of corticosteroids was allowed and did not appear to influence the safety or efficacy of ZEPOSIA.

Anti-neoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids) should be co-administered with caution because of the risk of additive immune system effects during such therapy. When switching to ZEPOSIA from immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects.

'''Vaccinations'''

Patients without a healthcare professional-confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating ZEPOSIA. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with ZEPOSIA, following which initiation of treatment with ZEPOSIA should be postponed for 4 weeks to allow the full effect of vaccination to occur.

No clinical data are available on the efficacy and safety of vaccinations in patients taking ZEPOSIA. Vaccinations may be less effective if administered during ZEPOSIA treatment.

If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA. Avoid the use of live attenuated vaccines during and for 3 months after treatment with ZEPOSIA.

'''Progressive Multifocal Leukoencephalopathy'''
Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.

PML has been reported in patients treated with S1P receptor modulators, including ZEPOSIA, and other multiple sclerosis (MS) and UC therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants, duration of use). Based on data from patients with MS, longer treatment duration increases the risk of PML in patients treated with S1P receptor modulators, and the majority of PML cases have occurred in patients treated with S1P receptor modulators for at least 18 months. Physicians should be vigilant for clinical symptoms or MRI findings that may be suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. If PML is suspected, treatment with ZEPOSIA should be suspended until PML has been excluded by an appropriate diagnostic evaluation.

If PML is confirmed, treatment with ZEPOSIA should be discontinued.

Immune reconstitution inflammatory syndrome (IRIS) has been reported in MS patients treated with S1P receptor modulators who developed PML and subsequently discontinued treatment. IRIS presents as a clinical decline in the patient’s condition that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes on MRI. The time to onset of IRIS in patients with PML was generally within a few months after S1P receptor modulator discontinuation. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken.

'''Bradyarrhythmia and Atrioventricular Conduction Delays'''
Since initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction delays, an up-titration scheme should be used to reach the maintenance dosage of ZEPOSIA.

ZEPOSIA was not studied in patients who had:

*A myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization within the last 6 months

*New York Heart Association Class III / IV heart failure

*Cardiac conduction or rhythm disorders, including sick sinus syndrome, significant QT prolongation (QTcF > 450 msec in males, > 470 msec in females), risk factors for QT prolongation, or other conduction abnormalities or cardiac condition that in the opinion of the treating investigator could jeopardize the patient's health

*Other pre-existing stable cardiac conditions without clearance from a cardiologist

*Severe untreated sleep apnea

*A resting heart rate less than 55 beats per minute (bpm) at baseline
Reduction in Heart Rate

Initiation of ZEPOSIA may result in a transient decrease in heart rate. After the initial dose of ZEPOSIA 0.23 mg, the greatest mean decrease from baseline in heart rate occurred at Hour 5 on Day 1 (decrease of 1.2 bpm in MS Study 1 and Study 2, and 0.7 bpm in UC Study 1 and Study 3), returning to near baseline at Hour 6. With continued up-titration, the maximal heart rate effect of ozanimod occurred on Day 8. The utility of performing first-dose cardiac monitoring when initiating ZEPOSIA in patients with characteristics similar to those studied in the clinical trials of ZEPOSIA is unclear. Heart rates below 40 bpm were not observed. Initiation of ZEPOSIA without titration may result in greater decreases in heart rate.

In MS Study 1 and Study 2, bradycardia was reported on the day of treatment initiation in 0.6% of patients treated with ZEPOSIA compared to no patients who received IFN beta-1a. After Day 1, the incidence of bradycardia was 0.8% in patients treated with ZEPOSIA compared to 0.7% of patients who received IFN beta-1a. In UC Study 1 and Study 3, bradycardia was reported on the day of treatment initiation in 1 patient (0.2%) treated with ZEPOSIA compared to none in patients who received placebo. After Day 1, bradycardia was reported in 1 patient (0.2%) treated with ZEPOSIA. In UC Study 2, bradycardia was not reported.

Atrioventricular Conduction Delays

Initiation of ZEPOSIA may result in transient atrioventricular conduction delays. At ZEPOSIA exposures higher than the recommended dosage without dose titration, first- and second-degree type 1 atrioventricular blocks were observed in healthy volunteers; however, in MS Study 1 and Study 2 and UC Study 1 and Study 3 with dose titration, Mobitz type 2 second- or third-degree atrioventricular blocks were not reported in patients treated with ZEPOSIA.

If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals:

*With significant QT prolongation (QTcF > 450 msec in males, > 470 msec in females)

With arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs

*With ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension

*With a history of with second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sinoatrial heart block
'''Liver Injury'''
Clinically significant liver injury, including acute liver failure requiring transplant, has occurred in patients treated with ZEPOSIA in the postmarketing setting. Signs of liver injury, including elevated serum hepatic enzymes and elevated total bilirubin, have occurred as early as ten days after the first dose.

In MS Study 1 and Study 2, elevations of ALT to 5-fold the upper limit of normal (ULN) or greater occurred in 1.6% of patients treated with ZEPOSIA 0.92 mg and 1.3% of patients who received IFN beta-1a. Elevations of 3-fold the ULN or greater occurred in 5.5% of patients treated with ZEPOSIA and 3.1% of patients who received IFN beta-1a. The median time to an elevation of 3-fold the ULN was 6 months. The majority (79%) of patients continued treatment with ZEPOSIA with values returning to less than 3-fold the ULN within approximately 2-4 weeks. ZEPOSIA was discontinued for a confirmed elevation greater than 5-fold the ULN. Overall, the discontinuation rate because of elevations in hepatic enzymes was 1.1% of patients with MS treated with ZEPOSIA 0.92 mg and 0.8% of patients who received IFN beta-1a.

In UC Study 1, elevations of ALT to 5-fold the ULN or greater occurred in 0.9% of patients treated with ZEPOSIA 0.92 mg and 0.5% of patients who received placebo, and in UC Study 2 elevations occurred in 0.9% of patients and no patients, respectively. In UC Study 1, elevations of ALT to 3-fold the ULN or greater occurred in 2.6% of UC patients treated with ZEPOSIA 0.92 mg and 0.5% of patients who received placebo, and in UC Study 2 elevations occurred in 2.3% of patients and no patients, respectively. In controlled and uncontrolled UC studies, the majority (96%) of patients with ALT greater than 3-fold the ULN continued treatment with ZEPOSIA with values returning to less than 3-fold the ULN within approximately 2 to 4 weeks. Overall, the discontinuation rate because of elevations in hepatic enzymes was 0.4% in patients treated with ZEPOSIA 0.92 mg, and none in patients who received placebo in the controlled UC studies.

Individuals with an AST or ALT greater than 1.5-fold ULN were excluded from MS Study 1 and Study 2 and greater than 2 times the ULN for UC Study 1 and Study 3. There are no data to establish that patients with preexisting liver disease are at increased risk to develop elevated liver function test values when taking ZEPOSIA. Dosage adjustment in patients with mild or moderate hepatic impairment (Child-Pugh class A or B) is required [see Dosage and Administration (2.3)], and use of ZEPOSIA in patients with severe hepatic impairment (Child-Pugh class C) is not recommended.

Obtain transaminase and bilirubin levels, if not recently available (i.e., within 6 months), before initiation of ZEPOSIA. Obtain transaminase levels and total bilirubin levels periodically during treatment and until two months after ZEPOSIA discontinuation.

Patients should be monitored for signs and symptoms of any hepatic injury. Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, should have hepatic enzymes promptly checked, and ZEPOSIA should be interrupted. Treatment should not be resumed if a plausible alternative etiology for the signs and symptoms cannot be established, because these patients are at risk for severe drug-induced liver injury.

'''Fetal Risk'''
There are no adequate and well-controlled studies in pregnant women. Based on animal studies, ZEPOSIA may cause fetal harm. Because it takes approximately 3 months to eliminate ZEPOSIA from the body, women of childbearing potential should use effective contraception to avoid pregnancy during treatment and for 3 months after stopping ZEPOSIA.

'''Increased Blood Pressure'''
In MS Study 1 and Study 2, patients treated with ZEPOSIA had an average increase of approximately 1 to 2 mm Hg in systolic pressure over patients who received IFN beta-1a, and no effect on diastolic pressure. The increase in systolic pressure was first detected after approximately 3 months of treatment and persisted throughout treatment. Hypertension was reported as an adverse reaction in 3.9% of patients treated with ZEPOSIA 0.92 mg and in 2.1% of patients who received IFN beta-1a. Two patients treated with ZEPOSIA in MS Study 1 and one patient treated with interferon (IFN) beta-1a in Study 2 experienced a hypertensive crisis that was not clearly influenced by a concomitant medication.

The mean increase in systolic blood pressure (SBP) and diastolic blood pressure (DBP) in UC patients treated with ZEPOSIA is similar to patients with MS. In UC Study 1 and Study 3, the average increase from baseline in SBP was 3.7 mm Hg in patients treated with ZEPOSIA and 2.3 mm Hg in patients treated with placebo. In UC Study 2, the average increase from baseline in SBP was 5.1 mm Hg in patients treated with ZEPOSIA and 1.5 mm Hg in patients treated with placebo. There was no effect on DBP.

Hypertension was reported as an adverse reaction in 1.2% of patients treated with ZEPOSIA 0.92 mg and none in patients treated with placebo in UC Study 1 and Study 3, and in 2.2% and 2.2% of patients in UC Study 2, respectively. Hypertensive crisis was reported in two patients receiving ZEPOSIA and one patient receiving placebo.

Blood pressure should be monitored during treatment with ZEPOSIA and managed appropriately.

'''Respiratory Effects'''
Dose-dependent reductions in absolute forced expiratory volume over 1 second (FEV1) were observed in MS patients treated with ZEPOSIA as early as 3 months after treatment initiation. In the MS pooled analyses of Study 1 and Study 2, the decline in absolute FEV1 from baseline in patients treated with ZEPOSIA compared to patients who received IFN beta-1a was 60 mL (95% CI: -100, -20) at 12 months. The mean difference in percent predicted FEV1 at 12 months between patients treated with ZEPOSIA and patients who received IFN beta-1a was 1.9% (95% CI: -2.9, -0.8). Dose-dependent reductions in forced vital capacity (FVC) (absolute value and %-predicted) were also seen at Month 3 in pooled analyses comparing patients treated with ZEPOSIA to patients who received IFN beta-1a [60 mL, 95% CI (-110, -10); 1.4%, 95% CI: (-2.6, -0.2)], though significant reductions were not seen at other timepoints. There is insufficient information to determine the reversibility of the decrease in FEV1 or FVC after drug discontinuation. One patient in MS Study 1 discontinued ZEPOSIA because of dyspnea.

In UC Study 1 the mean difference in decline in absolute FEV1 from baseline in patients treated with ZEPOSIA compared to patients who received placebo was 22 mL (95% CI: -84, 39) at 10 weeks. The mean difference in percent predicted normal (PPN) FEV1 at 10 weeks between patients treated with ZEPOSIA compared to those who received placebo was 0.8% (95% CI: -2.6, 1.0). The difference in reductions in FVC (absolute value and %-predicted) seen at Week 10 in UC Study 1, comparing patients who were treated with ZEPOSIA to those who received placebo was 44 mL, 95% CI (-114, 26); 0.5%, 95% CI (-2.3, 1.2), respectively. There is insufficient information to determine the reversibility of observed decreases in FEV1 or FVC after discontinuation of ZEPOSIA, or whether changes could be progressive with continued use.

Spirometric evaluation of respiratory function should be performed during therapy with ZEPOSIA, if clinically indicated.

'''Macular Edema'''
S1P receptor modulators, including ZEPOSIA, have been associated with an increased risk of macular edema. Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with ZEPOSIA. Perform an examination of the fundus, including the macula, periodically while on therapy and any time there is a change in vision.

In MS Study 1 and Study 2, macular edema was observed in 0.3% of patients treated with ZEPOSIA and in 0.3% of patients who received IFN beta-1a. Macular edema was reported in a total of 1 (0.2%) patient in UC Study 1 and Study 3, and in 1 (0.4%) patient in UC Study 2 treated with ZEPOSIA, and in no patients who received placebo.

Continuation of ZEPOSIA therapy in patients with macular edema has not been evaluated. Macular edema over an extended period of time (i.e., 6 months) can lead to permanent visual loss. Consider discontinuing ZEPOSIA if macular edema develops; this decision should include an assessment of the potential benefits and risks for the individual patient. The risk of recurrence after rechallenge has not been evaluated.

Macular Edema in Patients with a History of Uveitis or Diabetes Mellitus

Patients with a history of uveitis and patients with a history of diabetes mellitus are at increased risk of macular edema during ZEPOSIA therapy.

'''Cutaneous Malignancies'''
The risk of cutaneous malignancies (including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma) is increased in patients treated with S1P receptor modulators. Cases of BCC, SCC, and melanoma have been reported in patients treated with ZEPOSIA; melanoma and BCC were reported in controlled trials [see Adverse Reactions (6.1)]. Kaposi’s sarcoma and Merkel cell carcinoma have also been reported in patients treated with S1P receptor modulators in the postmarketing setting.

Skin examinations are recommended prior to or shortly after the start of treatment and periodically thereafter for all patients, particularly those with risk factors for skin cancer. Providers and patients are advised to monitor for suspicious skin lesions. If a suspicious skin lesion is observed, it should be promptly evaluated. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Concomitant phototherapy with UV-B radiation or PUVA photochemotherapy is not recommended in patients taking ZEPOSIA.

'''Posterior Reversible Encephalopathy Syndrome'''
Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving a S1P receptor modulator. In MS controlled clinical trials with ZEPOSIA, one case of PRES was reported. Should a ZEPOSIA-treated patient develop any unexpected neurological or psychiatric symptoms/signs (e.g., cognitive deficits, behavioral changes, cortical visual disturbances, or any other neurological cortical symptoms/signs), any symptom/sign suggestive of an increase of intracranial pressure, or accelerated neurological deterioration, the physician should promptly schedule a complete physical and neurological examination and should consider an MRI. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, treatment with ZEPOSIA should be discontinued.

'''Unintended Additive Immunosuppressive Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Drugs'''
When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk of disease reactivation, when initiating ZEPOSIA.

Initiating treatment with ZEPOSIA after treatment with alemtuzumab is not recommended.

'''Severe Increase in Multiple Sclerosis Disability after Stopping ZEPOSIA'''
In MS, severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of a S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping ZEPOSIA treatment. Patients should be observed for a severe increase in disability upon ZEPOSIA discontinuation and appropriate treatment should be instituted, as required.

After stopping ZEPOSIA in the setting of PML, monitor for development of immune reconstitution inflammatory syndrome (PML-IRIS).

'''Immune System Effects after Stopping ZEPOSIA'''
After discontinuing ZEPOSIA, the median time for peripheral blood lymphocytes to return to the normal range was approximately 30 days, with approximately 80% to 90% of patients in the normal range within 3 months. Use of immunosuppressants within this period may lead to an additive effect on the immune system, and therefore caution should be applied when initiating other drugs 4 weeks after the last dose of ZEPOSIA.
|clinicalTrials='''Common Adverse Reactions'''

''Multiple Sclerosis''

The safety of ZEPOSIA was evaluated in two randomized, double-blind, active comparator-controlled clinical studies (MS Study 1 and MS Study 2) in which 882 patients received ZEPOSIA 0.92 mg.

The most common adverse reactions that occurred in at least 4% of ZEPOSIA-treated patients and greater than in patients who received IFN beta-1a were upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension.

''Ulcerative Colitis''

The safety of ZEPOSIA was evaluated in two randomized, double-blind, placebo-controlled clinical studies [UC Study 1 (induction), n=429; and UC Study 2 (maintenance), n=230] in adult patients with moderately to severely active ulcerative colitis. Additional data from the induction period of a randomized, double-blind, placebo-controlled study (UC Study 3, NCT01647516) included 67 patients who received ZEPOSIA 0.92 mg once daily.

Common adverse reactions in UC Study 1 and Study 3 and in UC Study 2 are listed in Tables 3 and 4, respectively. The most common adverse reactions that occurred in at least 4% of ZEPOSIA-treated patients and greater than in patients who received placebo were liver test increased, upper respiratory infection, and headache.
'''Other Adverse Reactions'''

''Reduction in Heart Rate''

Initiation of ZEPOSIA may result in transient decrease in heart rate in MS and UC patients.

''Respiratory Effects''

Dose-dependent reductions in absolute FEV1 and FVC were observed in MS and UC patients treated with ZEPOSIA.

''Malignancies''

Malignancies, such as melanoma, basal cell carcinoma, breast cancer, seminoma, cervical carcinoma, and adenocarcinomas, including rectal adenocarcinoma, were reported with ZEPOSIA in controlled trials of MS and UC. An increased risk of cutaneous malignancies has been reported with S1P receptor modulators.

''Hypersensitivity''

Hypersensitivity, including rash and urticaria, has been reported with ZEPOSIA in active-controlled MS clinical trials.

''Peripheral Edema''

Peripheral edema was observed in 3% of ZEPOSIA-treated patients and in 0.4% of patients who received placebo in UC Study 2.
|postmarketing=The following adverse reactions have been identified during postapproval use of ZEPOSIA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hepatobiliary Disorders: Liver injury
|drugInteractions=*Anti-Neoplastic, Immune-Modulating, or Non-Corticosteroid Immunosuppressive Therapies: ZEPOSIA has not been studied in combination with anti-neoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapies with the exception of cyclosporine, which had no pharmacokinetic interaction

*Anti-Arrhythmic Drugs, QT Prolonging Drugs, Drugs That May Decrease Heart Rate: ZEPOSIA has not been studied in patients taking QT prolonging drugs.
Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) anti-arrhythmic drugs have been associated with cases of Torsades de Pointes in patients with bradycardia.

*Combination Beta Blocker and Calcium Channel Blocker: The co-administration of ZEPOSIA with both a beta blocker and a calcium channel blocker has not been studied. However, there is a potential of additive effects on heart rate.

*Vaccination: During, and for up to three months after, discontinuation of treatment with ZEPOSIA, vaccinations may be less effective. The use of live attenuated vaccines may carry the risk of infection.
|useInLaborDelivery=There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZEPOSIA during pregnancy. Healthcare providers are encouraged to register patients on-line, or pregnant women may register themselves at https://www.zeposiapregnancyregistry.com/or by calling 1-877-301-9314. Currently this registry is enrolling women with MS. Information regarding registration of pregnant women with UC will be made available in the future.

'''Risk Summary'''

There are no adequate data on the developmental risk associated with the use of ZEPOSIA in pregnant women. In animal studies, administration of ozanimod during pregnancy produced adverse effects on development, including embryolethality, an increase in fetal malformations, and neurobehavioral changes, in the absence of maternal toxicity. In rabbits, fetal blood vessel malformations occurred at clinically relevant maternal ozanimod and metabolite exposures (see Data). The receptor affected by ozanimod (sphingosine1-phosphate) has been demonstrated to have an important role in embryogenesis, including vascular and neural development.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
|useInNursing=There are no data on the presence of ozanimod in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Following oral administration of ozanimod, ozanimod and/or metabolites were detected in the milk of lactating rat at levels higher than those in maternal plasma.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ZEPOSIA and any potential adverse effects on the breastfed infant from ZEPOSIA or from the underlying maternal condition.
|useInPed=Safety and effectiveness in pediatric patients have not been established.
|useInGeri=Clinical studies of ZEPOSIA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. No clinically significant differences in the pharmacokinetics of ozanimod and CC112273 were observed based on age. Monitor elderly patients for cardiac and hepatic adverse reactions, because of the greater frequency of reduced cardiac and hepatic function in the elderly population.
|useInGender='''Contraception'''

Before initiation of ZEPOSIA treatment, women of childbearing potential should be counseled on the potential for a serious risk to the fetus and the need for contraception during treatment with ZEPOSIA. Because of the time it takes to eliminate the drug from the body after stopping treatment, the potential risk to the fetus may persist and women of childbearing age should also use effective contraception for 3 months after stopping ZEPOSIA.
|useInHepaticImpair=In patients with mild (Child-Pugh class A) or moderate hepatic impairment (Child-Pugh class B), the exposures of ozanimod and its active metabolites are higher than those in healthy controls, which may increase the risk of adverse reactions. Therefore, dosage adjustment in patients with mild or moderate hepatic impairment is required.

The pharmacokinetics of ozanimod and its active metabolites were not evaluated in patients with severe hepatic impairment (Child-Pugh class C). Therefore, use of ZEPOSIA in patients with severe hepatic impairment is not recommended.
|administration=Initiate ZEPOSIA with a 7-day titration. After initial titration, the recommended dosage of ZEPOSIA is 0.92 mg taken orally once daily starting on Day 8.
|monitoring=*Because the elimination of ZEPOSIA after discontinuation may take up to 3 months, continue monitoring for infections throughout this period.
*Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken.
*he utility of performing first-dose cardiac monitoring when initiating ZEPOSIA in patients with characteristics similar to those studied in the clinical trials of ZEPOSIA is unclear. Heart rates below 40 bpm were not observed. Initiation of ZEPOSIA without titration may result in greater decreases in heart rate
*Patients should be monitored for signs and symptoms of any hepatic injury. Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, should have hepatic enzymes promptly checked, and ZEPOSIA should be interrupted.
*Blood pressure should be monitored during treatment with ZEPOSIA and managed appropriately.
*Providers and patients are advised to monitor for suspicious skin lesions. If a suspicious skin lesion is observed, it should be promptly evaluated.
*After stopping ZEPOSIA in the setting of PML, monitor for development of immune reconstitution inflammatory syndrome (PML-IRIS)
*Monitor elderly patients for cardiac and hepatic adverse reactions, because of the greater frequency of reduced cardiac and hepatic function in the elderly population.
|mechAction=Ozanimod is a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1 and 5. Ozanimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. Ozanimod has minimal or no activity on S1P2, S1P3, and S1P4. The mechanism by which ozanimod exerts therapeutic effects in multiple sclerosis and ulcerative colitis is unknown but may involve the reduction of lymphocyte migration into the central nervous system and intestine.
|PD='''Reduction in Blood Lymphocyte Counts'''

In active-controlled MS and controlled UC clinical trials, mean lymphocyte counts decreased to approximately 45% of baseline at 3 months (approximate mean blood lymphocyte counts 0.8 × 109/L), and low lymphocyte counts were maintained during treatment with ZEPOSIA.

After discontinuing ZEPOSIA 0.92 mg, the median time for peripheral blood lymphocytes to return to the normal range was 30 days, with approximately 90% of patients in the normal range within 3 months.

'''Reduction in Heart Rate'''

ZEPOSIA may cause a transient decrease in heart rate on initiation of dosing. An up-titration schedule of ZEPOSIA 0.23 mg followed by doses of 0.46 mg, and 0.92 mg attenuates the magnitude of heart rate reductions.

'''Tyramine Challenge Test'''

No clinically significant effect in tyramine induced pressor response was observed when steady state ZEPOSIA 0.92 mg (recommended dose) or 1.84 mg was co-administered with increasing doses of oral tyramine (a monoamine oxidase substrate).

'''Drug Interaction Studies'''

'''Sympathomimetic Agents'''

No clinically significant differences in heart rate or blood pressure was observed when ZEPOSIA 1.84 mg daily (two times the recommended dosage) for 28 days was co-administered with a single dose of 60 mg pseudoephedrine (a sympathomimetic agent) compared to pseudoephedrine alone.

'''Beta Blocker or Calcium Channel Blocker'''

The effect of co-administration of the maintenance dosage of ZEPOSIA, propranolol, or diltiazem, or administration with both a beta blocker and a calcium channel blocker taken together has not been studied.

'''Pulmonary Function'''

Dose-dependent reductions in FEV1 and FVC were observed in patients treated with ZEPOSIA.

'''Cardiac Electrophysiology'''

Following a 14-day titration regimen of once daily doses of ozanimod 0.23 mg for 4 days, 0.46 mg for 3 days, 0.92 mg for 3 days, and 1.84 mg (2 times the maximum approved recommended dose) for 4 days in healthy subjects, ZEPOSIA did not prolong the QTc interval to any clinically relevant extent.
|PK=The steady state exposure parameters of ozanimod and its major active metabolite, CC112273 are summarized in Table 7. Population pharmacokinetic analysis indicated no meaningful differences in these pharmacokinetic parameters in patients with relapsing MS or UC.

'''Absorption'''

The Tmax of ozanimod is approximately 6 to 8 hours.

'''Effect of Food'''

No clinically significant differences in the Cmax and AUC of ozanimod were observed following administration of ZEPOSIA with either a high-fat, high-calorie meal (1000 calories, 50% fat) or a low-fat, low-calorie meal (300 calories, 10% fat) compared to fasted conditions.

'''Distribution'''

The mean (CV%) apparent volume of distribution of ozanimod (Vz/F) is 5590 L (27%). Human plasma proteins binding of ozanimod, CC112273 and CC1084037 is approximately 98.2%, 99.8%, and 99.3%, respectively.

'''Elimination'''

The mean (CV%) plasma half-life (t1/2) of ozanimod is approximately 21 hours (15%). The mean (CV%) effective half-life (t1/2) of CC112273 and its direct interconverting metabolite CC1084037 was approximately 11 days (104%) in relapsing MS patients. The mean (CV%) apparent oral clearance for ozanimod was approximately 192 L/h (37%).

'''Metabolism'''

Ozanimod is metabolized by multiple enzymes to form circulating major active metabolites (e.g., CC112273 and CC1084037) and minor active metabolites (e.g., RP101988, RP101075, and RP112509) with similar activity and selectivity for S1P1 and S1P5. Ozanimod is metabolized by ALDH/ADH to form carboxylate metabolite RP101988 and by CYP3A4 to form RP101075. RP101075 is then metabolized either by NAT-2 to form a minor active metabolite RP101442 or by MAO-B to form CC112273. CC112273 is then metabolized by CYP2C8 to form RP112509 or reduced to form CC1084037. CC1084037 is metabolized by AKR 1C1/1C2 and/or 3β- and 11β-HSD to form CC112273. The interconversion between CC112273 and CC1084037 favors CC112273. Approximately 94% of circulating total active drug exposure is represented by ozanimod (6%), CC112273 (73%), and CC1084037 (15%), in humans.

'''Excretion'''

Following a single oral dose of radiolabeled ozanimod 0.92 mg, approximately 26% of the radioactivity was recovered in urine and 37% in feces, primarily composed of inactive metabolites.

'''Specific Populations'''

'''Geriatric Patients'''

Population pharmacokinetic analyses showed that steady state exposure (AUC) of CC112273 in UC patients over 65 years of age was approximately 3% to 4% greater than patients 45 to 65 years of age and 27% greater than adult patients under 45 years of age. There is no meaningful difference in the pharmacokinetics in elderly patients with UC.

'''Male and Female Patients'''

No clinically significant differences in the pharmacokinetics of ozanimod and CC112273 were observed based on sex or weight.

'''Racial or Ethnic Groups'''

In a dedicated Japanese PK bridging study, following repeated dosing of 0.96 mg ZEPOSIA, ozanimod exposures (Cmax and AUCtau) were unchanged and CC112273 exposures (Cmax and AUCtau) were approximately 28% and 43% higher, respectively, in Japanese subjects (N=10) compared to Caucasian subjects (N=12). These differences are not considered clinically meaningful.

'''Patients with Renal Impairment'''

In a dedicated renal impairment trial, following a single oral dose of 0.23 mg ZEPOSIA, exposures (AUClast) for ozanimod and CC112273 were approximately 27% higher and 23% lower, respectively, in subjects with end stage renal disease (N=8) compared to subjects with normal renal function (N=8). Based on this trial, renal impairment has no clinically important effects on pharmacokinetics of ozanimod or CC112273.

'''Patients with Hepatic Impairment'''

In a hepatic impairment study, following an 8-day titration regimen of once daily doses of ZEPOSIA 0.23 mg on days 1 to 4, 0.46 mg on days 5 to 7, and 0.92 mg on day 8, in subjects with mild hepatic impairment (Child-Pugh class A, N=8), mean exposures (AUClast) of ozanimod and active metabolites CC112273 and CC1084037 on day 8 increased by 60%, 98%, and 107%, respectively, compared to healthy controls (N=8). In subjects with moderate hepatic impairment (Child-Pugh class B, N=8) mean exposures (AUClast) of ozanimod and active metabolites CC112273 and CC1084037 on day 8 increased by 17%, 38%, and 61%, respectively, compared to healthy controls.

The pharmacokinetics of ozanimod or its active metabolites were not evaluated in patients with severe hepatic impairment (Child-Pugh class C).

'''Smokers'''

Population PK analyses showed that CC112273 steady-state exposure (AUC) was approximately 50% lower in smokers than in nonsmokers, although for smokers this reduction in exposure did not result in meaningful differences in absolute lymphocyte count (ALC) reduction or an apparent impact on clinical efficacy.

'''Drug Interaction Studies'''

'''Clinical/In Vivo Studies'''

'''Strong CYP3A and P-gp Inhibitors'''

No clinically significant differences in the pharmacokinetics of ozanimod and its major active metabolites CC112273 and CC1084037 were observed when co-administered with itraconazole (P-gp and strong CYP3A inhibitor).

'''Strong CYP2C8 Inhibitors'''

Co-administration of ozanimod with gemfibrozil (a strong CYP2C8 inhibitor) increased exposure (AUC) of active metabolites CC112273 and CC1084037 by approximately 47% and 69%, respectively, with no change in the AUC of ozanimod .

'''BCRP Inhibitors'''

Co-administration of ozanimod with cyclosporine (BCRP inhibitor) had no effect on the exposure of ozanimod or the major active metabolites CC112273 and CC1084037.

'''Strong CYP2C8 Inducers'''

Co-administration of rifampin (a strong inducer of CYP3A and P-gp, and a moderate inducer of CYP2C8) 600 mg once daily at steady state and a single dose of ZEPOSIA 0.92 mg reduced the exposure (AUC) for ozanimod, CC112273, and CC1084037 by approximately 24%, 60%, and 55%, respectively. The effect on CC112273 and CC1084037 is primarily caused by induction of CYP2C8 .

'''Prednisone and Prednisolone'''

Population pharmacokinetic analyses showed that concomitant administration of prednisone or prednisolone in patients with UC did not alter the apparent clearance of the predominant active metabolite CC112273. The impact of prednisone or prednisolone on the pharmacokinetics of CC1084037 is unknown.

'''Monoamine Oxidase Inhibitors'''

No clinical studies evaluating the drug interaction potential of ozanimod with MAO inhibitors have been conducted.

'''Monoamine Oxidase Substrates'''

Co-administration of steady state 0.92 mg or 1.84 mg ozanimod had no effect on the plasma concentrations of oral tyramine, an MAO substrate.

'''Oral Contraceptives'''

No clinically significant differences in the pharmacokinetic of oral contraceptive containing ethinyl estradiol and norethindrone were observed when co-administered with ozanimod.

'''In Vitro Studies'''

'''Cytochrome P450 (CYP) Enzymes'''

Ozanimod, CC112273, CC1084037, and other metabolites do not inhibit CYPs 1A2, 2B6, 2C19, 2C8, 2C9, 2D6, and 3A, and do not induce CYPs 1A2, 2B6, and 3A.

In vitro, CC112273 and CC1084037 inhibited MAO-B (IC50 values of 5.72 nM and 58 nM, respectively) with more than 1000-fold selectivity over monoamine oxidase A (MAO-A).

'''Transporter Systems'''

Ozanimod, CC112273, CC1084037, and other metabolites do not inhibit P-gp, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, or MATE2-K. CC112273 and CC1084037 do not inhibit BCRP at clinically relevant concentrations.
|clinicalStudies='''Multiple Sclerosis'''
The efficacy of ZEPOSIA was demonstrated in 2 randomized, double-blind, double-dummy, parallel-group, active comparator-controlled clinical trials of similar design, in patients with relapsing forms of MS [MS Study 1 (NCT02294058) and MS Study 2 (NCT02047734)]. Patients in Study 1 were treated until the last enrolled patient completed 1 year of treatment. Patients in Study 2 were treated for 24 months. Both studies included patients who had experienced at least 1 relapse within the prior year, or 1 relapse within the prior 2 years with evidence of at least a gadolinium-enhancing (GdE) lesion in the prior year, and had an Expanded Disability Status Scale (EDSS) score from 0 to 5.0 at baseline. Patients with primary progressive MS were excluded.

Patients were randomized to receive either ZEPOSIA 0.92 mg given orally once daily, beginning with a dosage titration, or interferon (IFN) beta-1a, the active comparator, 30 mcg given intramuscularly once weekly. Neurological evaluations were performed at baseline, every 3 months, and at the time of a suspected relapse. Brain MRI scans were performed at baseline, 6 months (Study 1), 1 year (Studies 1 and 2), and 2 years (Study 2).

The primary endpoint of both Study 1 and Study 2 was the annualized relapse rate (ARR) over the treatment period (Study 1) and 24 months (Study 2). Additional outcome measures included: 1) the number of new or enlarging MRI T2 hyperintense lesions over 12 and 24 months, 2) the number of MRI T1 Gadolinium-enhancing (Gd+) lesions at 12 and 24 months, and 3) the time to confirmed disability progression, defined as at least a 1-point increase from baseline EDSS confirmed after 3 months and after 6 months. Confirmed disability progression was evaluated in a pooled analysis of Studies 1 and 2.

In Study 1, a total of 895 patients were randomized to receive ZEPOSIA (n=447) or IFN beta-1a (n=448); of these patients, 94% who received ZEPOSIA and 92% who received IFN beta-1a completed the study. The mean age was 35.4 years, 99.8% were White, and 65% were female. The mean time since MS symptom-onset was 6.9 years, and the median EDSS score at baseline was 2.5; 31% had been treated with a non-steroid therapy for MS. At baseline, the mean number of relapses in the prior year was 1.3 and 48% of patients had one or more T1 Gd-enhancing lesions (mean 1.8) on their baseline MRI scan.

In Study 2, a total of 874 patients were randomized to receive ZEPOSIA (n=433) or IFN beta-1a (n=441); of these patients, 90% who received ZEPOSIA and 85% who received IFN beta-1a completed the study. The mean age was 35.6 years, 98% were White, and 68% were female. The mean time since MS symptom onset was 6.6 years, and the median EDSS score at baseline was 2.5; 29% of patients had been treated with a non-steroid therapy for MS. At baseline, the mean number of relapses in the prior year was 1.3 and 43% of patients had one or more T1 Gd-enhancing lesions (mean 1.7).

The ARR was statistically significantly lower in patients treated with ZEPOSIA 0.92 mg than in patients who received IFN beta-1a 30 mcg IM. The number of new or enlarging T2 lesions and the number of GdE lesions were statistically significantly lower in patients treated with ZEPOSIA 0.92 mg than in patients who received IFN beta-1a.

There was no statistically significant difference in the three-month and six-month confirmed disability progression between ZEPOSIA and IFN beta-1a-treated patients over 2 years.

'''Ulcerative Colitis'''
The efficacy and safety of ZEPOSIA were evaluated in two multicenter, randomized, double-blind, placebo-controlled clinical studies [UC Study 1 (induction) and UC Study 2 (maintenance) (NCT02435992)] in adult patients with moderately to severely active ulcerative colitis.

'''UC Study 1'''

In UC Study 1, a total of 645 patients were randomized 2:1 to either ZEPOSIA 0.92 mg given orally once daily or placebo for 10 weeks, beginning with a dosage titration. The trial included adult patients with moderately to severely active UC who had an inadequate response or were intolerant to any of the following: oral aminosalicylates, corticosteroids, immunomodulators (e.g., 6-mercaptopurine and azathioprine), or a biologic (e.g., TNF blocker and/or vedolizumab). Patients were required to be on stable doses of oral aminosalicylates and/or corticosteroids (prednisone daily dose up to 20 mg equivalent or budesonide extended-release tablets) prior to enrollment. Seventy-one percent of patients were receiving mesalamine, 13% sulfasalazine, and 33% oral corticosteroids. A total of 30% of patients had previously failed or were intolerant to TNF blockers. Of these patients, 63% received at least two biologics including TNF blockers.

The disease activity was assessed by the Mayo score (0 to 12) which consists of four subscores (0 to 3 for each subscore): stool frequency, rectal bleeding, findings on centrally-read endoscopy, and physician global assessment. An endoscopy subscore of 2 was defined by marked erythema, lack of vascular pattern, friability, and erosions; an endoscopy subscore of 3 was defined by spontaneous bleeding and ulceration. Enrolled patients had Mayo scores between 6 to 12; at baseline, patients had a median Mayo score of 9, with 86% of patients having moderate disease (Mayo score 6-10), and 14% having severe disease (Mayo score 11-12).

Concomitant immunomodulators or biologic therapies were not permitted.

The primary endpoint was clinical remission at Week 10, defined using a 3-component Mayo score without the physician global assessment: rectal bleeding subscore = 0, stool frequency subscore = 0 or 1 (and a decrease of ≥ 1 point from the baseline stool frequency subscore), and endoscopy subscore = 0 or 1 (an endoscopy subscore of 0 defined as normal or inactive disease, and an endoscopy subscore of 1 defined as presence of erythema, decreased vascular pattern and no friability).

The secondary endpoints were clinical response, endoscopic improvement, and endoscopic-histologic mucosal improvement. Clinical response (reduction from baseline in the 3-component Mayo score of ≥ 2 points and ≥ 35%, and a reduction from baseline in the rectal bleeding subscore of ≥ 1 point or an absolute rectal bleeding subscore of 0 or 1), endoscopic improvement (Mayo endoscopy subscore of 0 or 1), and endoscopic-histologic mucosal improvement [combined endoscopic improvement and histologic improvement of colonic tissue (no neutrophils in the epithelial crypts or lamina propria and no increase in eosinophils, no crypt destruction, and no erosions, ulcerations, or granulation tissue, i.e., Geboes < 2.0)].

A significantly greater proportion of patients treated with ZEPOSIA achieved clinical remission, clinical response, endoscopic improvement, and endoscopic-histologic mucosal improvement compared to placebo at Week 10

'''UC Study 2'''

In UC Study 2, a total of 457 patients who received ZEPOSIA in either UC Study 1 or in an open-label arm and achieved clinical response at Week 10 were re-randomized 1:1 and were treated with either ZEPOSIA 0.92 mg (n=230) or placebo (n=227) for 42 weeks (UC Study 2), for a total of 52 weeks of treatment.

Patients were permitted to be on stable doses of oral aminosalicylates. Corticosteroid tapering was required upon entering this study for patients who were receiving corticosteroids during the induction period. Concomitant oral immunomodulators or biologic therapies were not permitted. At study entry, 35% of patients were in clinical remission; 29% of patients were on corticosteroids; and 31% of patients had an inadequate response, loss of response, or intolerance to TNF blockers.

The primary endpoint was the proportion of patients in clinical remission at Week 52. The secondary endpoints at Week 52 were the proportion of patients with clinical response, endoscopic improvement, endoscopic-histologic mucosal improvement, corticosteroid-free clinical remission, and maintenance of clinical remission at Week 52 among patients who achieved clinical remission at Week 10 in UC Study 1.
|howSupplied=ZEPOSIA is available as capsules in the following dosage strengths:

*0.23 mg ozanimod: light grey opaque body/light grey opaque cap imprinted with black ink "OZA" on the cap and "0.23 mg" on the body

*0.46 mg ozanimod: light grey opaque body/orange opaque cap imprinted with black ink "OZA" on the cap and "0.46 mg" on the body

*0.92 mg ozanimod: orange opaque body/orange opaque cap imprinted with black ink "OZA" on the cap and "0.92 mg" on the body
|storage=Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F)
|fdaPatientInfo='''Risk of Infections'''

Inform patients that they may be more likely to get infections, some of which could be life-threatening, when taking ZEPOSIA and for 3 months after stopping it, and that they should contact their healthcare provider if they develop symptoms of infection. Inform patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection. Advise patients that some vaccines containing live virus (live attenuated vaccines) should be avoided during treatment with ZEPOSIA. Advise patients that if immunizations are planned, they should be administered at least 1 month prior to initiation of ZEPOSIA. Inform patients that the use of live attenuated vaccines should be avoided during and for 3 months after treatment with ZEPOSIA.

'''Progressive Multifocal Leukoencephalopathy'''

Inform patients that cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients who received ZEPOSIA and other S1P receptor modulators. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months. Instruct the patient of the importance of contacting their healthcare provider if they develop any symptoms suggestive of PML. Inform the patient that typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.

'''Cardiac Effects'''

Advise patients that initiation of ZEPOSIA treatment may result in a transient decrease in heart rate. Inform patients that to reduce this effect, dose titration is required. Advise patients that the dose titration is also required if a dose is missed for 1 day or more during the first 14 days of treatment.

'''Liver Injury'''

Inform patients that ZEPOSIA may cause liver injury. Advise patients that they should contact their healthcare provider if they have any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine.

'''Pregnancy and Fetal Risk'''

Inform patients that, based on animal studies, ZEPOSIA may cause fetal harm. Discuss with women of childbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant. Advise women of childbearing potential of the need for effective contraception during treatment with ZEPOSIA and for 3 months after stopping ZEPOSIA. Advise a female patient to immediately inform her healthcare provider if she is pregnant or planning to become pregnant.

'''Pregnancy Registry'''

Encourage multiple sclerosis patients to enroll in the ZEPOSIA Pregnancy Registry if they become pregnant while taking ZEPOSIA.

'''Respiratory Effects'''

Advise patients that they should contact their healthcare provider if they experience new onset or worsening dyspnea.

'''Macular Edema'''

Advise patients that ZEPOSIA may cause macular edema, and that they should obtain an eye exam near the start of treatment with ZEPOSIA, have their eyes monitored periodically by an eye care professional while receiving therapy, and contact their healthcare provider if they experience any changes in their vision while taking ZEPOSIA. Inform patients with diabetes mellitus or a history of uveitis that their risk of macular edema may be increased.

'''Cutaneous Malignancies'''

Inform patients that the risk of basal cell carcinoma, squamous cell carcinoma, and melanoma is increased in patients treated with S1P receptor modulators. Advise patients that any suspicious skin lesions should be promptly evaluated. Advise patients to limit exposure to sunlight and ultraviolet light by wearing protective clothing and using a sunscreen with high protection factor.

'''Posterior Reversible Encephalopathy Syndrome'''

Advise patients to immediately report to their healthcare provide any symptoms involving sudden onset of severe headache, altered mental status, visual disturbances, or seizure. Inform patients that delayed treatment could lead to permanent neurological consequences.

'''Severe Increase in Multiple Sclerosis Disability after Stopping ZEPOSIA'''

Inform patients with multiple sclerosis that severe increase in disability has been reported after discontinuation of a S1P receptor modulator like ZEPOSIA. Advise patients to contact their physician if they develop worsening symptoms of MS following discontinuation of ZEPOSIA.

'''Immune System Effects after Stopping ZEPOSIA'''

Advise patients that ZEPOSIA continues to have effects, such as lowering effects on peripheral lymphocyte count, for up to 3 months after the last dose.
|alcohol=Alcohol-Ozanimod interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=ZEPOSIA
}}

Selumetinib

2025-05-11T13:37:05Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=selumetinib |aOrAn=a |drugClass=selectively inhibiting MEK1 and MEK2 |indication=KOSELUGO is indicated for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN). |adverseReactions=The following clinically significant adverse reactions are described elsewhere in the labeling:..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=selumetinib
|aOrAn=a
|drugClass=selectively inhibiting MEK1 and MEK2
|indication=KOSELUGO is indicated for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN).
|adverseReactions=The following clinically significant adverse reactions are described elsewhere in the labeling:

*Cardiomyopathy

*Ocular toxicity

*Gastrointestinal toxicity

*Skin toxicity

*Increased creatine phosphokinase
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=KOSELUGO is indicated for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN).

'''DOSAGE'''
*10 mg: white to off-white, opaque, hard capsule sealed with a clear band and marked with “SEL 10” in black ink.

*25 mg: blue, opaque, hard capsule sealed with a clear band and marked with “SEL 25” in black ink.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Selumetinib in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Selumetinib in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Selumetinib in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Selumetinib in pediatric patients.
|contraindications=None
|warnings='''Cardiomyopathy'''
Cardiomyopathy, defined as a decrease in left ventricular ejection fraction (LVEF) ≥ 10% below baseline, occurred in 23% of 74 pediatric patients who received KOSELUGO in SPRINT. Four percent of patients experienced decreased LVEF below the institutional lower limit of normal (LLN). Grade 3 decreased LVEF occurred in one patient and resulted in dose reduction. All patients with decreased LVEF were asymptomatic and identified during routine echocardiography. Decreased LVEF resolved in 71% of these patients.

Left ventricular dysfunction or decreased LVEF resulting in permanent discontinuation of KOSELUGO occurred in an unapproved population of adult patients with multiple tumor types who received KOSELUGO. Decreased LVEF resulting in permanent discontinuation of KOSELUGO occurred in a pediatric population with NF1 in an expanded access program.

The safety of KOSELUGO has not been established in patients with a history of impaired LVEF or a baseline ejection fraction that is below the institutional LLN.

Assess ejection fraction by echocardiogram prior to initiating treatment, every 3 months during the first year of treatment, every 6 months thereafter, and as clinically indicated. Withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of adverse reaction. In patients who interrupt KOSELUGO for decreased LVEF, obtain an echocardiogram or a cardiac MRI every 3 to 6 weeks. Upon resolution of decreased LVEF to greater than or equal to the institutional LLN, obtain an echocardiogram or a cardiac MRI every 2 to 3 months or as directed by the cardiologist.

'''Ocular Toxicity'''
Blurred vision, photophobia, cataracts, and ocular hypertension occurred in 15% of 74 pediatric patients receiving KOSELUGO in SPRINT. Blurred vision resulted in dose interruption in 2.7% of patients. Ocular toxicity resolved in 82% of 11 patients.

Serious ocular toxicities including retinal vein occlusion (RVO) and retinal pigment epithelial detachment (RPED), occurred in an unapproved population of adult patients with multiple tumor types who received KOSELUGO as a single agent or in combination with other anti-cancer agents. RPED occurred in the pediatric population during treatment with single agent KOSELUGO and resulted in permanent discontinuation.

Conduct comprehensive ophthalmic assessments prior to initiating KOSELUGO, at regular intervals during treatment, and for new or worsening visual changes. Permanently discontinue KOSELUGO in patients with RVO. Withhold KOSELUGO in patients with RPED, follow up with optical coherence tomography assessments every 3 weeks until resolution, and resume KOSELUGO at a reduced dose. For other ocular toxicities, withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of the adverse reaction.

'''Gastrointestinal Toxicity'''
Diarrhea occurred in 77% of 74 pediatric patients who received KOSELUGO in SPRINT, including Grade 3 in 15% of patients. Diarrhea resulting in permanent discontinuation occurred in 1.4% of patients. Diarrhea resulting in dose interruption or dose reduction occurred in 15% and 1.4% of patients, respectively. The median time to first onset of diarrhea was 17 days and the median duration was 2 days.

Serious gastrointestinal toxicities, including perforation, colitis, ileus, and intestinal obstruction, occurred in an unapproved population of adult patients with multiple tumor types who received KOSELUGO as a single agent or in combination with other anti-cancer agents. Colitis occurred in an unapproved population of pediatric patients with multiple tumor types who received KOSELUGO as a single agent.

Advise patients to start an anti-diarrheal agent (e.g., loperamide) immediately after the first episode of unformed, loose stool and to increase fluid intake during diarrhea episodes. Withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of adverse reaction.

'''Skin Toxicity'''
Rash occurred in 91% of 74 pediatric patients who received KOSELUGO in SPRINT. The most frequent rashes included dermatitis acneiform (54%), maculopapular rash (39%), and eczema (28%). Grade 3 rash occurred in 8% of patients. Rash resulted in dose interruption in 11% of patients and dose reduction in 4% of patients.

Other skin toxicities, including severe palmar-plantar erythrodysesthesia syndrome, occurred in an unapproved population of adult patients with multiple tumor types who received KOSELUGO as a single agent or in combination with other anti-cancer agents.

Monitor for severe skin rashes. Withhold, reduce dose, or permanently discontinue KOSELUGO based on the severity of adverse reaction.

'''Increased Creatine Phosphokinase'''
Increased creatine phosphokinase (CPK) occurred in 76% of 74 pediatric patients who received KOSELUGO in SPRINT, including Grade 3 or 4 in 9% of patients. Increased CPK resulted in dose reduction in 7% of patients. Increased CPK concurrent with myalgia occurred in 8% of patients, including one patient who permanently discontinued KOSELUGO for myalgia.

Rhabdomyolysis occurred in an unapproved adult population who received KOSELUGO as a single agent.

Obtain serum CPK prior to initiating KOSELUGO, periodically during treatment, and as clinically indicated. If increased CPK occurs, evaluate patients for rhabdomyolysis or other causes. Withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of adverse reaction.

'''Increased Levels of Vitamin E and Risk of Bleeding'''
KOSELUGO capsules contain vitamin E (10 mg capsules contain 32 mg vitamin E as the excipient, D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS); while KOSELUGO 25 mg capsules contain 36 mg vitamin E as TPGS). Vitamin E can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors. Daily vitamin E intake that exceeds the recommended or safe limits may increase the risk of bleeding. Supplemental vitamin E is not recommended if daily vitamin E intake (including the amount of vitamin E in KOSELUGO and supplement) will exceed the recommended or safe limits.

An increased risk of bleeding in patients may occur in patients who are coadministered vitamin-K antagonists or anti-platelet antagonists with KOSELUGO. Monitor for bleeding in these patients. Increase international normalized ratio (INR) monitoring, as appropriate, in patients taking a vitamin-K antagonist. Perform anticoagulant assessments, including INR or prothrombin time, more frequently and adjust the dose of vitamin K antagonists or anti-platelet agents as appropriate.

'''Embryo-Fetal Toxicity'''
Based on findings from animal studies and its mechanism of action, KOSELUGO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of selumetinib to mice during organogenesis caused reduced fetal weight, adverse structural defects, and effects on embryo-fetal survival at approximate exposures > 5-times the human exposure at the clinical dose of 25 mg/m2 twice daily. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in the WARNINGS AND PRECAUTIONS reflects exposure to KOSELUGO in 74 pediatric patients who received a dosage ranging from 20 mg/m2 to 30 mg/m2 orally twice daily in SPRINT. Among these patients, the duration of KOSELUGO exposure, including dose interruptions, was 12 months or longer (91%), more than 2 years (74%), or more than 4 years (23%). The WARNINGS AND PRECAUTIONS also includes additional data from adult and pediatric patients who received KOSELUGO administered at various doses across a range of tumors in other clinical trials.

'''Neurofibromatosis Type 1 (NF1) with Inoperable Plexiform Neurofibromas (PN)'''

The safety of KOSELUGO was evaluated in SPRINT Phase II Stratum 1. Eligible patients were 2-18 years of age with NF1 who had inoperable PN that was causing significant morbidity. Patients were excluded for abnormal LVEF, uncontrolled hypertension (blood pressure > the 95th percentile for age, height, and sex), any current or past history of RVO or RPED, intraocular pressure > 21 mmHg (or upper limit of normal adjusted by age), uncontrolled glaucoma, and inability to swallow whole capsules. Patients received KOSELUGO 25 mg/m2 orally twice daily (n=50). Among these patients, 88% were exposed for 12 months or longer and 66% were exposed for greater than 2 years.

Serious adverse reactions occurred in 24% of patients who received KOSELUGO. Serious adverse reactions that occurred in 2 or more patients were anemia, hypoxia and diarrhea.

Permanent discontinuation due to an adverse reaction occurred in 12% of patients who received KOSELUGO. Adverse reactions resulting in permanent discontinuation of KOSELUGO included increased blood creatinine, increased weight, diarrhea, paronychia, malignant peripheral nerve sheath tumor, acute kidney injury, and skin ulcer.

Dosage interruptions and dose reductions due to adverse reactions occurred in 80% and 24% of patients who received KOSELUGO, respectively. Adverse reactions requiring a dosage interruption or reduction in ≥ 5% of patients were vomiting, paronychia, diarrhea, nausea, abdominal pain, rash, skin infection, influenza-like illness, pyrexia and weight gain.

The most common adverse reactions (≥ 40%) were vomiting, rash (all), abdominal pain, diarrhea, nausea, dry skin, fatigue, musculoskeletal pain, pyrexia, acneiform rash, stomatitis, headache, paronychia, and pruritus.
|drugInteractions='''Strong or Moderate CYP3A4 Inhibitors or Fluconazole'''
Concomitant use of KOSELUGO with a strong or moderate CYP3A4 inhibitor or fluconazole increased selumetinib plasma concentrations, which may increase the risk of adverse reactions.

'''Strong or Moderate CYP3A4 Inducers'''
Concomitant use of KOSELUGO with a strong or moderate CYP3A4 inducer decreased selumetinib plasma concentrations, which may reduce KOSELUGO efficacy.

'''Vitamin E'''
KOSELUGO contains vitamin E and daily vitamin E intake that exceeds the recommended or safe limits may increase the risk of bleeding. An increased risk of bleeding may occur in patients taking a vitamin-K antagonist or an anti-platelet agent with KOSELUGO.
|useInLaborDelivery=Based on findings from animal studies and its mechanism of action, KOSELUGO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of KOSELUGO in pregnant women to evaluate drug-associated risk. In animal reproduction studies, administration of selumetinib to mice during organogenesis caused reduced fetal weight, adverse structural defects, and effects on embryofetal survival at exposures approximately > 5 times the human exposure at the clinical dose of 25 mg/m2 twice daily. Advise pregnant women of the potential risk to the fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
|useInNursing=There are no data on the presence of selumetinib or its active metabolite in human milk or their effects on the breastfed child or milk production. Selumetinib and its active metabolite were present in the milk of lactating mice. Due to the potential for adverse reactions in a breastfed child, advise women not to breastfeed during treatment with KOSELUGO and for 1 week after the last dose.
|useInPed=The safety and effectiveness have been established in pediatric patients 2 years of age and older with NF1 who have inoperable PN and the information on this use is discussed throughout the labeling. The safety and effectiveness of KOSELUGO have not been established in pediatric patients younger than 2 years of age.
|useInGeri=Clinical studies did not include patients 65 years of age and older.
|useInGender=KOSELUGO can cause fetal harm when administered to a pregnant woman.

'''Pregnancy Testing'''

Verify the pregnancy status of females of reproductive potential prior to initiating KOSELUGO.

'''Contraception'''

''Females''

Advise females of reproductive potential to use effective contraception during treatment and for 1 week after the last dose.

''Males''

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose.
|useInRenalImpair=No dose adjustment is recommended in patients with renal impairment or those with End Stage Renal Disease
|useInHepaticImpair=Selumetinib exposures increased in patients with moderate or severe hepatic impairment. Reduce the dose of KOSELUGO for patients with moderate hepatic impairment (Child-Pugh B). A recommended dosage of KOSELUGO for use in patients with severe hepatic impairment (Child-Pugh C) has not been established
|administration=rally twice daily (approximately every 12 hours) until disease progression or unacceptable toxicity.
|monitoring=*Monitor for severe skin rashes. Withhold, reduce dose, or permanently discontinue KOSELUGO based on severity of adverse reaction
*Monitor for bleeding in these patients. Increase international normalized ratio (INR) monitoring, as appropriate, in patients taking a vitamin-K antagonist.
|overdose=Dialysis is not helpful as KOSELUGO is highly protein bound and is extensively metabolized.
|mechAction=Selumetinib is an inhibitor of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2). MEK1/2 proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. Both MEK and ERK are critical components of the RAS-regulated RAF-MEK-ERK pathway, which is often activated in different types of cancers.

In genetically modified mouse models of NF1 that generate neurofibromas that recapitulate the genotype and phenotype of human NF1, oral dosing of selumetinib inhibited ERK phosphorylation, and reduced neurofibroma numbers, volume, and proliferation.
|PD=The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of KOSELUGO have not been fully characterized.

'''Cardiac Electrophysiology'''

At a dose 1.5-times the maximum recommended dose, KOSELUGO does not prolong the QT/QTc interval to any clinically relevant extent.
|PK=At the recommended dosage of 25 mg/m2 twice daily in pediatric patients (2 to ≤ 18 years old), the mean maximum plasma concentration (Cmax) (coefficient of variation [CV%]) following the first dose and at steady state was 731 (62%) ng/mL and 798 (52%) ng/mL, respectively. The mean area under the plasma drug concentration curve (AUC0-12h) following the first dose was 2009 (35%) ng•h/mL and the AUC0-6h at steady state was 1958 (41%) ng•h/mL. Selumetinib AUC and Cmax increases proportionally over a dose range from 20 mg/m2 to 30 mg/m2 (0.8- to 1.2-times the recommended dose). The accumulation was 1.1-fold following administration of KOSELUGO 25 mg/m2 twice daily.

'''Absorption'''

The mean absolute oral bioavailability of selumetinib was 62% in healthy adults. The median time to peak plasma concentrations (Tmax) at steady-state in pediatric patients was 1 to 1.5 hours.

'''Effect of Food'''

Selumetinib Cmax and AUC decreased by 24% and 8%, respectively, following a low-fat meal (400 calories, 25% fat) in adolescent patients with NF1 and inoperable PN administered multiple doses of 25 mg/m2 twice daily and Tmax was delayed by approximately 0.6 hours.

A population PK analysis including children and adolescent patients with NF1 and inoperable PN, adult patients with cancers, and healthy adults showed that a low- or high-fat meal had no clinically relevant effect on the AUC of selumetinib.

'''Distribution'''

The mean apparent volume of distribution at steady state (Vss) of selumetinib across a dose range of 20 mg/m2 to 30 mg/m2 (0.8- to 1.2-times the recommended dosage) ranged from 78 L to 171 L in pediatric patients.

The plasma protein binding was 98.4% in humans in vitro. Selumetinib binds to serum albumin (96%) and α-1 acid glycoprotein (< 35%).

'''Elimination'''

In pediatric patients, selumetinib had an apparent oral clearance (CL/F) of 8.8 L/hr and a mean elimination half-life of approximately 6.2 hours following a dose of 25 mg/m2.

'''Metabolism'''

Selumetinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C19, CYP1A2, CYP2C9, CYP2E1, and CYP3A5. Selumetinib also undergoes glucuronidation by UGT1A1 and UGT1A3. It is estimated that 56% of the observed intrinsic clearance of selumetinib could be attributed to CYP metabolism and about 29% attributed to direct glucuronidation by UGT enzymes in vitro. The active metabolite, N-desmethyl selumetinib, is generated by CYP2C19 and CYP1A2 with additional contribution by CYP2C9 and CYP2A6, and metabolized through the same routes as selumetinib.

N-desmethyl selumetinib represents less than 10% of selumetinib levels in human plasma, but is approximately 3- to 5-times more potent than the parent compound, contributing to about 21% to 35% of the overall pharmacologic activity.

'''Excretion'''

After a single oral dose of radiolabeled selumetinib 75 mg (1.5-times the recommended dose) to healthy adults, 59% of the dose was recovered in feces (19% as unchanged) and 33% in urine (< 1% as parent).

'''Specific Populations'''

''Racial or Ethnic Groups''

No clinically meaningful effect on the pharmacokinetics of selumetinib or N-desmethyl selumetinib were observed based on race (White, Asian, Black).

''Patients with Renal Impairment''

Following administration of a single dose of 50 mg, selumetinib exposures were similar in subjects with End Stage Renal Disease (CLcr < 15 mL/min) who required dialysis compared to subjects with normal renal function (CLcr ≥ 90 mL/min).

''Patients with Hepatic Impairment''

Following administration of a single-dose of selumetinib, dose normalized total AUC0-INF decreased by 14% in subjects with mild hepatic impairment (Child-Pugh A), and increased by 59% in subjects with moderate hepatic impairment (Child-Pugh B) and by 57% in subjects with severe hepatic impairment (Child-Pugh class C) compared to subjects with normal hepatic function. Selumetinib unbound AUC0-INF decreased by 31% in subjects with mild hepatic impairment (Child-Pugh A), and increased by 41% in subjects with moderate hepatic impairment (Child-Pugh B), and 3.2-fold in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function.

'''Drug Interaction Studies'''

''Clinical Studies and Model-Informed Approaches''

Effect of Strong or Moderate CYP3A4 Inhibitors: Concomitant use of itraconazole (strong CYP3A4 inhibitor) increased selumetinib AUC by 49% and Cmax by 19%. Concomitant use of erythromycin (moderate CYP3A4 inhibitor) is predicted to increase selumetinib AUC by 41% and Cmax by 23%.

Effect of Fluconazole: Concomitant use of fluconazole (strong CYP2C19 inhibitor and moderate CYP3A4 inhibitor) increased selumetinib AUC by 53% and Cmax by 26%.

Effect of Strong or Moderate CYP3A4 Inducers: Concomitant use of rifampicin (strong CYP3A4 inducer) decreased selumetinib AUC by 51% and Cmax by 26%. Concomitant use of efavirenz (moderate CYP3A4 inducer) is predicted to decrease selumetinib AUC by 38% and Cmax by 22%.

''In Vitro Studies''

CYP Enzymes: Selumetinib does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or CYP2E1. Selumetinib does not induce CYP3A4, CYP1A2, or CYP2B6.

Transporter Systems: Selumetinib does not inhibit breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2K transporters.

Selumetinib is a substrate of BCRP and P-gp transporters.
|nonClinToxic='''Carcinogenesis, Mutagenesis, Impairment of Fertility'''
''Carcinogenicity''

Selumetinib was not carcinogenic in a 6-month study in rasH2 transgenic mice at exposures 24-times (males) and 36-times (females) and in 2-year carcinogenicity study in rats at exposures 20-times (male) and 15-times the human exposure (AUC) at the clinical dose of 25 mg/m2.

''Mutagenicity''

Selumetinib was not mutagenic or clastogenic in vitro. Selumetinib did result in an increase in micronucleated immature erythrocytes (chromosome aberrations) in mouse micronucleus studies, predominantly via an aneugenic mode of action, but at doses > 160 mg/kg (~38-times the human Cmax at the clinical dose of 25 mg/m2).

''Impairment of Fertility''

In a 6-month mouse study, selumetinib did not affect male mating performance at any dose up to 20 mg/kg twice daily (approximately 33-times the human exposure based on AUC at the clinical dose of 25 mg/m2 twice daily). In female mice exposed to selumetinib at 12.5 mg/kg twice daily, mating performance and fertility were not affected. The NOAEL for both maternal toxicity and effects on reproductive performance was 2.5 mg/kg twice daily (approximately 5-times the human exposure based on AUC at the clinical dose of 25 mg/m2 twice daily).

'''Animal Toxicology and/or Pharmacology'''
In a 26-week repeat-dose toxicology study, selumetinib at a dose of 20 mg/kg (approximately 33-times the human exposure based on AUC at the clinical dose of 25 mg/m2 twice daily) led to significant urinary tract obstruction as well as inflammation and luminal hemorrhage of the urethra leading to early death in male mice.
|clinicalStudies='''Neurofibromatosis Type 1 (NF1) with Inoperable Plexiform Neurofibromas (PN)'''
The efficacy of KOSELUGO was evaluated in SPRINT Phase II Stratum 1, an open-label, multicenter, single arm trial (NCT01362803). Eligible patients were required to have NF1 with inoperable PN, defined as a PN that could not be completely removed without risk for substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the PN. Patients were also required to have significant morbidity related to the target PN. Morbidities that were present in ≥ 20% of patients included disfigurement, motor dysfunction, pain, airway dysfunction, visual impairment, and bladder/bowel dysfunction. Patients received KOSELUGO 25 mg/m2 orally twice daily until disease progression or unacceptable toxicity.

The major efficacy outcome measure was overall response rate (ORR), defined as the percentage of patients with complete response (defined as disappearance of the target PN) or confirmed partial response (defined as ≥ 20% reduction in PN volume confirmed at a subsequent tumor assessment within 3-6 months). The target PN, defined as the PN that caused relevant clinical symptoms or complications (PN-related morbidities), was evaluated for response rate using centrally read volumetric magnetic resonance imaging (MRI) analysis per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria. Tumor response was evaluated at baseline and while on treatment after every 4 cycles for 2 years, and then every 6 cycles. An additional efficacy outcome measure was duration of response (DoR).

A total of 50 pediatric patients received KOSELUGO. The median age was 10.2 years (range 3.5 to 17.4 years); 60% were male; and 84% were White, 8% were Black and 2% were Asian.

Efficacy results are provided in Table 8. The median time to onset of response was 7.2 months (range: 3.3 months to 1.6 years).
|howSupplied=*10 mg:White to off-white, opaque, hard capsule sealed with a clear band and marked with “SEL 10” in black ink.
*25 mg:
Blue, opaque, hard capsule sealed with a clear band and marked with “SEL 25” in black ink.
|storage=Store at 20°C to 25°C (68°F to 77°F) with excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Dispense in original bottle. Keep the bottle tightly closed. Do not remove desiccant. Protect from moisture
|fdaPatientInfo=Advise the patient to read the FDA-approved patient labeling (Patient Information).

'''Cardiomyopathy'''

Advise patients and caregivers that KOSELUGO can cause a reduction in LVEF and to immediately report any signs or symptoms of cardiomyopathy to their healthcare provider.

'''Ocular Toxicity'''

Advise patients and caregivers that KOSELUGO can cause ocular toxicity that can lead to blindness and to contact their healthcare provider if the patient experiences any changes in their vision.

'''Gastrointestinal Toxicity'''

Advise patients and caregivers that KOSELUGO can cause diarrhea and to contact their healthcare provider at the onset of diarrhea.

'''Skin Toxicity'''

Advise patients and caregivers that KOSELUGO can cause serious skin toxicities and to contact their healthcare provider for severe skin changes.

'''Increased Creatine Phosphokinase'''

Advise patients and caregivers that KOSELUGO can cause increased CPK and to report any signs and symptoms of muscle pain or weakness to their healthcare provider.

'''Increased Vitamin E Levels and Risk of Bleeding'''

Advise patients and caregivers to notify their healthcare provider if they are taking a supplement containing vitamin E, a vitamin-K antagonist or an anti-platelet agent.

'''Embryo-Fetal Toxicity'''

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.

*Advise females of reproductive potential to use effective contraception during treatment with KOSELUGO and for 1 week after the last dose.

Advise males with female partners of reproductive potential to use effective contraception during treatment with KOSELUGO and for at least 1 week after the last dose.
'''Lactation'''

Advise women not to breastfeed during treatment with KOSELUGO and for 1 week after the last dose.

'''Drug Interactions'''

Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid St. John’s wort, grapefruit or grapefruit juice while taking KOSELUGO.

'''Dosing and Administration'''

Inform patients and caregivers on how to take KOSELUGO and what to do for missed or vomited doses.
|alcohol=Alcohol-Selumetinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=Koselugo
}}

Tucatinib

2025-05-10T14:56:28Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=tucatinib |aOrAn=a |drugClass=human epidermal growth factor receptor-2 (HER2) inhibitor |indication='''Metastatic Breast Cancer''' TUKYSA is indicated in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior ant..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=tucatinib
|aOrAn=a
|drugClass=human epidermal growth factor receptor-2 (HER2) inhibitor
|indication='''Metastatic Breast Cancer'''
TUKYSA is indicated in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

'''Unresectable or Metastatic Colorectal Cancer'''
TUKYSA is indicated in combination with trastuzumab for the treatment of adult patients with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
|adverseReactions=The following clinically significant adverse reactions are described elsewhere in the labeling:
*Diarrhea

*Hepatotoxicity
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult='''Metastatic Breast Cancer'''
TUKYSA is indicated in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

'''Unresectable or Metastatic Colorectal Cancer'''
TUKYSA is indicated in combination with trastuzumab for the treatment of adult patients with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

'''DOSAGE'''
Tablets:
*50 mg: round, yellow, film-coated, debossed with “TUC” on one side and “50” on the other side.
*150 mg: oval-shaped, yellow, film-coated, debossed with “TUC” on one side and “150” on the other side.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Tucatinib in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Tucatinib in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Tucatinib in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Tucatinib in pediatric patients.
|contraindications=None
|warnings='''Diarrhea'''
TUKYSA can cause severe diarrhea including dehydration, hypotension, acute kidney injury, and death.

If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA.

TUKYSA with trastuzumab and capecitabine

In HER2CLIMB, 81% of patients who received TUKYSA experienced diarrhea, including 0.5% with Grade 4 diarrhea and 12% with Grade 3 diarrhea. Both patients who developed Grade 4 diarrhea subsequently died, with diarrhea as a contributor to death. The median time to onset of the first episode of diarrhea was 12 days and the median time to resolution was 8 days. Diarrhea led to dose reductions of TUKYSA in 6% of patients and discontinuation of TUKYSA in 1% of patients. Prophylactic use of antidiarrheal treatment was not required on HER2CLIMB.

TUKYSA with trastuzumab

In MOUNTAINEER, diarrhea occurred in 64% of patients, including Grade 3 (3.5%), Grade 2 (10%), and Grade 1 (50%).

'''Hepatotoxicity'''
TUKYSA can cause severe hepatotoxicity.

Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatotoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA.

TUKYSA with trastuzumab and capecitabine

In HER2CLIMB, 8% of patients who received TUKYSA had an ALT increase > 5 × ULN, 6% had an AST increase > 5 × ULN, and 1.5% had a bilirubin increase > 3 × ULN (Grade ≥3). Hepatotoxicity led to dose reduction of TUKYSA in 8% of patients and discontinuation of TUKYSA in 1.5% of patients.

TUKYSA with trastuzumab

In MOUNTAINEER, 6% of patients had a bilirubin increase > 3 × ULN (Grade ≥3), 6% had an AST increase > 5 × ULN, and 4.7% had an ALT increase > 5 × ULN. Hepatotoxicity led to dose reduction of TUKYSA in 3.5% of patients and discontinuation of TUKYSA in 2.3% of patients.

'''Embryo-Fetal Toxicity'''
Based on findings from animal studies and its mechanism of action, TUKYSA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of tucatinib to pregnant rats and rabbits during organogenesis caused embryo-fetal mortality, reduced fetal weight and fetal abnormalities at maternal exposures ≥ 1.3 times the human exposure (AUC) at the recommended dose.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TUKYSA and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TUKYSA and for 1 week after the last dose.

TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for pregnancy and contraception information.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

'''HER2-Positive Metastatic Breast Cancer'''

The safety of TUKYSA in combination with trastuzumab and capecitabine was evaluated in HER2CLIMB. Patients received either TUKYSA 300 mg twice daily plus trastuzumab or a non-US approved trastuzumab product, and capecitabine (n=404) or placebo plus trastuzumab or a non-US approved trastuzumab product and capecitabine (n=197). The median duration of treatment was 5.8 months (range: 3 days, 2.9 years) for the TUKYSA arm.

Serious adverse reactions occurred in 26% of patients who received TUKYSA. Serious adverse reactions in ≥ 2% of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal adverse reactions occurred in 2% of patients who received TUKYSA including sudden death, sepsis, dehydration, and cardiogenic shock.

Adverse reactions leading to treatment discontinuation occurred in 6% of patients who received TUKYSA. Adverse reactions leading to treatment discontinuation of TUKYSA in ≥1% of patients were hepatotoxicity (1.5%) and diarrhea (1%).

Adverse reactions leading to dose reduction occurred in 21% of patients who received TUKYSA. Adverse reactions leading to dose reduction of TUKYSA in ≥2% of patients were hepatotoxicity (8%) and diarrhea (6%).

The most common adverse reactions in patients who received TUKYSA (≥20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, hepatotoxicity, vomiting, stomatitis, decreased appetite, anemia, and rash.

'''Increased Creatinine'''

The mean increase in serum creatinine was 32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.

'''RAS Wild-Type, HER2-Positive Unresectable or Metastatic Colorectal Cancer'''

The safety of TUKYSA in combination with trastuzumab or a non-US approved trastuzumab product was evaluated in 86 patients enrolled in MOUNTAINEER with unresectable or metastatic colorectal cancer [see Clinical Studies (14.2)]. The median duration of exposure to TUKYSA was 6.9 months (range 0.7, 49.3).

Serious adverse reactions occurred in 22% of patients. Serious adverse reactions that occurred in ≥ 2% of patients were intestinal obstruction (7%), urinary tract infection (3.5%), pneumonia (2.3%), abdominal pain (2.3%) and rectal perforation (2.3%).

Permanent discontinuation of TUKYSA due to an adverse reaction occurred in 6% of patients. The adverse reaction which resulted in permanent discontinuation of TUKYSA in ≥2% of patients was increased ALT (2.3%). Dosage interruptions of TUKYSA due to an adverse reaction occurred in 23% of patients. Adverse reactions which required dosage interruption in ≥3% of patients were increased ALT (3.5%) and diarrhea (3.5%). Dose reductions of TUKYSA due to an adverse reaction occurred in 9% of patients. Adverse reactions which required dose reductions in ≥2% of patients were increased ALT (2.3%) and diarrhea (2.3%).

The most common adverse reactions reported in ≥ 20% of patients treated with TUKYSA and trastuzumab were diarrhea, fatigue, rash, nausea, abdominal pain, infusion related reactions, and pyrexia. The most common laboratory abnormalities reported in ≥ 20% of patients were increased creatinine, increased glucose, increased ALT, decreased hemoglobin, increased AST, increased bilirubin, increased alkaline phosphatase, decreased lymphocytes, decreased albumin, decreased leukocytes, and decreased sodium.
|drugInteractions='''Strong CYP3A Inducers or Moderate CYP2C8 Inducers'''
Concomitant use of TUKYSA with a strong CYP3A or moderate CYP2C8 inducer decreased tucatinib plasma concentrations which may reduce TUKYSA activity.

'''Strong or Moderate CYP2C8 Inhibitors'''
Concomitant use of TUKYSA with a strong CYP2C8 inhibitor increased tucatinib plasma concentrations which may increase the risk of TUKYSA toxicity.

'''CYP3A Substrates'''
Concomitant use of TUKYSA with a CYP3A substrate increased the plasma concentrations of CYP3A substrate which may increase the toxicity associated with a CYP3A substrate.

'''P-glycoprotein (P-gp) Substrates'''
Concomitant use of TUKYSA with a P-gp substrate increased the plasma concentrations of P-gp substrate which may increase the toxicity associated with a P-gp substrate.
|useInLaborDelivery=TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for pregnancy information.

Based on findings in animals and its mechanism of action, TUKYSA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available human data on TUKYSA use in pregnant women to inform a drug-associated risk. In animal reproduction studies, administration of tucatinib to pregnant rats and rabbits during organogenesis resulted in embryo-fetal mortality, reduced fetal weight and fetal abnormalities at maternal exposures ≥ 1.3 times the human exposure (AUC) at the recommended dose. Advise pregnant women and females of reproductive potential of the potential risk to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.
|useInNursing=TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for lactation information.

There are no data on the presence of tucatinib or its metabolites in human or animal milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with TUKYSA and for 1 week after the last dose.
|useInPed=The safety and effectiveness of TUKYSA in pediatric patients have not been established.
|useInGeri=In HER2CLIMB, 82 patients who received TUKYSA were ≥ 65 years, of whom 8 patients were ≥ 75 years. The incidence of serious adverse reactions in those receiving TUKYSA was 34% in patients ≥ 65 years compared to 24% in patients <65 years. The most frequent serious adverse reactions in patients ≥65 years who received TUKYSA were diarrhea (9%), vomiting (6%), and nausea (5%). There were no observed overall differences in the effectiveness of TUKYSA in patients ≥ 65 years compared to younger patients. There were too few patients ≥75 years to assess differences in effectiveness or safety.

In MOUNTAINEER, 12 patients were ≥65 years of age. There were too few patients ≥65 years to assess differences in effectiveness or safety.
|useInGender=TUKYSA can cause fetal harm when administered to a pregnant woman. TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for contraception and infertility information.

'''Pregnancy Testing'''

Verify the pregnancy status of females of reproductive potential prior to initiating treatment with TUKYSA.

'''Contraception'''

''Females''

Advise females of reproductive potential to use effective contraception during treatment with TUKYSA and for 1 week after the last dose.

''Males''

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TUKYSA and for 1 week after the last dose.

''Infertility''

Based on findings from animal studies, TUKYSA may impair male and female fertility
|useInRenalImpair=The use of TUKYSA in combination with capecitabine and trastuzumab is not recommended in patients with severe renal impairment (creatinine clearance [CLcr]: < 30 mL/min estimated by Cockcroft-Gault Equation), because capecitabine is contraindicated in patients with severe renal impairment. Refer to the Full Prescribing Information of capecitabine for additional information in severe renal impairment.

No dose adjustment is recommended for patients with mild or moderate renal impairment (CLcr: 30 to 89 mL/min).
|useInHepaticImpair=Tucatinib exposure is increased in patients with severe hepatic impairment (Child-Pugh C). Reduce the dose of TUKYSA for patients with severe (Child-Pugh C) hepatic impairment.

No dose adjustment for TUKYSA is required for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.
|administration='''Metastatic Breast Cancer'''

The recommended dosage of TUKYSA is 300 mg taken orally twice daily in combination with trastuzumab and capecitabine until disease progression or unacceptable toxicity.

'''Unresectable or Metastatic Colorectal Cancer'''

The recommended dosage of TUKYSA is 300 mg taken orally twice daily in combination with trastuzumab until disease progression or unacceptable toxicity.

Advise patients to swallow TUKYSA tablets whole and not to chew, crush, or split prior to swallowing. Advise patients not to ingest tablet if it is broken, cracked, or not otherwise intact.

Advise patients to take TUKYSA approximately 12 hours apart and at the same time each day with or without a meal.

If the patient vomits or misses a dose of TUKYSA, instruct the patient to take the next dose at its usual scheduled time.

When given in combination with TUKYSA, the recommended dosage of capecitabine is 1000 mg/m2 orally twice daily taken within 30 minutes after a meal. TUKYSA and capecitabine can be taken at the same time. Refer to the Full Prescribing Information for trastuzumab and capecitabine for additional information.
|monitoring=*Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatotoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA
|mechAction=Tucatinib is a tyrosine kinase inhibitor of HER2. In vitro, tucatinib inhibits phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell proliferation, and showed anti-tumor activity in HER2 expressing tumor cells. In vivo, tucatinib inhibited the growth of HER2 expressing tumors. The combination of tucatinib and trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either drug alone.
|PD='''Exposure Response Relationship'''

Tucatinib exposure-response relationships and the time course of pharmacodynamics response have not been fully characterized.

'''Cardiac Electrophysiology'''

No large mean increase in QTc (i.e., > 20 ms) was detected following treatment with TUKYSA at the recommended dose of 300 mg taken orally twice daily.
|PK=Tucatinib AUC0-INF and Cmax increased proportionally over a dosage range from 50 mg to 300 mg (0.17 to 1 times the approved recommended dosage). Time to steady state was approximately 4 days. Steady-state pharmacokinetic parameters following administration of TUKYSA 300 mg twice daily for 7 days in patients with mBC and mCRC are described in Table 9. The geometric mean (CV%) tucatinib AUC accumulation ratios ranged from 2.0 (26) fold to 2.5 (28) fold.

'''Absorption'''

The median time to peak plasma concentration of tucatinib was approximately 2 hours (range 1 to 4 hours).

'''Effects of Food'''

Following administration of a single oral dose of TUKYSA in 11 subjects after a high-fat meal (approximately 58% fat, 26% carbohydrate, and 16% protein), the mean AUC0-INF increased by 1.5-fold, the Tmax shifted from 1.5 hours to 4 hours, and Cmax was unaltered. The effect of food on the pharmacokinetics of tucatinib was not clinically meaningful.

'''Distribution'''

The geometric mean (CV%) apparent volume of distribution of tucatinib at steady-state were 903 (42) L and 829 (21) L in patients with mBC and mCRC, respectively. The plasma protein binding was 97.1% at clinically relevant concentrations.

At steady-state, concentrations of tucatinib and its metabolite ONT-993 in the cerebrospinal fluid were comparable to unbound plasma concentrations.

'''Elimination'''

At steady-state, tucatinib effective half-life was approximately 11.9 hours and geometric mean (CV%) apparent clearance was 53 (43) L/h in patients with mBC. Tucatinib effective half-life was approximately 16.4 hours and geometric mean (CV%) apparent clearance was 89 (49) L/h in patients with mCRC.

'''Metabolism'''

Tucatinib is metabolized primarily by CYP2C8 and to a lesser extent via CYP3A.

'''Excretion'''

Following a single oral dose of 300 mg radiolabeled tucatinib, approximately 86% of the total radiolabeled dose was recovered in feces (16% of the administered dose as unchanged tucatinib) and 4.1% in urine with an overall total recovery of 90% within 13 days post-dose. In plasma, approximately 76% of the plasma radioactivity was unchanged, 19% was attributed to identified metabolites, and approximately 5% was unassigned.

'''Specific Populations'''

Age (18-77 years), albumin (19 to 52 g/L), creatinine clearance (CLcr: 60 to 89 mL/min (n = 63); CLcr 30 to 59 mL/min (n = 6)), body weight (41 to 146 kg), sex (male (n = 170), female (n = 113)) and race (White (n = 205), Black (n = 37), or Asian (n = 25)) did not have a clinically meaningful effect on tucatinib exposure.

'''Renal Impairment'''

No clinically significant differences in the pharmacokinetics of tucatinib were observed in patients with mild to moderate renal impairment (CLcr: 30 to 89 mL/min by Cockcroft-Gault). The effect of severe renal impairment (CLcr: < 30 mL/min) on the pharmacokinetics of tucatinib is unknown.

'''Hepatic Impairment'''

Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment had no clinically relevant effect on tucatinib exposure. Tucatinib AUC0-INF was increased by 1.6 fold in subjects with severe (Child-Pugh C) hepatic impairment compared to subjects with normal hepatic function.
|nonClinToxic=Carcinogenicity studies have not been conducted with tucatinib.

Tucatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Tucatinib was not clastogenic in either an in vitro chromosome aberration assay or an in vivo mouse bone marrow micronucleus assay.

Fertility studies in animals have not been conducted. In repeat-dose toxicity studies up to 13 weeks duration, decreased corpora lutea/corpus luteum cyst, increased interstitial cells of the ovary, atrophy of the uterus, and mucification of the vagina were observed in female rats at doses ≥ 6 mg/kg/day (approximately 0.1 times the human exposure at the recommended dose based on AUC). Atrophy and edema of the testes and oligospermia/germ cell debris in the epididymides were observed in male rats at ≥ 120 mg/kg/day (approximately 13 times the human exposure at the recommended dose based on AUC).
|clinicalStudies='''HER2-Positive Metastatic Breast Cancer'''
The efficacy of TUKYSA in combination with trastuzumab and capecitabine was evaluated in 612 patients in HER2CLIMB (NCT02614794), a randomized (2:1), double-blind, placebo-controlled trial. Patients were required to have HER2-positive, unresectable locally advanced or metastatic breast cancer, with or without brain metastases, and prior treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1) separately or in combination, in the neoadjuvant, adjuvant or metastatic setting. HER2 positivity was based on archival or fresh tissue tested with an FDA-approved test at a central laboratory prior to enrollment with HER2 positivity defined as HER2 IHC 3+ or ISH positive.

Patients with brain metastases, including those with progressing or untreated lesions, were eligible provided they were neurologically stable and did not require immediate radiation or surgery. The trial excluded patients with leptomeningeal disease. Randomization was stratified by the presence or history of brain metastases (yes vs. no), Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1), and region (U.S., Canada, or rest of world).

Patients received TUKYSA 300 mg or placebo orally twice daily with a trastuzumab or a non-US approved trastuzumab product loading dose of 8 mg/kg on Day 1 of Cycle 1 if needed and then a maintenance dose of 6 mg/kg on Day 1 of every 21-day cycle thereafter and capecitabine 1000 mg/m2 orally twice daily on Days 1 through 14 of every 21-day cycle. An alternate trastuzumab dosing regimen was 600 mg administered subcutaneously on Day 1 of every 21-day cycle. Patients were treated until disease progression or unacceptable toxicity. Tumor assessments, including brain-MRI in patients with presence or history of brain metastases at baseline, occurred every 6 weeks for the first 24 weeks and every 9 weeks thereafter.

The major efficacy outcome measure was progression-free survival (PFS) in the first 480 randomized patients assessed by blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Additional efficacy outcome measures were evaluated in all randomized patients and included overall survival (OS), PFS among patients with a history or presence of brain metastases (PFSBrainMets), and confirmed objective response rate (ORR).

The median age was 54 years (range: 22 - 82); 116 (19%) patients were age 65 or older. The majority were White (73%) and female (99%) and 51% had an ECOG performance status of 1. Sixty percent had estrogen and/or progesterone receptor-positive disease. Forty-eight percent had a presence or history of brain metastases; of these patients, 23% had untreated brain metastases, 40% had treated but stable brain metastases, and 37% had treated but radiographically progressing brain metastases. Seventy-four percent of patients had visceral metastases. Patients had received a median of 4 (range, 2 to 17) prior lines of systemic therapy and a median of 3 (range, 1 to 14) prior lines of systemic therapy in the metastatic setting. All patients received prior trastuzumab and T-DM1 and all but two patients had prior pertuzumab.

Efficacy results are summarized in Table 12 and Figure 1 and 2. Efficacy results were consistent across patient subgroups defined by stratification factors (presence or history of brain metastases, ECOG status, region of world) and hormone receptor status.

'''HER2-Positive Metastatic Colorectal Cancer'''
The efficacy of TUKYSA in combination with trastuzumab was evaluated in 84 patients in MOUNTAINEER (NCT03043313), an open-label, multicenter trial. Patients were required to have HER2-positive, RAS wild-type, unresectable or metastatic colorectal cancer and prior treatment with fluoropyrimidines, oxaliplatin, irinotecan, and anti-vascular endothelial growth factor (VEGF) monoclonal antibody (mAb). Patients whose disease had deficient mismatch repair (dMMR) proteins or microsatellite instability-high (MSI-H) must have also received an anti-programmed cell death protein-1 (PD-1) mAb. Patients who received prior anti-HER2 targeting therapy were excluded. HER2 positivity as defined by HER2 overexpression or gene amplification was prospectively determined in local laboratories using immunohistochemistry (IHC), in situ hybridization (ISH), and/or next generation sequencing (NGS) on tumor tissue. RAS status was performed as standard of care prior to study entry based on expanded RAS testing including KRAS exons 2, 3, and 4 and NRAS exons 2, 3, and 4.

The median age was 55 years (range: 24 to 77); 12 (14%) patients were age 65 or older. Seventy-seven percent of patients were White, 4% were Black, 4% were Asian, and 4% were Hispanic or Latino. Sixty-one percent of patients were male. Seventy percent of patients had lung metastases, 64% had liver metastases, 60% had an ECOG performance status of 0, 37% had an ECOG performance status of 1, and 4% had an ECOG performance status of 2. Ninety-nine percent of patients received prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan and 83% and 52% received anti-VEGF antibodies and anti-EGFR antibodies respectively; 23%, 38%, and 39% received 1, 2, or ≥3 prior lines of therapy, respectively.

Patients received TUKYSA 300 mg orally twice per day with a loading dose of trastuzumab or a non-US approved trastuzumab product 8 mg/kg intravenously on Day 1 of Cycle 1, followed by a maintenance dose of trastuzumab 6 mg/kg on Day 1 of each subsequent 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.

The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR) as assessed by blinded independent central review (BICR) according to RECIST version 1.1.
|howSupplied=TUKYSA 50 mg tablets are supplied as yellow, film-coated, round tablets containing 50 mg of tucatinib. Each tablet is debossed with “TUC” on one side and “50” on the other side, and is packaged as follows:

*50 mg tablets: 60 count in 75 cc bottle: NDC 51144-001-60

*TUKYSA 150 mg tablets are supplied as yellow, film-coated, oval-shaped tablets containing 150 mg of tucatinib. Each tablet is debossed with “TUC” on one side and “150” on the other side, and is packaged as follows:

*150 mg tablets: 60 count in 75 cc bottle: NDC 51144-002-60

*150 mg tablets: 120 count in 150 cc bottle: NDC 51144-002-12
|storage=Store at controlled room temperature, 20ºC to 25ºC (68ºF to 77ºF); excursions permitted from 15ºC to 30ºC (59ºF to 86ºF)

Dispense to patient in original container only. Store in original container to protect from moisture. Replace cap securely each time after opening. Do not discard desiccant.

Once opened, use within 3 months. Discard any unused tablets 3 months after opening the bottle.
|fdaPatientInfo='''Diarrhea'''

*Inform patients that TUKYSA has been associated with severe diarrhea. Instruct patients on how to manage diarrhea and to inform their provider immediately if there is any change in bowel patterns.

'''Hepatotoxicity'''

*Inform patients that TUKYSA has been associated with severe hepatotoxicity and that they should report signs and symptoms of liver dysfunction to their healthcare provider immediately.

'''Embryo-Fetal Toxicity'''

*Inform pregnant women and females of reproductive potential of the risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.

*Advise females of reproductive potential to use effective contraception during treatment with TUKYSA and for 1 week after the last dose.

*Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TUKYSA and for 1 week after the last dose.

*Refer to the Full Prescribing Information of trastuzumab and capecitabine for pregnancy and contraception information.
'''Lactation'''

*Advise women not to breastfeed during treatment with TUKYSA and for 1 week after the last dose [see Use in Specific Populations (8.2)]. Refer to the Full Prescribing Information of trastuzumab and capecitabine for lactation information.
'''Infertility'''

*Advise males and females of reproductive potential that TUKYSA may impair fertility [see Use in Specific Populations (8.3)]. Refer to the Full Prescribing Information of trastuzumab and capecitabine for infertility information.
|alcohol=Alcohol-Tucatinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=TUKYSA
}}

Pemigatinib

2025-05-09T12:49:27Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=pemigatinib |aOrAn=a |drugClass=inhibits FGFR kinase activity |indicationType=treatment |indication='''Cholangiocarcinoma''' PEMAZYRE is indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test...."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=pemigatinib
|aOrAn=a
|drugClass=inhibits FGFR kinase activity
|indicationType=treatment
|indication='''Cholangiocarcinoma'''
PEMAZYRE is indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

'''Myeloid/Lymphoid Neoplasms with FGFR1 Rearrangement'''
PEMAZYRE is indicated for the treatment of adults with relapsed or refractory myeloid/lymphoid neoplasms (MLNs) with fibroblast growth factor receptor 1 (FGFR1) rearrangement.
|adverseReactions=The following adverse reactions are discussed elsewhere in the labeling:

*Ocular Toxicity
*Hyperphosphatemia and Soft Tissue Mineralization
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult='''Cholangiocarcinoma'''
PEMAZYRE is indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

'''Myeloid/Lymphoid Neoplasms with FGFR1 Rearrangement'''
PEMAZYRE is indicated for the treatment of adults with relapsed or refractory myeloid/lymphoid neoplasms (MLNs) with fibroblast growth factor receptor 1 (FGFR1) rearrangement.

'''DOSAGE'''
'''Cholangiocarcinoma'''

The recommended dosage of PEMAZYRE is 13.5 mg orally once daily for 14 consecutive days followed by 7 days off therapy, in 21-day cycles. Continue treatment until disease progression or unacceptable toxicity occurs.

'''Myeloid/Lymphoid Neoplasms with FGFR1 Rearrangement'''

The recommended dosage of PEMAZYRE is 13.5 mg orally once daily on a continuous basis. Continue treatment until disease progression or unacceptable toxicity occurs.

Tablets:

*4.5 mg: round, white to off-white tablet debossed on one side with "I" and "4.5" on the other side.
*9 mg: oval, white to off-white tablet debossed on one side with "I" and "9" on the other side.
*13.5 mg: round, white to off-white tablet debossed on one side with "I" and "13.5" on the other side.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Pemigatinib in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Pemigatinib in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Pemigatinib in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Pemigatinib in pediatric patients.
|contraindications=None.
|warnings='''Ocular Toxicity'''
Retinal Pigment Epithelial Detachment (RPED)

PEMAZYRE can cause RPED, which may cause symptoms such as blurred vision, visual floaters, or photopsia. Clinical trials of PEMAZYRE did not conduct routine monitoring including optical coherence tomography (OCT) to detect asymptomatic RPED; therefore, the incidence of asymptomatic RPED with PEMAZYRE is unknown.

Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, RPED occurred in 11% of patients, including Grade 3-4 RPED in 1.3%. The median time to first onset of RPED was 56 days. RPED led to dose interruption of PEMAZYRE in 3.1% of patients, and dose reduction and permanent discontinuation in 1.3% and in 0.2% of patients, respectively. RPED resolved or improved to Grade 1 levels in 76% of patients who required dosage modification of PEMAZYRE for RPED.

Perform a comprehensive ophthalmological examination including OCT prior to initiation of PEMAZYRE and every 2 months for the first 6 months and every 3 months thereafter during treatment. For onset of visual symptoms, refer patients for ophthalmologic evaluation urgently, with follow-up every 3 weeks until resolution or discontinuation of PEMAZYRE.

Modify the dose or permanently discontinue PEMAZYRE as recommended.

'''Dry Eye'''

Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, dry eye occurred in 31% of patients, including Grade 3-4 in 1.6% of patients. Treat patients with ocular demulcents as needed.

'''Hyperphosphatemia and Soft Tissue Mineralization'''
PEMAZYRE can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcification, calcinosis, and non-uremic calciphylaxis. Increases in phosphate levels are a pharmacodynamic effect of PEMAZYR. Among 635 patients who received a starting dose of PEMAZYRE 13.5 mg across clinical trials, hyperphosphatemia was reported in 93% of patients based on laboratory values above the upper limit of normal. The median time to onset of hyperphosphatemia was 8 days (range 1-169). Phosphate lowering therapy was required in 33% of patients receiving PEMAZYRE.

Monitor for hyperphosphatemia and initiate a low phosphate diet when serum phosphate level is > 5.5 mg/dL. For serum phosphate levels > 7 mg/dL, initiate phosphate lowering therapy and withhold, reduce the dose, or permanently discontinue PEMAZYRE based on duration and severity of hyperphosphatemia [see Dosage and Administration (2.3)].

'''Embryo-Fetal Toxicity'''
Based on findings in an animal study and its mechanism of action, PEMAZYRE can cause fetal harm when administered to a pregnant woman. Oral administration of pemigatinib to pregnant rats during the period of organogenesis caused fetal malformations, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure based on area under the curve (AUC) at the clinical dose of 13.5 mg.

Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose .
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in the WARNINGS AND PRECAUTIONS section reflects exposure to PEMAZYRE at a starting dose of 13.5 mg orally once daily (intermittent or continuous administration) in 635 patients with advanced malignancies. Among the 635 patients, 31% were exposed for 6 months or longer and 11% were exposed greater than one year, including patients with previously treated, advanced, or metastatic cholangiocarcinoma in FIGHT-202 and patients with MLNs with FGFR1 rearrangement in FIGHT-203.

'''Cholangiocarcinoma'''

'''FIGHT-202'''

The safety of PEMAZYRE was evaluated in FIGHT-202, which included 146 patients with previously treated, locally advanced or metastatic cholangiocarcinoma [see Clinical Studies (14.1)]. Patients were treated orally with PEMAZYRE 13.5 mg once daily for 14 days on followed by 7 days off therapy until disease progression or unacceptable toxicity. The median duration of treatment was 181 days (range: 7 to 730 days).

The median age of PEMAZYRE-treated patients was 59 years (range 26-78), 58% were females, and 71% were White.

Serious adverse reactions occurred in 45% of patients receiving PEMAZYRE. Serious adverse reactions in ≥ 2% of patients who received PEMAZYRE included abdominal pain, pyrexia, cholangitis, pleural effusion, acute kidney injury, cholangitis infective, failure to thrive, hypercalcemia, hyponatremia, small intestinal obstruction, and urinary tract infection. Fatal adverse reactions occurred in 4.1% of patients, including failure to thrive, bile duct obstruction, cholangitis, sepsis, and pleural effusion.

Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received PEMAZYRE. Adverse reactions requiring permanent discontinuation in ≥ 1% of patients included intestinal obstruction and acute kidney injury.

Dosage interruptions due to an adverse reaction occurred in 43% of patients who received PEMAZYRE. Adverse reactions requiring dosage interruption in ≥ 1% of patients included stomatitis, palmar-plantar erythrodysesthesia syndrome, arthralgia, fatigue, abdominal pain, AST increased, asthenia, pyrexia, ALT increased, cholangitis, small intestinal obstruction, alkaline phosphatase increased, diarrhea, hyperbilirubinemia, electrocardiogram QT prolonged, decreased appetite, dehydration, hypercalcemia, hyperphosphatemia, hypophosphatemia, back pain, pain in extremity, syncope, acute kidney injury, onychomadesis, and hypotension.

Dose reductions due to an adverse reaction occurred in 14% of patients who received PEMAZYRE. Adverse reactions requiring dosage reductions in ≥ 1% of patients who received PEMAZYRE included stomatitis, arthralgia, palmar-plantar erythrodysesthesia syndrome, asthenia, and onychomadesis.

'''Increased Creatinine'''

Within the first 21-day cycle of PEMAZYRE dosing, serum creatinine increased (mean increase of 0.2 mg/dL) and reached steady state by Day 8, and then decreased during the 7 days off therapy. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology (12.3)].

'''Myeloid/Lymphoid Neoplasms with FGFR1 Rearrangement'''

'''FIGHT-203'''

The safety of PEMAZYRE was evaluated in FIGHT-203, which included 34 patients who were treated for MLN with FGFR1 rearrangement [see Clinical Studies (14.2)]. Patients were treated with PEMAZYRE 13.5 mg once daily on a continuous schedule (the approved recommended starting dosage) or for 14 days on followed by 7 days off therapy (an unapproved dosage regimen in MLN with FGFR1 rearrangement) until disease progression, unacceptable toxicity, or they were able to receive allogeneic stem cell transplant. The median duration of treatment was 205 days (range: 30-1347 days).

Serious adverse reactions occurred in 53% of patients receiving PEMAZYRE at all dosages. Serious adverse reactions in > 5% of patients included acute kidney injury. Fatal adverse reactions occurred in 9% of patients who received PEMAZYRE, including acute kidney injury, multiple organ dysfunction syndrome, and malignant neoplasm progression, occurring in one patient each.

Permanent discontinuation due to an adverse reaction occurred in 12% of patients who received PEMAZYRE at all dosages. Adverse reactions requiring permanent discontinuation included cardiac failure, multiple organ dysfunction syndrome, blood alkaline phosphatase increase, and calciphylaxis.

In patients who started treatment on the recommended dosage (n = 20), adverse reactions requiring dosage interruption of PEMAZYRE occurred in 80% of patients. Adverse reactions which required dosage interruption in > 2 patients treated at the recommended dosage included nail toxicities (20%) and hyperphosphatemia (15%).

Dose reductions of PEMAZYRE due to an adverse reaction occurred in 80% of patients who started treatment on the recommended dosage. Adverse reactions requiring dose reductions occurring in > 2 patients were nail toxicities (20%), hyperphosphatemia (20%), and alopecia (15%).

The most common (≥ 20%) adverse reactions were hyperphosphatemia, nail toxicity, alopecia, stomatitis, diarrhea, dry eye, fatigue, rash, abdominal pain, anemia, constipation, dry mouth, epistaxis, serous retinal detachment, extremity pain, decreased appetite, dry skin, dyspepsia, back pain, nausea, blurred vision, peripheral edema, and dizziness.

The most common (≥ 20%) laboratory abnormalities were increased phosphate, decreased lymphocytes, decreased leukocytes, increased alkaline phosphatase, decreased hemoglobin, increased alanine aminotransferase, increased aspartate aminotransferase, decreased neutrophils, increased creatinine, decreased phosphate, decreased sodium, increased glucose, decreased platelets, decreased calcium, increased calcium, decreased potassium, and increased bilirubin.
|drugInteractions='''Effect of Other Drugs on PEMAZYRE'''
Strong and Moderate CYP3A Inducers

Concomitant use of PEMAZYRE with a strong or moderate CYP3A inducer decreases pemigatinib plasma concentrations, which may reduce the efficacy of PEMAZYRE. Avoid concomitant use of strong and moderate CYP3A inducers with PEMAZYRE.

'''Strong and Moderate CYP3A Inhibitors'''

Concomitant use of a strong or moderate CYP3A inhibitor with PEMAZYRE increases pemigatinib plasma concentrations, which may increase the incidence and severity of adverse reactions. Avoid concomitant use of strong and moderate CYP3A inhibitors with PEMAZYRE. Reduce PEMAZYRE dosage if concomitant use of strong and moderate CYP3A inhibitors cannot be avoided
|useInLaborDelivery=Based on findings in an animal study and its mechanism of action, PEMAZYRE can cause fetal harm or loss of pregnancy when administered to a pregnant woman. There are no available data on the use of PEMAZYRE in pregnant women. Oral administration of pemigatinib to pregnant rats during the period of organogenesis at maternal plasma exposures below the human exposure at the clinical dose of 13.5 mg resulted in fetal malformations, fetal growth retardation, and embryo-fetal death. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectivel
|useInNursing=There are no data on the presence of pemigatinib or its metabolites in human milk or their effects on either the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children from PEMAZYRE, advise women not to breastfeed during treatment and for 1 week after the last dose.
|useInPed=In 4- or 13-week repeat-dose toxicology studies in rats and non-human primates, animals displayed toxicities in bone and teeth at pemigatinib exposures lower than the human exposure at the clinical dose of 13.5 mg. Physeal and cartilage dysplasia were present in multiple bones in both species, and tooth (incisor) abnormalities (complete loss of ameloblasts with associated secondary changes) occurred in rats. Six weeks after cessation of dosing, these findings did not show complete evidence of recovery, and additional tooth-related findings (mal-aligned, whitened, broken, and trimmed/thinned incisors) developed in the 13-week study.
|useInGeri=In FIGHT-202 in patients with cholangiocarcinoma, 32% of patients were 65 years and older, and 8% of patients were 75 years and older. In FIGHT-203 in patients with MLN with FGFR1 rearrangement, 44% of patients were 65 years and older, and 2.9% of patients were 75 years and older.

No overall differences in safety or effectiveness were observed between these patients and younger patients.
|useInGender=PEMAZYRE can cause fetal harm when administered to pregnant women.

'''Pregnancy Testing'''

Verify pregnancy status of females of reproductive potential prior to initiating PEMAZYRE.

'''Contraception'''

'''Females'''

Advise females of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose.

'''Males'''

Advise males with female partners of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose.
|useInRenalImpair=Reduce the recommended dosage of PEMAZYRE for patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2, estimated by MDRD equation).

No dosage adjustment is recommended for patients with mild or moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2). No dosage adjustment is recommended for patients with end-stage renal disease (eGFR < 15 mL/min/1.73 m2) who are receiving intermittent hemodialysis.
|useInHepaticImpair=Reduce the recommended dosage of PEMAZYRE for patients with severe hepatic impairment (total bilirubin > 3 × ULN with any AST).

No dosage adjustment is recommended for patients with mild (total bilirubin > upper limit of normal [ULN] to 1.5 × ULN or AST > ULN) or moderate (total bilirubin >1.5–3 × ULN with any AST) hepatic impairment.
|monitoring=Monitor for hyperphosphatemia and initiate a low phosphate diet when serum phosphate level is > 5.5 mg/dL. For serum phosphate levels > 7 mg/dL, initiate phosphate lowering therapy and withhold, reduce the dose, or permanently discontinue PEMAZYRE based on duration and severity of hyperphosphatemia
|mechAction=Pemigatinib is a small molecule kinase inhibitor that targets FGFR1, 2 and 3 with IC50 values of less than 2 nM. Pemigatinib also inhibited FGFR4 in vitro at a concentration approximately 100 times higher than those that inhibit FGFR1, 2, and 3. Pemigatinib inhibited FGFR1-3 phosphorylation and signaling and decreased cell viability in cancer cell lines with activating FGFR amplifications and fusions that resulted in constitutive activation of FGFR signaling. Constitutive FGFR signaling can support the proliferation and survival of malignant cells. Pemigatinib exhibited anti-tumor activity in mouse xenograft models of human tumors with FGFR1, FGFR2, or FGFR3 alterations resulting in constitutive FGFR activation including a patient-derived xenograft model of cholangiocarcinoma that expressed an oncogenic FGFR2-Transformer-2 beta homolog (TRA2b) fusion protein and the KG1 leukemia model that carries a translocation of FGFR1 (FGFR1OP2-FGFR1).
|PD='''Serum Phosphate'''

Pemigatinib increased serum phosphate levels as a consequence of FGFR inhibition. Serum phosphate increased with increasing exposure across the dose range of 1 to 20 mg once daily (0.07 to 1.5 times the recommended dose), with increased risk of hyperphosphatemia with higher pemigatinib exposure.

'''Cardiac Electrophysiology'''

At a dose 1.5 times the maximum recommended dose, PEMAZYRE does not result in a large mean increase (i.e. > 20 ms) of the QTc interval.
|PK=The geometric mean (CV%) steady-state pemigatinib AUC0-24h was 2620 nM·h (54%) and Cmax was 236 nM (56%) for 13.5 mg orally once daily. Steady state pemigatinib concentrations increased proportionally over the dose range of 1 to 20 mg (0.07 to 1.5 times the recommended dose). Steady-state was achieved within 4 days and pemigatinib accumulated with a median accumulation ratio of 1.63 (range 0.63 to 3.28) following repeated once daily dosing.

'''Absorption'''

The median time to achieve peak pemigatinib plasma concentration (Tmax) was 1.13 (0.50‑6.00) hours.

'''Effect of Food'''

Administration of PEMAZYRE with a high-fat and high-calorie meal (approximately 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500‑600 calories from fat) had no clinically significant effect on pemigatinib pharmacokinetics.

'''Distribution'''

The estimated apparent volume of distribution was 235 L (60.8%) following a 13.5 mg oral dose. Protein binding of pemigatinib was 90.6% and was independent of concentration in vitro.

'''Elimination'''

The geometric mean (%CV) elimination half-life (t½) of pemigatinib was 15.4 (51.6%) hours and the geometric mean apparent clearance (CL/F) was 10.6 L/h (54%).

'''Metabolism'''

Pemigatinib is predominantly metabolized by CYP3A4 in vitro. The major drug-related moiety in plasma was unchanged pemigatinib.

'''Excretion'''

Following a single oral 11 mg dose of radiolabeled pemigatinib, 82.4% of the dose was recovered in feces (1.4% as unchanged) and 12.6% in urine (1% as unchanged).

'''Specific Populations'''

No clinically significant differences in the systemic exposure of pemigatinib were observed based on age (21 ‑ 79 years), sex, race/ethnicity (White 68.2%, Asian 16%, Black 6.3%, Hispanic 6%, other 3.5%) or body weight (39.8 ‑ 156 kg).

'''Patients with Renal Impairment'''

No clinically significant differences in the systemic exposure of pemigatinib were observed in mild to moderate renal impairment (eGFR 30 to 89 mL/min, MDRD) or end-stage renal disease (eGFR <15 mL/min/1.73 m2) on intermittent hemodialysis. Compared to subjects with normal renal function, the geometric mean pemigatinib AUC0–inf increased by 59% in patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2).

'''Patients with Hepatic Impairment'''

No clinically significant differences in the systemic exposure of pemigatinib were observed in mild (total bilirubin > upper limit of normal [ULN] to 1.5 × ULN or AST > ULN) to moderate (total bilirubin >1.5–3 × ULN with any AST) hepatic impairment. Compared to subjects with normal hepatic function, the geometric mean pemigatinib AUC0–inf increased by 136% in subjects with severe hepatic impairment (total bilirubin > 3 × ULN with any AST).

'''Drug Interaction Studies'''

'''Clinical Studies and Model-Based Approaches'''

CYP3A Inhibitors: Itraconazole (strong CYP3A inhibitor) increased Cmax by 17% and increased AUC by 88% following a single oral PEMAZYRE dose of 4.5 mg [see Drug Interactions (7.1)]. Concomitant use of moderate CYP3A inhibitors is predicted to increase pemigatinib exposure by approximately 50-80%.

CYP3A Inducers: Rifampin (strong CYP3A inducer) decreased pemigatinib Cmax by 62% and AUC by 85% following a single oral PEMAZYRE dose of 13.5 mg. Concomitant use of a moderate CYP3A inducer is predicted to decrease pemigatinib exposure by more than 50%.

Other Drugs: No clinically significant differences in pemigatinib exposure when co-administered with esomeprazole (proton pump inhibitor) or ranitidine (histamine-2 antagonist). No clinically significant differences in glucose levels were observed when metformin (OCT2/MATE1 substrate) was co-administered with pemigatinib.

'''In Vitro Studies'''

CYP Enzymes: Pemigatinib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 or an inducer of CYP1A2, CYP2B6, or CYP3A4.

Transporter Systems: Pemigatinib is a substrate of both P-gp and BCRP. P-gp or BCRP inhibitors are not expected to affect pemigatinib exposure at clinically relevant concentrations. Pemigatinib is an inhibitor of P-gp, OCT2, and MATE1. Pemigatinib may increase serum creatinine by decreasing renal tubular secretion of creatinine; this may occur due to inhibition of renal transporters OCT2 and MATE1 and may not affect glomerular function
|nonClinToxic=Carcinogenicity studies have not been conducted with pemigatinib.

Pemigatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in either an in vitro chromosome aberration assay or an in vivo micronucleus assay in rats.

Dedicated fertility studies with pemigatinib have not been conducted. Oral administration of pemigatinib did not result in any dose-related findings likely to result in impaired fertility in male and female reproductive organs.
|clinicalStudies='''Cholangiocarcinoma'''
FIGHT-202 (NCT02924376), a multicenter open-label single-arm trial, evaluated the efficacy of PEMAZYRE in 107 patients with locally advanced unresectable or metastatic cholangiocarcinoma whose disease had progressed on or after at least 1 prior therapy and who had an FGFR2 gene fusion or non-fusion rearrangement, as determined by a clinical trial assay performed at a central laboratory. Qualifying in-frame fusions and other rearrangements were predicted to have a breakpoint within intron 17/exon 18 of the FGFR2 gene leaving the FGFR2 kinase domain intact.

Patients received PEMAZYRE in 21-day cycles at a dosage of 13.5 mg orally once daily for 14 consecutive days, followed by 7 days off therapy. PEMAZYRE was administered until disease progression or unacceptable toxicity. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) as determined by an independent review committee (IRC) according to RECIST v1.1.

The median age was 56 years (range: 26 to 77 years), 61% were female, 74% were White, and 95% had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (42%) or 1 (53%). Ninety-eight percent of patients had intrahepatic cholangiocarcinoma. Eighty-six percent of patients had in-frame FGFR2 gene fusions and the most commonly identified FGFR2 fusion was FGFR2-BICC1 (34%). Fourteen percent of patients had other FGFR2 rearrangements that could not be confidently predicted to be in-frame fusions, including rearrangements without an identifiable partner gene. All patients had received at least 1 prior line of systemic therapy, 27% had 2 prior lines of therapy, and 12% had 3 or more prior lines of therapy. Ninety-six percent of patients had received prior platinum-based therapy including 76% with prior gemcitabine/cisplatin.

'''Myeloid/Lymphoid Neoplasms with FGFR1 Rearrangement'''

FIGHT-203 (NCT03011372), a multicenter open-label, single-arm trial, evaluated the efficacy of PEMAZYRE in 28 patients with MLNs with FGFR1 rearrangement. Inclusion criteria included documented myeloid/lymphoid neoplasms with 8p11 rearrangement shown to be an FGFR1 activating mutation, based on cytogenetic evaluation. Patients could have relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or after a disease modifying therapy, or were not a candidate for allo-HSCT or other disease modifying therapies.

Patients received PEMAYZRE 13.5 mg once daily in 21-day cycles, either on a continuous schedule (the approved recommended starting dosage) or as an intermittent schedule (14 days on, 7 days off, an unapproved dosage regimen in MLN with FGFR1 rearrangement). PEMAZYRE was administered until disease progression or unacceptable toxicity or until patients were able to receive allo-HSCT. The median age was 65 years (range: 39-78), 64% were female, 68% were White, 3.6% were Black or African American, 11% were Asian, 3.6% were American Indian/Alaska Native, 3.6% were other race, and race was unknown or not collected for 11% of patients; 3.6% were Hispanic, 68% were not Hispanic, 11% were other ethnicity, and ethnicity was not reported in 18%, and 88% had an ECOG performance status of 0 or 1.

In patients with chronic phase in the marrow with or without extramedullary disease (EMD) (N = 18), efficacy was established based on complete response (CR). CR was defined based on the MDS/MPN Working Group response criteria (2015) for MDS/MPN neoplasms with the additional requirement that peripheral eosinophils are < 0.5 × 109/L, and, if relevant, CR in EMD using Lugano criteria (Cheson 2014). The CR rate was 78% (14/18; 95% CI: 52, 94). The median time to response of CR was 104 days (range, 44 to 435 days). The median duration of CR was not reached (range, 1+ to 988+ days).

In patients with blast phase in the marrow with or without EMD (N = 4), efficacy was established based on CR. CR was defined as < 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets > 100,000/microliter and absolute neutrophil counts > 1,000/microliter). Of the 4 patients with blast phase, two patients achieved a CR (duration: 1+ and 94 days).

In patients with EMD only (N = 3), efficacy was established based on CR using Lugano criteria (Cheson 2014). In the 3 patients with EMD only, 1 patient achieved a CR (duration: 64+ days).

For all patients (N = 28 including 3 patients without evidence of morphologic disease), the complete cytogenetic response rate was 79% (22/28; 95% CI: 59, 92).
|howSupplied=PEMAZYRE tablets are available as follows:

*4.5 mg: Round, white to off-white debossed on one side with “I” and “4.5” on the other side in bottles of 14 with child-resistant closure, NDC 50881-026-01
*9 mg: Oval, white to off-white debossed on one side with “I” and “9” on the other side in bottles of 14 with child-resistant closure, NDC 50881-027-01
*13.5 mg: Round, white to off-white debossed on one side with “I” and “13.5” on the other side in bottles of 14 with child-resistant closure, NDC 50881-028-01
|storage=Store PEMAZYRE tablets at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
|fdaPatientInfo='''Ocular Toxicity'''

Advise patients that PEMAZYRE may cause ocular toxicity including RPED and to immediately inform their healthcare provider if they experience any visual changes. Also advise patients that they should use artificial tear or substitutes, hydrating or lubricating eye gels in order to prevent or treat dry eyes .

'''Hyperphosphatemia and Soft Tissue Mineralization'''

Inform patients that they may experience increase in phosphate levels and of the need to monitor serum phosphate levels. Advise patients to immediately inform their healthcare provider of any symptoms related to acute change in phosphate levels such as muscle cramps, numbness, or tingling around the mouth .

'''Nail Disorders'''

Advise patients that PEMAZYRE may cause nail disorders.

'''Embryo-Fetal Toxicity'''

Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of pregnancy.
Advise females of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the last dose.
Advise males with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 1 week after receiving the last dose of PEMAZYRE.
'''Lactation'''

Advise patients not to breastfeed during treatment with PEMAZYRE and for 1 week after the last dose.
'''Administration'''

Instruct patients do not crush, chew, split or dissolve tablets.
Instruct patients if they miss a dose by 4 or more hours or if they vomit after taking a dose, resume dosing with the next scheduled dose. Extra tablets should not be taken to make up for the missed dose.
'''Drug Interactions'''

Advise patients to inform their healthcare providers of all concomitant medications, herbal and dietary supplements. Advise patients to avoid grapefruit products during treatment with PEMAZYRE .
|alcohol=Alcohol-Pemigatinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=PEMAZYRE
}}

Sacituzumab govitecan

2025-05-09T12:19:17Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=sacituzumab govitecan |aOrAn=a |drugClass=Trop-2-directed antibody and topoisomerase inhibitor conjugate |indication='''Locally Advanced or Metastatic Breast Cancer''' TRODELVY is indicated for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one o..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=sacituzumab govitecan
|aOrAn=a
|drugClass=Trop-2-directed antibody and topoisomerase inhibitor conjugate
|indication='''Locally Advanced or Metastatic Breast Cancer'''
TRODELVY is indicated for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease.
TRODELVY is indicated for the treatment of adult patients with unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+ or IHC 2+/ISH–) breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting.
|hasBlackBoxWarning=Yes
|adverseReactions=*Neutropenia
*Diarrhea
*Hypersensitivity and Infusion-Related Reactions
*Nausea and Vomiting
|blackBoxWarningTitle='''NEUTROPENIA AND DIARRHEA'''
|blackBoxWarningBody=''''TRODELVY can cause severe, life-threatening, or fatal neutropenia. Withhold TRODELVY for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment. Primary prophylaxis with G-CSF is recommended for all patients at increased risk of febrile neutropenia. Initiate anti-infective treatment in patient with febrile neutropenia without delay [see Warnings and Precautions (5.1)].
TRODELVY can cause severe diarrhea. Monitor patients with diarrhea and give fluid and electrolytes as needed. At the onset of diarrhea, evaluate for infectious causes and, if negative, promptly initiate loperamid. If severe diarrhea occurs, withhold TRODELVY until resolved to ≤ Grade 1 and reduce subsequent doses
|fdaLIADAdult='''Locally Advanced or Metastatic Breast Cancer'''
TRODELVY is indicated for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease.
TRODELVY is indicated for the treatment of adult patients with unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (IHC 0, IHC 1+ or IHC 2+/ISH–) breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting.

'''DOSAGE'''
The recommended dosage of TRODELVY is 10 mg/kg administered as an intravenous infusion once weekly on Days 1 and 8 of 21-day treatment cycles. Continue treatment until disease progression or unacceptable toxicity. Do not administer TRODELVY at doses greater than 10 mg/kg.

Administer TRODELVY as an intravenous infusion only. Do not administer as an intravenous push or bolus.

First infusion: Administer infusion over 3 hours. Observe patients during the infusion and for at least 30 minutes following the initial dose, for signs or symptoms of infusion-related reactions
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Sacituzumab govitecan in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Sacituzumab govitecan in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Sacituzumab govitecan in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Sacituzumab govitecan in pediatric patients.
|contraindications=TRODELVY is contraindicated in patients who have experienced a severe hypersensitivity reaction to TRODELVY
|warnings='''Neutropenia'''
TRODELVY can cause severe, life-threatening, or fatal neutropenia as early as the first cycle of treatment. Neutropenia occurred in 64% of patients treated with TRODELVY. Grade 3–4 neutropenia occurred in 49% of patients. Febrile neutropenia occurred in 6% of patients. The median time to first onset of neutropenia (including febrile neutropenia) was 16 days (range: 1 to 435 days). Neutropenia occurred earlier in patients with reduced UGT1A1 activity. Neutropenic colitis occurred in 1.4% of patients.

Primary prophylaxis with G-CSF is recommended starting in the first cycle of treatment in all patients at increased risk of febrile neutropenia, including older patients, patients with previous neutropenia, poor performance status, organ dysfunction, or multiple comorbidities.

Monitor absolute neutrophil count (ANC) during treatment. Withhold TRODELVY for ANC below 1500/mm3 on Day 1 of any cycle or below 1000/mm3 on Day 8 of any cycle. Withhold TRODELVY for neutropenic fever. Dose modifications may be required due to neutropenia. Treat neutropenia with G-CSF and administer prophylaxis in subsequent cycles as clinically indicated or indicated in Table 2.

'''Diarrhea'''
TRODELVY can cause severe diarrhea. Diarrhea occurred in 64% of all patients treated with TRODELVY. Grade 3–4 diarrhea occurred in 11% of all patients treated with TRODELVY. One patient had intestinal perforation following diarrhea. Diarrhea that led to dehydration and subsequent acute kidney injury occurred in 0.7% of all patients.

Withhold TRODELVY for Grade 3–4 diarrhea at the time of scheduled treatment administration and resume when resolved to ≤ Grade 1.

At the onset of diarrhea, evaluate for infectious causes and if negative, promptly initiate loperamide, 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after diarrhea resolves. Additional supportive measures (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated.

Patients who exhibit an excessive cholinergic response to treatment with TRODELVY (e.g., abdominal cramping, diarrhea, salivation, etc.) can receive appropriate premedication (e.g., atropine) for subsequent treatments.

5.3 Hypersensitivity and Infusion-Related Reactions
TRODELVY can cause serious hypersensitivity reactions including life-threatening anaphylactic reactions. Severe signs and symptoms included cardiac arrest, hypotension, wheezing, angioedema, swelling, pneumonitis, and skin reactions.

Hypersensitivity reactions within 24 hours of dosing occurred in 35% of patients treated with TRODELVY. Grade 3–4 hypersensitivity occurred in 2% of patients treated with TRODELVY. The incidence of hypersensitivity reactions leading to permanent discontinuation of TRODELVY was 0.2%. The incidence of anaphylactic reactions was 0.2%.

Premedication for infusion reactions in patients receiving TRODELVY is recommended. Have medications and emergency equipment to treat infusion-related reactions, including anaphylaxis, available for immediate use when administering TRODELVY.

Closely monitor patients for hypersensitivity and infusion-related reactions during each TRODELVY infusion and for at least 30 minutes after completion of each infusion.

Permanently discontinue TRODELVY for Grade 4 infusion-related reactions.

'''Nausea and Vomiting'''
TRODELVY is emetogenic and can cause severe nausea and vomiting. Nausea occurred in 64% of all patients treated with TRODELVY. Grade 3–4 nausea occurred in 3% of patients.

Vomiting occurred in 35% of all patients treated with TRODELVY. Grade 3–4 vomiting occurred in 2% of these patients.

Premedicate with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK1 receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy-induced nausea and vomiting (CINV).

Withhold TRODELVY doses for Grade 3 nausea or Grade 3–4 vomiting at the time of scheduled treatment administration and resume with additional supportive measures when resolved to ≤ Grade 1.

Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting.

'''Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity'''
Patients homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia; and may be at increased risk for other adverse reactions when treated with TRODELVY.

The incidence of neutropenia and anemia was analyzed in 948 patients who received TRODELVY and had UGT1A1 genotype results. In patients homozygous for the UGT1A1 *28 allele (n=112), the incidence of Grade 3–4 neutropenia was 58%. In patients heterozygous for the UGT1A1*28 allele (n=420), the incidence of Grade 3–4 neutropenia was 49%. In patients homozygous for the wild-type allele (n=416), the incidence of Grade 3–4 neutropenia was 43%. In patients homozygous for the UGT1A1 *28 allele, the incidence of Grade 3–4 anemia was 21%. In patients heterozygous for the UGT1A1*28 allele, the incidence of Grade 3–4 anemia was 10%. In patients homozygous for the wild-type allele, the incidence of Grade 3–4 anemia was 9%.

The median time to first neutropenia including febrile neutropenia was 9 days in patients homozygous for the UGT1A1*28 allele, 15 days in patients heterozygous for the UGT1A1*28 allele, and 20 days in patients homozygous for the wild-type allele. The median time to first anemia was 21 days in patients homozygous for the UGT1A1*28 allele, 25 days in patients heterozygous for the UGT1A1*28 allele, and 28 days in patients homozygous for the wild-type allele.

Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue TRODELVY based on clinical assessment of the onset, duration and severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 enzyme activity.

'''Embryo-Fetal Toxicity'''
Based on its mechanism of action, TRODELVY can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. TRODELVY contains a genotoxic component, SN-38, and targets rapidly dividing cells. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TRODELVY and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRODELVY and for 3 months after the last dose
|clinicalTrials='''ASCENT Study'''

The safety of TRODELVY was evaluated in a randomized, active-controlled, open-label study (ASCENT) in patients with mTNBC who had previously received a taxane and at least two prior chemotherapies. Patients were randomized (1:1) to receive either TRODELVY (n=258) or single agent chemotherapy (n=224) and were treated until disease progression or unacceptable toxicity. For patients treated with TRODELVY, the median duration of treatment was 4.4 months (range: 0 to 23 months).

Serious adverse reactions occurred in 27% of patients receiving TRODELVY. Serious adverse reactions in > 1% of patients receiving TRODELVY included neutropenia (7%), diarrhea (4%), and pneumonia (3%). Fatal adverse reactions occurred in 1.2% of patients who received TRODELVY, including respiratory failure (0.8%) and pneumonia (0.4%). TRODELVY was permanently discontinued for adverse reactions in 5% of patients. Adverse reactions leading to permanent discontinuation in ≥ 1 % of patients who received TRODELVY were pneumonia (1%) and fatigue (1%).

Adverse reactions leading to a treatment interruption of TRODELVY occurred in 63% of patients. The most frequent (≥5%) adverse reactions leading to a treatment interruption were neutropenia (47%), diarrhea (5%), respiratory infection (5%), and leukopenia (5%).

Adverse reactions leading to a dose reduction of TRODELVY occurred in 22% of patients. The most frequent (>4%) adverse reactions leading to a dose reduction were neutropenia (11%) and diarrhea (5%).

Granulocyte-colony stimulating factor (G-CSF) was used in 44% of patients who received TRODELVY.

'''Study IMMU-132-01'''

The safety of TRODELVY was evaluated in a single-arm, open-label study (IMMU-132-01) in patients with mTNBC and other malignancies, which included 108 patients with mTNBC who had received at least two prior anticancer therapies for metastatic disease. TRODELVY was administered as an intravenous infusion once weekly on Days 1 and 8 of 21-day treatment cycles at doses up to 10 mg/kg until disease progression or unacceptable toxicity. The median treatment duration in these 108 patients was 5.1 months (range: 0 to 51 months).

Serious adverse reactions occurred in 31% of the patients. Serious adverse reactions in > 1% of patients receiving TRODELVY included febrile neutropenia (6%) vomiting (5%), nausea (3%), dyspnea (3%), diarrhea (4%), anemia (2%), pleural effusion, neutropenia, pneumonia, dehydration (each 2%).

TRODELVY was permanently discontinued for adverse reactions in 2% of patients. Adverse reactions leading to permanent discontinuation were anaphylaxis, anorexia/fatigue, headache (each 0.9%). Forty- five percent (45%) of patients experienced an adverse reaction leading to treatment interruption. The most common adverse reaction leading to treatment interruption was neutropenia (33%). Adverse reactions leading to dose reduction occurred in 33% of patients treated with TRODELVY, with 24% having one dose reduction, and 9% with two dose reductions. The most common adverse reaction leading to dose reductions was neutropenia/febrile neutropenia.

Tables 5 and 6 summarize adverse reactions and laboratory abnormalities occurring in ≥ 10% of patients with mTNBC in the IMMU-132-01 study.
|drugInteractions='''UGT1A1 Inhibitors'''

Concomitant administration of TRODELVY with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38. Avoid administering UGT1A1 inhibitors with TRODELVY.

'''UGT1A1 Inducers'''

Exposure to SN-38 may be reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Avoid administering UGT1A1 inducers with TRODELVY.
|useInLaborDelivery=Based on its mechanism of action, TRODELVY can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. TRODELVY contains a genotoxic component, SN-38, and is toxic to rapidly dividing cells. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 – 4% and 15 – 20%, respectively.
|useInNursing=There is no information regarding the presence of sacituzumab govitecan-hziy or SN-38 in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment and for 1 month after the last dose of TRODELVY.
|useInPed=Safety and effectiveness of TRODELVY have not been established in pediatric patients.
|useInGeri=Of the 366 patients with TNBC who were treated with TRODELVY, 19% of patients were 65 years and 3% were 75 years and older. Patients 65 and older had an increased incidence of neutropenia, including fatal outcomes. No other differences in safety and effectiveness were observed between patients ≥ 65 years of age and younger patients.

Of the 322 patients with HR+/HER2- breast cancer who were treated with TRODELVY, 26% of patients were 65 years and older and 6% were 75 years and older. No overall differences in effectiveness were observed between patients ≥ 65 years of age and younger patients. There was a higher discontinuation rate due to adverse reactions in patients aged 65 years or older (14%) compared with younger patients (3%).
|useInGender='''Pregnancy Testing'''

Verify the pregnancy status of females of reproductive potential prior to the initiation of TRODELVY.

'''Contraception'''

''Females''

TRODELVY can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with TRODELVY and for 6 months after the last dose.

''Males''

Because of the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRODELVY and for 3 months after the last dose.

''Infertility''

''Females''

Based on findings in animals, TRODELVY may impair fertility in females of reproductive potential
|useInHepaticImpair=No adjustment to the starting dosage is required when administering TRODELVY to patients with mild hepatic impairment .

The safety of TRODELVY in patients with moderate (total bilirubin > 1.5 to 3.0 × ULN) or severe (total bilirubin > 3.0 × upper limit of normal [ULN]) hepatic impairment has not been established. TRODELVY has not been tested in patients with AST or ALT > 3 ULN without liver metastases, or AST or ALT > 5 ULN with liver metastases. No recommendations can be made for the starting dosage in these patients.
|administration=Administer TRODELVY as an intravenous infusion only. Do not administer as an intravenous push or bolus.
|overdose=In a clinical trial, planned doses of up to 18 mg/kg (approximately 1.8 times the maximum recommended dose of 10 mg/kg) of TRODELVY were administered. In these patients, a higher incidence of severe neutropenia was observed.
|mechAction=Sacituzumab govitecan-hziy is a Trop-2-directed antibody-drug conjugate. Sacituzumab is a humanized antibody that recognizes Trop-2. The small molecule, SN-38, is a topoisomerase I inhibitor, which is covalently attached to the antibody by a linker. Pharmacology data suggest that sacituzumab govitecan-hziy binds to Trop-2-expressing cancer cells and is internalized with the subsequent release of SN-38 via hydrolysis of the linker. SN-38 interacts with topoisomerase I and prevents re-ligation of topoisomerase I-induced single strand breaks. The resulting DNA damage leads to apoptosis and cell death. Sacituzumab govitecan-hziy decreased tumor growth in mouse xenograft models of triple-negative breast cancer.
|PD=The TRODELVY exposure-response relationships and pharmacodynamic time course for efficacy have not been fully characterized.

'''Cardiac electrophysiology'''

The maximum mean change from baseline was 9.7 msec (the upper bound of the two-sided 90% confidence interval is 16.8 msec) at the recommended dose. A positive exposure-response relationship was observed between QTc increases and SN-38 concentrations.
|PK=The serum pharmacokinetics of sacituzumab govitecan-hziy and SN-38 were evaluated in patients with mBC who received sacituzumab govitecan-hziy as a single agent at a dose of 10 mg/kg. The pharmacokinetic parameters of sacituzumab govitecan-hziy and free SN-38 are presented

'''Distribution'''

Based on population pharmacokinetic analysis, steady state volume of distribution of sacituzumab govetican-hziy is 3.6L.

'''Elimination'''

The median elimination half-life (t1/2) of sacituzumab govitecan-hziy and free SN-38 in patients with metastatic triple negative breast cancer was 23.4 and 17.6 hours, respectively. Based on population pharmacokinetic analysis, the estimated mean (%CV) clearance of the sacituzumab govitecan-hziy is 0.13 L/h (12%).

'''Metabolism'''

No metabolism studies with sacituzumab govitecan-hziy have been conducted. SN-38 (the small molecule moiety of sacituzumab govitecan-hziy) is metabolized via UGT1A1. The glucuronide metabolite of SN-38 (SN-38G) was detectable in the serum of patients.

'''Specific Populations'''

Pharmacokinetic analyses in patients treated with TRODELVY did not identify an effect of age (27 to 88 years), race (White, Black, or Asian), or mild renal impairment to moderate renal impairment (CLcr 30 to 89 mL/min) on the pharmacokinetics of sacituzumab govitecan-hziy. Renal elimination is known to contribute minimally to the excretion of SN-38, the small molecule moiety of sacituzumab govitecan-hziy. There are no data on the pharmacokinetics of sacituzumab govitecan-hziy in patients with severe renal impairment (CLcr 15 to 29 mL/min), or end-stage renal disease (CLcr < 15 mL/min).

'''Patients with Hepatic Impairment'''

The exposure of sacituzumab govitecan-hziy is similar in patients with mild hepatic impairment (total bilirubin ≤ ULN with AST > ULN, or bilirubin >1.0 to ≤ 1.5 ULN with any AST; n=257) to patients with normal hepatic function (total bilirubin and AST < ULN; n=526).

Sacituzumab govitecan-hziy and free SN-38 exposures are unknown in patients with moderate (total bilirubin > 1.5 to 3.0 × ULN) or severe (total bilirubin > 3.0 × ULN) hepatic impairment.

'''Drug Interaction Studies'''

No drug-drug interaction studies were conducted with sacituzumab govitecan-hziy or its components. Inhibitors or inducers of UGT1A1 may increase or decrease SN-38 exposure, respectively
|nonClinToxic=Carcinogenicity studies have not been conducted with sacituzumab govitecan-hziy.

SN-38 was clastogenic in an in vitro mammalian cell micronucleus test in Chinese hamster ovary cells and was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay.

Fertility studies with sacituzumab govitecan-hziy have not been conducted. In a repeat-dose toxicity study in cynomolgus monkeys, intravenous administration of sacituzumab govitecan-hziy on Day 1 and Day 4 resulted in endometrial atrophy, uterine hemorrhage, increased follicular atresia of the ovary, and atrophy of vaginal epithelial cells at doses ≥ 60 mg/kg (≥ 6 times the human recommended dose of 10 mg/kg based on body weight).
|clinicalStudies='''Locally Advanced or Metastatic Triple-Negative Breast Cancer'''
'''ASCENT'''

Efficacy was evaluated in a multicenter, open-label, randomized study (ASCENT; NCT02574455) conducted in 529 patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who had relapsed after at least two prior chemotherapies for breast cancer (one of which could be in the neoadjuvant or adjuvant setting provided progression occurred within a 12 month period). All patients received previous taxane treatment in either the adjuvant, neoadjuvant, or advanced stage unless there was a contraindication or intolerance to taxanes during or at the end of the first taxane cycle. Magnetic resonance imaging (MRI) to determine brain metastases was required prior to enrollment for patients with known or suspected brain metastases. Patients with brain metastases were allowed to enroll up to a pre-defined maximum of 15% of patients in the ASCENT study. Patients with known Gilbert's disease or bone-only disease were excluded.

Patients were randomized (1:1) to receive TRODELVY 10 mg/kg as an intravenous infusion on Days 1 and 8 of a 21-day (n=267) or physician's choice of single agent chemotherapy (n=262). Single agent chemotherapy was determined by the investigator before randomization from one of the following choices: eribulin (n=139), capecitabine (n=33), gemcitabine (n=38), or vinorelbine (n=52).

Patients were treated until disease progression or unacceptable toxicity. The major efficacy outcome was progression-free survival (PFS) in patients without brain metastases at baseline (i.e., BMNeg) as measured by a blinded, independent, centralized review assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. Additional efficacy measures included PFS for the full population (all patients with and without brain metastases) and overall survival (OS).

The median age of patients in the full population (n = 529) was 54 years (range: 27 to 82 years); 99.6% were female; 79% were White, 12% were Black/African American; and 81% of patients were < 65 years of age. All patients had an ECOG performance status of 0 (43%) or 1 (57%). Forty-two percent of patients had hepatic metastases, 9% were BRCA1/BRCA2 mutational status positive, and 70% were TNBC at diagnosis. Twelve percent had baseline brain metastases previously treated and stable (n=61; 32 on TRODELVY arm and 29 on single agent chemotherapy arm). Overall, 29% of patients had received prior PD-1/PD-L1 therapy. Thirteen percent of patients in the TRODELVY group in the full population received only 1 prior line of systemic therapy in the metastatic setting.

The efficacy results are summarized in Table 10 and are shown in Figure 1 and Figure 2. Efficacy results for the subgroup of patients who had received only 1 prior line of systemic therapy in the metastatic setting (in addition to having disease recurrence or progression within 12 months of neoadjuvant/adjuvant systemic therapy) were consistent with those who had received at least two prior lines in the metastatic setting.

An exploratory analysis of PFS in patients with previously treated, stable brain metastases showed a stratified HR of 0.65 (95% CI: 0.35, 1.22). The median PFS in the TRODELVY arm was 2.8 months (95% CI: 1.5, 3.9) and the median PFS with single agent chemotherapy was 1.6 months (95% CI: 1.3, 2.9). Exploratory OS analysis in the same population showed a stratified HR of 0.87 (95% CI: 0.47, 1.63). The median OS in the TRODELVY arm was 6.8 months (95% CI: 4.7, 14.1) and the median OS with single agent chemotherapy was 7.4 months (95% CI: 4.7, 11.1).

'''IMMU-132-01'''

The efficacy of TRODELVY was evaluated in a multicenter, single-arm, study (NCT01631552) that enrolled 108 patients with metastatic triple-negative breast cancer (mTNBC) who had received at least two prior anticancer therapies for metastatic disease. Patients with bulky disease, defined as a mass > 7 cm, were not eligible. Patients with treated brain metastases not receiving high dose steroids (> 20 mg prednisone or equivalent) for at least four weeks were eligible. Patients with known Gilbert's disease were excluded.

Patients received TRODELVY 10 mg/kg intravenously on Days 1 and 8 of a 21-day treatment cycle. Patients were treated with TRODELVY until disease progression or intolerance to the therapy. Tumor imaging was obtained every 8 weeks, with confirmatory CT/MRI scans obtained 4–6 weeks after an initial partial or complete response, until progression requiring treatment discontinuation. Major efficacy outcome measures were investigator assessed overall response rate (ORR) using RECIST 1.1 and duration of response.

The median age was 55 years (range: 31 to 80 years); 87% of patients were younger than 65 years. The majority of patients were female (99%) and White (76%). At study entry, all patients had an ECOG performance status of 0 (29%) or 1 (71%). Seventy-six percent had visceral disease, 42% had hepatic metastases, 56% had lung/pleura metastases, and 2% had brain metastases. Twelve patients (11%) had Stage IV disease at the time of initial diagnosis.

The median number of prior systemic therapies received in the metastatic setting was 3 (range: 2 to 10). Prior chemotherapies in the metastatic setting included carboplatin or cisplatin (69%), gemcitabine (55%), paclitaxel or docetaxel (53%), capecitabine (51%), eribulin (45%), doxorubicin (24%), vinorelbine (16%), cyclophosphamide (19%), and ixabepilone (8%).

Overall, 98% of patients had received prior taxanes and 86% had received prior anthracyclines either in the (neo)adjuvant or metastatic setting.

14.2 Locally Advanced or Metastatic HR-Positive, HER2-Negative Breast Cancer
TROPiCS-02 Study

The efficacy of TRODELVY was evaluated in a multicenter, open label, randomized study (TROPiCS-02; NCT03901339) conducted in 543 patients with unresectable locally advanced or metastatic HR-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH–) breast cancer whose disease has progressed after the following in any setting: a CDK 4/6 inhibitor, endocrine therapy, and a taxane; patients received at least two prior chemotherapies in the metastatic setting (one of which could be in the neoadjuvant or adjuvant setting if recurrence occurred within 12 months).

Patients were randomized (1:1) to receive TRODELVY 10 mg/kg as an intravenous infusion on Days 1 and 8 of a 21 day cycle (n=272) or single agent chemotherapy (n=271). Single agent chemotherapy was determined by the investigator before randomization from one of the following choices: eribulin (n=130), vinorelbine (n=63), gemcitabine (n=56), or capecitabine (n=22). Randomization was stratified by the following factors: prior chemotherapy regimens for metastatic disease (2 vs. 3–4), visceral metastasis (Yes or No), and endocrine therapy in the metastatic setting for at least 6 months (Yes or No).

Patients were treated until disease progression or unacceptable toxicity. Administration of TRODELVY was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. The primary efficacy outcome measure was PFS as determined by BICR per RECIST v1.1. Additional efficacy measures included OS, ORR by BICR, and DOR by BICR.

The median age of patients in the study population was 56 years (range: 27–86 years), 26% of patients were 65 years or over. The majority of patients were female (99%); 67% were White, 4% were Black and 3% were Asian, and 26% were of unknown race. Patients received a median of 7 (range: 3 to 17) prior systemic regimens in any setting and 3 (range: 0 to 8) prior systemic chemotherapy regimens in the metastatic setting. Approximately 42% of patients had 2 prior chemotherapy regimens for treatment of metastatic disease compared to 58% of patients who had 3 to 4 prior chemotherapy regimens and all patients had an ECOG performance status of 0 (45%) or 1 (55%). Ninety-five percent of patients had visceral metastases. Most patients received endocrine therapy in the metastatic setting for ≥ 6 months (86%).

TRODELVY demonstrated a statistically significant improvement in PFS and OS versus single agent chemotherapy.
|howSupplied=TRODELVY (sacituzumab govitecan-hziy) for injection is a sterile, off-white to yellowish lyophilized powder in a single-dose vial. Each TRODELVY vial is individually boxed in a carton:

*NDC 55135-132-01 contains one 180 mg vial
|storage=Store vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of reconstitution. Do not freeze.
|fdaPatientInfo='''Neutropenia'''

Advise patients of the risk of neutropenia. Instruct patients to immediately contact their healthcare provider if they experience fever, chills, or other signs of infection.

'''Diarrhea'''

Advise patients of the risk of diarrhea. Instruct patients to immediately contact their healthcare provider if they experience diarrhea for the first time during treatment; black or bloody stools; symptoms of dehydration such as lightheadedness, dizziness, or faintness; inability to take fluids by mouth due to nausea or vomiting; or inability to get diarrhea under control within 24 hours.

'''Hypersensitivity and Infusion-Related Reactions'''

Inform patients of the risk of serious infusion reactions and anaphylaxis. Instruct patients to immediately contact their healthcare provider if they experience facial, lip, tongue, or throat swelling, urticaria, difficulty breathing, lightheadedness, dizziness, chills, rigors, wheezing, pruritus, flushing, rash, hypotension, or fever that occur during or within 24 hours following the infusion.

'''Nausea/Vomiting'''

Advise patients of the risk of nausea and vomiting. Premedication according to established guidelines with a two or three drug regimen for prevention of chemotherapy-induced nausea and vomiting (CINV) is also recommended. Additional antiemetics, sedatives, and other supportive measures may also be employed as clinically indicated. All patients should receive take-home medications for preventing and treating delayed nausea and vomiting, with clear instructions. Instruct patients to immediately contact their healthcare provider if they experience uncontrolled nausea or vomiting.

'''Embryo-Fetal Toxicity'''

Advise female patients to contact their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy.

'''Contraception'''

Advise female patients of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of TRODELVY.

Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of TRODELVY .

'''Lactation'''

Advise women not to breastfeed during treatment and for 1 month after the last dose of TRODELVY.

'''Infertility'''

Advise females of reproductive potential that TRODELVY may impair fertility.
|alcohol=Alcohol-Sacituzumab govitecan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=TRODELVY
}}

Opicapone

2025-05-08T12:52:31Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=opicapone |aOrAn=a |drugClass=reversible and selectively peripheral COMT inhibition |indication=ONGENTYS is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease (PD) experiencing “off” episodes. |adverseReactions=The following clinically significant adverse reactions are discussed in more detail in other sections of the labeling: *Ca..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=opicapone
|aOrAn=a
|drugClass=reversible and selectively peripheral COMT inhibition
|indication=ONGENTYS is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease (PD) experiencing “off” episodes.
|adverseReactions=The following clinically significant adverse reactions are discussed in more detail in other sections of the labeling:

*Cardiovascular Effects with Concomitant Use of Drugs Metabolized by Catechol-O-Methyltransferase (COMT)
*Falling Asleep During Activities of Daily Living and Somnolence
*Hypotension/Syncope
Dyskinesia
Hallucinations and Psychosis
Impulse Control/Compulsive Disorders
Withdrawal-Emergent Hyperpyrexia and Confusion
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=ONGENTYS is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease (PD) experiencing “off” episodes.

The recommended dosage of ONGENTYS is 50 mg administered orally once daily at bedtime. Patients should not eat food for 1 hour before and for at least 1 hour after intake of ONGENTYS
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Opicapone in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Opicapone in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Opicapone in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Opicapone in pediatric patients.
|contraindications=ONGENTYS is contraindicated in patients with:

*Concomitant use of non-selective monoamine oxidase (MAO) inhibitors
*Pheochromocytoma, paraganglioma, or other catecholamine secreting neoplasms.
|warnings='''Cardiovascular Effects with Concomitant Use of Drugs Metabolized by Catechol-O-Methyltransferase (COMT)'''
Possible arrhythmias, increased heart rate, and excessive changes in blood pressure may occur with concomitant use of ONGENTYS and drugs metabolized by COMT (e.g., isoproterenol, epinephrine, norepinephrine, dopamine, and dobutamine), regardless of the route of administration (including inhalation). Monitor patients treated concomitantly with ONGENTYS and drugs metabolized by COMT.

'''Falling Asleep During Activities of Daily Living and Somnolence'''
Patients treated with dopaminergic medications and medications that increase levodopa exposure, including ONGENTYS, have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes has resulted in accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event.

Before initiating treatment with ONGENTYS, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with dopaminergic therapy, such as concomitant sedating medications or the presence of a sleep disorder. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), consider discontinuing ONGENTYS or adjusting other dopaminergic or sedating medications. If a decision is made to continue ONGENTYS, patients should be advised not to drive and to avoid other potentially dangerous activities.

'''Hypotension/Syncope'''
hypotension (orthostatic and non-orthostatic), syncope, and presyncope occurred in 5% of patients treated with ONGENTYS 50 mg compared to 1% of patients who received placebo. Monitor patients for hypotension (orthostatic and non-orthostatic) and advise patients about the risk for syncope and presyncope. If these adverse reactions occur, consider discontinuing ONGENTYS or adjusting the dosage of other medications that can lower blood pressure.

'''Dyskinesia'''
ONGENTYS potentiates the effects of levodopa and may cause dyskinesia or exacerbate pre-existing dyskinesia.

In controlled clinical trials (Study 1 and Study 2), dyskinesia occurred in 20% of patients treated with ONGENTYS 50 mg compared to 6% of patients who received placebo. Dyskinesia was also the most common adverse reaction leading to discontinuation of ONGENTYS.

Reducing the patient’s daily levodopa dosage or the dosage of another dopaminergic drug may mitigate dyskinesia that occurs during treatment with ONGENTYS.

'''Hallucinations and Psychosis'''
In Study 1 and Study 2, hallucinations (hallucinations, auditory hallucinations, visual hallucinations, mixed hallucinations) occurred in 3% of patients treated with ONGENTYS 50 mg compared to 1% of patients who received placebo. Delusions, agitation, or aggressive behavior occurred in 1% of patients treated with ONGENTYS 50 mg, and in no patient who received placebo. Consider stopping ONGENTYS if hallucinations or psychotic-like behaviors occur.

Patients with a major psychotic disorder should ordinarily not be treated with ONGENTYS because of the risk of exacerbating the psychosis with an increase in central dopaminergic tone. In addition, treatments for psychosis that antagonize the effects of dopaminergic medications may exacerbate the symptoms of PD.

'''Impulse Control/Compulsive Disorders'''
Patients treated with ONGENTYS can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more dopaminergic therapies that increase central dopaminergic tone. In some cases, these urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with ONGENTYS.

In Study 1 and Study 2, impulse control disorders occurred in 1% of patients treated with ONGENTYS 50 mg, and in no patient who received placebo. Re-evaluate the patient’s current therapy(ies) for Parkinson’s disease and consider stopping ONGENTYS if a patient develops such urges while taking ONGENTYS.

Use with caution in Parkinson’s patients with suspected or diagnosed dopamine dysregulation syndrome.

'''Withdrawal-Emergent Hyperpyrexia and Confusion'''
A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone. In the controlled clinical studies of ONGENTYS, patients discontinued ONGENTYS treatment without dose tapering or gradual withdrawal. There were no reports of neuroleptic malignant syndrome in ONGENTYS controlled clinical studies. When discontinuing ONGENTYS, monitor patients and consider adjustment of other dopaminergic therapies as needed.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

All patients were taking a stable dose of levodopa and a DOPA decarboxylase inhibitor, alone or in combination with other PD medications. In Study 1 and Study 2, the mean age of patients was 63.6 years, 59% of patients were male, and 89% of patients were Caucasian. At baseline, the mean duration of PD was 7.6 years.

Adverse Reactions Leading to Discontinuation of Treatment

In Study 1 and Study 2, a total of 8% of ONGENTYS 50 mg-treated patients and 6% of patients who received placebo discontinued due to adverse events. The most common adverse reaction leading to discontinuation was dyskinesia, reported in 3% of ONGENTYS 50 mg-treated patients and 0.4% of patients who received placebo.

'''Common Adverse Reactions'''

Adverse reactions that occurred in the pooled studies at an incidence of at least 2% and greater than placebo are presented in Table 1. The most common adverse reactions (incidence at least 4% and greater than placebo) were dyskinesia, constipation, blood creatine kinase increased, hypotension/syncope, and weight decreased.
|postmarketing=The following adverse reactions have been identified during postapproval use of ONGENTYS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.
|drugInteractions='''Non-Selective Monoamine Oxidase (MAO) Inhibitors'''
Both ONGENTYS and non-selective MAO inhibitors (e.g., phenelzine, isocarboxazid, and tranylcypromine) inhibit catecholamine metabolism, leading to increased levels of catecholamines. Concomitant use may increase the risk of possible arrhythmias, increased heart rate, and excessive changes in blood pressure.

Concomitant use of ONGENTYS with non-selective MAO inhibitors is contraindications. Selective MAO-B inhibitors can be used concomitantly with ONGENTYS.

'''Effect of ONGENTYS on Other Drugs'''
Drugs Metabolized by Catechol-O-Methyltransferase (COMT)

Concomitant use of ONGENTYS with drugs metabolized by COMT may affect the pharmacokinetics of those drugs, which may increase the risk of possible arrhythmias, increased heart rate, and excessive changes in blood pressure. Drugs known to be metabolized by COMT should be administered with caution. Monitor for changes in heart rate, rhythm, and blood pressure in patients concomitantly treated with ONGENTYS and drugs metabolized by COMT.
|useInLaborDelivery=There are no adequate data on the developmental risk associated with use of ONGENTYS in pregnant women. In animal studies, oral administration of opicapone during pregnancy resulted in adverse effects on embryofetal development (increased incidence of fetal abnormalities) at clinically relevant plasma exposures in one of two species tested. In addition, opicapone is always given concomitantly with levodopa/carbidopa, which is known to cause developmental toxicity in rabbits (see Data).

The background risk of major birth defects and miscarriage in the U.S. general population is 2-4% and 15-20% of clinically recognized pregnancies, respectively. The background risk for major birth defects and miscarriage in patients with Parkinson’s disease is unknown.
|useInNursing=There are no data on the presence of opicapone in human milk, the effects on the breastfed infant, or the effects on milk production. In lactating rats, oral administration of opicapone resulted in levels of opicapone or metabolites in milk similar to those in maternal plasma. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ONGENTYS and any potential adverse effects on the breastfed infant from ONGENTYS or from the underlying
|useInPed=Safety and effectiveness in pediatric patients have not been established.
|useInGeri=No dose adjustment is required for elderly patients. Of the total number of patients who received ONGENTYS 50 mg in Study 1 and Study 2, 52% of patients were 65 years and older. No overall differences in safety and effectiveness were observed between these patients and younger patients, but greater sensitivity to adverse reactions of some older individuals cannot be ruled out.
|useInRenalImpair=The renal route of elimination plays a minor role in the clearance of opicapone. Avoid use of ONGENTYS in patients with end-stage renal disease (ESRD) (CLcr <15 mL/min). No dosage adjustment is required for patients with mild, moderate, or severe renal impairment. However, because of a potential for increased exposure, monitor patients with severe renal impairment for adverse reactions and discontinue ONGENTYS if tolerability issues arise.
|useInHepaticImpair=Opicapone exposure is increased in patients with hepatic impairment. Avoid use of ONGENTYS in patients with severe (Child-Pugh C) hepatic impairment. Dosage adjustment is recommended for patients with moderate (Child-Pugh B) hepatic impairment. No dosage adjustment is required in patients with mild (Child-Pugh A) hepatic impairment.
|administration=The recommended dosage of ONGENTYS is 50 mg administered orally once daily at bedtime. Patients should not eat food for 1 hour before and for at least 1 hour after intake of ONGENTYS
|monitoring=*Monitor patients treated concomitantly with ONGENTYS and drugs metabolized by COMT
*Monitor patients for hypotension (orthostatic and non-orthostatic) and advise patients about the risk for syncope and presyncope. If these adverse reactions occur, consider discontinuing ONGENTYS or adjusting the dosage of other medications that can lower blood pressure.
*Monitor for changes in heart rate, rhythm, and blood pressure in patients concomitantly treated with ONGENTYS and drugs metabolized by COMT
*monitor patients with severe renal impairment for adverse reactions and discontinue ONGENTYS if tolerability issues arise.
*monitoring, and consider the possibility of multiple drug involvement. If an over-exposure occurs, call your poison control center at 1-800-222-1222 or www.poison.org.
|overdose=No specific antidotes for ONGENTYS are known. As a general measure, removal of ONGENTYS by gastric lavage and/or inactivation by administering activated charcoal should be considered. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. If an over-exposure occurs, call your poison control center at 1-800-222-1222 or www.poison.org.
|mechAction=Opicapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT).

COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include DOPA, catecholamines (dopamine, norepinephrine, and epinephrine), and their hydroxylated metabolites. When decarboxylation of levodopa is prevented by carbidopa, COMT becomes the major metabolizing enzyme for levodopa, catalyzing its metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD).
|PD='''COMT Activity'''

Once-daily administration of ONGENTYS 50 mg caused inhibition of COMT activity in erythrocytes; the maximal inhibition seen was 84% and was maintained >65% over a 24-hour dosing interval in patients with Parkinson’s disease. Following termination of treatment, COMT inhibition slowly returns to baseline levels, with >35% inhibition still observed 5 days after the last dose.

'''Effects on Levodopa'''

Peak (Cmax) and overall levodopa exposure (AUC) increased by 43-44% and 62-94%, respectively, in PD patients following once-daily administration of ONGENTYS at bedtime with levodopa/carbidopa administered every three or every four hours, as compared to after administration of levodopa/carbidopa alone.

'''Cardiac Electrophysiology'''

At a dose 16 times the recommended dosage, ONGENTYS does not prolong the QT interval to any clinically relevant extent.
|PK=Opicapone demonstrates dose-proportional pharmacokinetics over a 25 mg (0.5 times the recommended dosage) to 50 mg dose range. The pharmacokinetics of opicapone are similar in both PD patients and healthy subjects.

'''Absorption'''

After single-dose administration of ONGENTYS 50 mg, the median (range) plasma Tmax value was 2.0 (1.0-4.0) hours.

'''Effect of Food'''

Following a moderate fat/moderate calorie meal, the mean peak plasma concentration (Cmax) for opicapone decreased 62%, the mean overall plasma exposure (AUC) decreased 31%, and the Tmax was delayed by 4 hours. In Study 1, ONGENTYS was administered without regard to food. In Study 2, ONGENTYS administration and food consumption were separated by 1 hour.

'''Distribution'''

Opicapone is highly bound to plasma proteins (>99%), which is independent of concentration.

'''Elimination'''

The mean elimination half-life of opicapone is 1 to 2 hours.

'''Metabolism'''

Sulphation is the primary metabolic pathway of opicapone, based on clinical studies and in vitro assessments. Other metabolic pathways include glucuronidation, methylation (by COMT), reduction, and glutathione conjugation.

'''Excretion'''

After administration of a single dose of radiolabeled opicapone 100 mg (2 times the recommended dosage) to healthy subjects, approximately 70% of the dose was recovered in feces (22% as unchanged), 20% in expired air, and 5% in urine (<1% as unchanged).

'''Specific Populations'''

No clinically significant differences in the pharmacokinetics of opicapone were observed based on age (i.e., 18 to 40 years of age and ≥ 65 years of age), sex, or race/ethnicity (i.e., Japanese, Caucasian, Asian, and Black).

''Renal Impairment''

Based on population pharmacokinetic analyses, no clinically significant differences in the pharmacokinetics of opicapone were observed in patients with mild or moderate renal impairment (CLcr 30-89 mL/min using the Cockcroft-Gault equation) relative to those with normal renal function (CLcr >90 mL/min). Patients with severe renal impairment or ESRD (CLcr <30 mL/min) have not been studied .

'''Hepatic Impairment'''

The single-dose pharmacokinetics of opicapone was evaluated in subjects with mild (Child-Pugh: A) and moderate (Child-Pugh: B) hepatic impairment. In subjects with mild hepatic impairment, the mean overall opicapone plasma exposure (AUC) increased by 35%, which is not expected to be clinically significant. In subjects with moderate hepatic impairment, the mean overall opicapone plasma exposure (AUC) increased by 84%. Dosage adjustment for ONGENTYS is required in subjects with moderate hepatic impairment [see Dosage and Administration (2.2)]. ONGENTYS has not been studied in patients with severe hepatic impairment (Child-Pugh: C).

'''Drug Interaction Studies'''

''Clinical Studies''

No clinically significant differences in the pharmacokinetics of opicapone were observed when administered concomitantly with quinidine (index substrate of P-gp [MDR1]), acetaminophen, or rasagiline.

No clinically significant differences in the pharmacokinetics of the following drugs were observed when administered concomitantly with opicapone: S-warfarin (index substrate of CYP2C9), R-Warfarin (substrate of CYP1A2 and CYP3A4), or repaglinide (index substrate of CYP2C8 and OATP1B1).

No clinically significant differences in the pharmacokinetics of the following drugs for the treatment of Parkinson’s disease were observed when administered concomitantly with opicapone: rasagiline, selegiline, pramipexole, ropinirole, or amantadine.

''In Vitro Studies''

Opicapone does not affect protein binding of warfarin, diazepam, digoxin, or tolbutamide, in vitro.

CYP Enzymes: Opicapone is not an inhibitor or inducer of major CYPs.

Transporter Systems: Opicapone is a substrate of P-gp (MDR1) (see Clinical Studies), BCRP, MRP2, OATP1B3, and OATP2B1. No clinically significant transporter mediated interaction is expected for opicapone. Opicapone is not an inhibitor of P-gp (MDR1), BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B3, BSEP, MATE1, or MATE2-K.
|nonClinToxic='''Carcinogenesis'''

No increase in tumors was observed when opicapone was administered orally to mice (0, 100, 375, or 750 mg/kg/day) for up to 2 years (84-93 weeks at the high dose). The highest dose tested is approximately 70 times the recommended dose (RHD) in humans (50 mg/day) on a body surface area (mg/m2) basis.

No increase in tumors was observed when opicapone was administered orally to rats (0, 100, 500, or 1000 mg/kg/day) for 2 years. Plasma exposure (AUC) at the highest dose tested is approximately 24 times that in humans at the RHD (50 mg/day).

'''Mutagenesis'''

Opicapone was negative in in vitro (bacterial reverse mutation test (Ames), chromosomal aberrations in human peripheral blood lymphocytes) and in in vivo (rat bone marrow micronucleus) assays.

'''Impairment of Fertility'''

In male and female rats, oral administration of opicapone (0, 100, 500, or 1000 mg/kg/day) prior to and during mating and continuing in females to gestation day 6, resulted in no adverse effects on fertility or general reproductive performance. Plasma exposure (AUC) at the highest dose tested is approximately 40 times that in humans at the RHD.

The efficacy of ONGENTYS for the adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease (PD) experiencing “off” episodes was evaluated in two double-blind, randomized, parallel-group, placebo- and active-controlled (Study 1, NCT01568073), or placebo-controlled (Study 2, NCT01227655) studies of 14-15 week duration. All patients were treated with levodopa/ DOPA decarboxylase inhibitor (DDCI) (alone or in combination with other PD medications). The double-blind period for each study began with a period for levodopa/DDCI dose adjustment (up to 3 weeks), followed by a stable maintenance period of 12 weeks.
|clinicalStudies=Study 1

In Study 1, patients (n=600) were randomized to treatment with one of 3 doses of ONGENTYS. The intention to treat (ITT) population included patients treated with ONGENTYS 50 mg once daily (n=115) or placebo (n=120). Baseline demographic characteristics were similar across all treatment groups: approximately 60% of patients were male, mean age was 64 years, and all patients were Caucasian. Baseline PD characteristics in the treatment groups were: mean duration of PD of 7 years for ONGENTYS 50 mg compared to 7.7 years for placebo, and mean onset of motor fluctuations of 2.2 years prior to study enrollment. Eighty-two percent of patients in both groups used concomitant PD medications in addition to levodopa; the most commonly used were dopamine agonists (68%), amantadine (23%), MAO-B inhibitors (20%), and anticholinergics (5%).

The primary efficacy endpoint was the change in mean absolute OFF-time based on 24-hour patient diaries completed 3 days prior to each of the scheduled visits. ONGENTYS 50 mg significantly reduced mean absolute OFF-time compared to placebo.

Study 2

In Study 2, patients (n=427) were randomized to treatment with either one of two doses of ONGENTYS once daily (n=283) or placebo (n=144). The intention to treat (ITT) study population included patients treated with ONGENTYS 50 mg once daily (n=147) or placebo (n=135). Baseline demographic characteristics (ONGENTYS 50 mg vs. placebo) were: mean age (66 years vs. 62 years), male (61% vs. 53%), Caucasian (78% vs. 66%) and Asian (21% vs. 31%). Baseline PD characteristics were generally similar across treatment groups with a mean duration of PD of 8.2 years, and a mean onset of motor fluctuations of 3.2 years prior to study enrollment. Eighty-five percent of patients treated with ONGENTYS 50 mg compared to 81% of patients who received placebo used concomitant PD medications in addition to levodopa; the most commonly used were dopamine agonists (70%), amantadine (21%), MAO-B inhibitors (20%), and anticholinergics (12%).

The primary efficacy endpoint was the change in mean absolute OFF-time based on 24-hour patient diaries completed 3 days prior to each of the scheduled visits. ONGENTYS 50 mg significantly reduced mean absolute OFF-time compared to placebo.
|howSupplied=ONGENTYS (opicapone) capsules are available as:

*50 mg hard gelatin capsules, Size 1; dark blue opaque cap and dark pink opaque body; axially printed with “OPC” over “50” in white ink, on both the cap and body

*Bottle of 30 with child-resistant closure: NDC 64896-403-01

* 25 mg hard gelatin capsules, Size 1; light blue opaque cap and light pink opaque body; axially printed with “OPC” over “25” in blue ink, on both the cap and body
|storage=Store at a temperature below 30°C (86°F).
|fdaPatientInfo=Advise the patient to read the FDA-approved patient labeling (Patient Information).

Administration

Instruct patients and/or caregivers that ONGENTYS capsules should be taken at bedtime. Inform patients to not eat food for 1 hour before and for at least 1 hour after intake of ONGENTYS [see Dosage and Administration (2.1)].

Concomitant Medications

Certain medications can cause an interaction with ONGENTYS. Advise patients and/or caregivers to inform their healthcare provider of all the medicines the patient is taking, including over-the-counter medicines, dietary supplements, and herbal products [see Warnings and Precautions (5.1) and Drug Interactions (7)].
'''Falling Asleep During Activities of Daily Living'''

Advise patients and/or caregivers that somnolence has been reported with ONGENTYS. Patients treated with dopaminergic medications have reported falling asleep while engaged in activities of daily living. These adverse reactions may affect some patients’ ability to drive and operate machinery safely.

'''Hypotension/Syncope'''

Advise patients that ONGENTYS may cause hypotension or syncope.

'''Dyskinesia'''

Advise patients that ONGENTYS may cause dyskinesia or exacerbate pre-existing dyskinesia.

'''Hallucinations and Psychosis'''

Advise patients that ONGENTYS may cause hallucinations, delusions, or aggressive behavior and they should report any of these adverse reactions to their healthcare provider.

'''Impulse Control/Compulsive Disorders'''

Inform patients of the potential for experiencing intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and other intense urges and the inability to control these urges while taking ONGENTYS and one or more medications that increase central dopaminergic tone that are generally used for the treatment of PD. Advise patients that they should report any of these adverse reactions to their healthcare provider.

'''Withdrawal-Emergent Hyperpyrexia and Confusion'''

Advise patients to contact their healthcare provider before stopping ONGENTYS. Tell patients to inform their healthcare provider if they develop symptoms such as fever, confusion, or severe muscle stiffness after stopping ONGENTYS .
|alcohol=Alcohol-Opicapone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=ONGENTYS
}}

Capmatinib

2025-05-08T12:28:14Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=capmatinib |aOrAn=a |drugClass=kinase inhibitor targeting c-Met receptor tyrosine kinase |indicationType=treatment |indication=of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test. |adverseReactions=The following clinically signific..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=capmatinib
|aOrAn=a
|drugClass=kinase inhibitor targeting c-Met receptor tyrosine kinase
|indicationType=treatment
|indication=of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test.
|adverseReactions=The following clinically significant adverse reactions are described elsewhere in the labeling:

*ILD/Pneumonitis
*Hepatotoxicity
*Pancreatic Toxicity
*Hypersensitivity reactions
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=The recommended dosage of TABRECTA is 400 mg orally twice daily with or without food.

Swallow TABRECTA tablets whole. Do not break, crush or chew the tablets.

If a patient misses or vomits a dose, instruct the patient not to make up the dose, but to take the next dose at its scheduled time.

Tablets:

*150 mg: pale orange brown, ovaloid, curved film-coated with beveled edges, unscored, debossed with ‘DU’ on one side and ‘NVR’ on the other side
*200 mg: yellow, ovaloid, curved film-coated with beveled edges, unscored, debossed with ‘LO’ on one side and ‘NVR’ on the other side
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Capmatinib in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Capmatinib in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Capmatinib in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Capmatinib in pediatric patients.
|contraindications=None
|warnings='''Interstitial Lung Disease (ILD)/Pneumonitis'''
ILD/pneumonitis, which can be fatal, occurred in patients treated with TABRECTA [see Adverse Reactions (6.1)]. ILD/pneumonitis occurred in 4.8% of patients treated with TABRECTA in GEOMETRY mono-1, with 1.9% of patients experiencing Grade 3 ILD/pneumonitis and one patient experiencing death (0.3%). Nine patients (2.4%) discontinued TABRECTA due to ILD/pneumonitis. The median time-to-onset of Grade 3 or higher ILD/pneumonitis was 1.8 months (range: 0.2 months to 1.7 years).

Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold TABRECTA in patients with suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified [see Dosage and Administration (2.3)].

'''Hepatotoxicity'''
Hepatotoxicity occurred in patients treated with TABRECTA [see Adverse Reactions (6.1)]. Increased alanine aminotransferase (ALT)/aspartate aminotransferase (AST) occurred in 15% of patients treated with TABRECTA in GEOMETRY mono-1. Grade 3 or 4 increased ALT/AST occurred in 7% of patients. Three patients (0.8%) discontinued TABRECTA due to increased ALT/AST. The median time-to-onset of Grade 3 or higher increased ALT/AST was 1.8 months (range: 0.5 to 46.4 months).

Monitor liver function tests (including ALT, AST, and total bilirubin) prior to the start of TABRECTA, every 2 weeks during the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop increased transaminases or bilirubin. Based on the severity of the adverse reaction, withhold, dose reduce, or permanently discontinue TABRECA.

'''Pancreatic Toxicity'''
Elevations in amylase and lipase levels occurred in patients treated with TABRECTA . Increased amylase/lipase occurred in 14% of patients treated with TABRECTA in GEOMETRY mono-1. Grade 3 and 4 increased amylase/lipase occurred in 7% and 1.9% of patients, respectively. Three patients (0.8%) discontinued TABRECTA due to increased amylase/lipase. The median time-to-onset of Grade 3 or higher increased amylase/lipase was 2 months (range: 0.03 to 31.1 months). Pancreatitis (Grade 3) occurred in one patient (0.3%); TABRECTA was permanently discontinued for this event.

Monitor amylase and lipase at baseline and regularly during treatment with TABRECTA. Based on the severity of the adverse reaction, temporarily withhold, dose reduce, or permanently discontinue TABRECTA .

'''Hypersensitivity Reactions'''
Serious hypersensitivity reactions occurred in patients treated with TABRECTA in clinical trials other than GEOMETRY mono-1 [see Adverse Reactions (6.1)]. Signs and symptoms of hypersensitivity included pyrexia, chills, pruritus, rash, decreased blood pressure, nausea and vomiting. Based on the severity of the adverse reaction, temporarily withhold or permanently discontinue TABRECTA.

'''Risk of Photosensitivity'''
Based on findings from animal studies, there is a potential risk of photosensitivity reactions with TABRECTA. In GEOMETRY mono-1, it was recommended that patients use precautionary measures against ultraviolet exposure such as use of sunscreen or protective clothing during treatment with TABRECTA. Advise patients to limit direct ultraviolet exposure during treatment with TABRECTA.

'''Embryo-Fetal Toxicity'''
Based on findings from animal studies and its mechanism of action, TABRECTA can cause fetal harm when administered to a pregnant woman. Oral administration of capmatinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at exposures less than the human exposure based on area under the curve (AUC) at the 400 mg twice daily clinical dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TABRECTA and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with TABRECTA and for 1 week after the last dose.
|clinicalTrials='''Metastatic Non-Small Cell Lung Cancer'''

The safety of TABRECTA was evaluated in GEOMETRY mono-1. Patients received TABRECTA 400 mg orally twice daily until disease progression or unacceptable toxicity (N = 373). Among patients who received TABRECTA, 37% were exposed for at least 6 months and 22% were exposed for at least one year.

Serious adverse reactions occurred in 53% of patients who received TABRECTA. Serious adverse reactions in ≥ 2% of patients included dyspnea (7%), pneumonia (7%), pleural effusion (4.3%), musculoskeletal pain (3.8%), general physical health deterioration (2.9%), ILD/pneumonitis (2.7%), edema (2.4%), and vomiting (2.4%). Fatal adverse reactions occurred in 0.5% of patients who received TABRECTA, including pneumonitis (0.3%) and death, not otherwise specified (0.3%).

Permanent discontinuation of TABRECTA due to an adverse reaction occurred in 17% of patients. The most frequent adverse reactions (≥ 1%) leading to permanent discontinuation of TABRECTA were ILD/pneumonitis (2.4%), edema (2.4%), fatigue (1.3%), and pneumonia (1.1%).

Dose interruptions due to an adverse reaction occurred in 57% of patients who received TABRECTA. Adverse reactions requiring dosage interruption in > 2% of patients who received TABRECTA included edema, increased blood creatinine, nausea, increased lipase, vomiting, increased ALT, dyspnea, pneumonia, fatigue, increased amylase, increased AST, musculoskeletal pain, abdominal pain, and increased blood bilirubin.

Dose reductions due to an adverse reaction occurred in 26% of patients who received TABRECTA. Adverse reactions requiring dosage reductions in > 2% of patients who received TABRECTA included edema, increased ALT and increased blood creatinine.

The most common adverse reactions (≥ 20%) in patients who received TABRECTA were edema, nausea, musculoskeletal pain, fatigue, vomiting, dyspnea, cough, and decreased appetite.
|drugInteractions='''Effect of Other Drugs on TABRECTA'''
''Strong CYP3A Inhibitors''

Coadministration of TABRECTA with a strong CYP3A inhibitor increased capmatinib exposure, which may increase the incidence and severity of adverse reactions of TABRECTA [see Clinical Pharmacology (12.3)]. Closely monitor patients for adverse reactions during coadministration of TABRECTA with strong CYP3A inhibitors.

''Strong and Moderate CYP3A Inducers''

Coadministration of TABRECTA with a strong CYP3A inducer decreased capmatinib exposure. Coadministration of TABRECTA with a moderate CYP3A inducer may also decrease capmatinib exposure. Decreases in capmatinib exposure may decrease TABRECTA anti-tumor activity. Avoid coadministration of TABRECTA with strong and moderate CYP3A inducers.

'''Effect of TABRECTA on Other Drugs'''
''CYP1A2 Substrates''

Coadministration of TABRECTA increased the exposure of a CYP1A2 substrate, which may increase the adverse reactions of these substrates . If coadministration is unavoidable between TABRECTA and CYP1A2 substrates where minimal concentration changes may lead to serious adverse reactions, decrease the CYP1A2 substrate dosage in accordance with the approved prescribing information.

P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) Substrates

Coadministration of TABRECTA increased the exposure of a P-gp substrate and a BCRP substrate, which may increase the adverse reactions of these substrates. If coadministration is unavoidable between TABRECTA and P-gp or BCRP substrates where minimal concentration changes may lead to serious adverse reactions, decrease the P-gp or BCRP substrate dosage in accordance with the approved prescribing information.

'''MATE1 and MATE2K Substrates'''

Coadministration of TABRECTA may increase the exposure of MATE1 and MATE2K substrates, which may increase the adverse reactions of these substrates. If coadministration is unavoidable between TABRECTA and MATE1 or MATE2K substrates where minimal concentration changes may lead to serious adverse reactions, decrease the MATE1 or MATE2K substrate dosage in accordance with the approved prescribing information.
|useInLaborDelivery=Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], TABRECTA can cause fetal harm when administered to a pregnant woman. There are no available data on TABRECTA use in pregnant women. Oral administration of capmatinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at maternal exposures less than the human exposure based on AUC at the 400 mg twice daily clinical dose (see Data). Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
|useInNursing=There are no data on the presence of capmatinib or its metabolites in either human or animal milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with TABRECTA and for 1 week after the last dose.
|useInPed=Safety and effectiveness of TABRECTA in pediatric patients have not been established.
|useInGeri=In GEOMETRY mono-1, 61% of the 373 patients were 65 years or older and 18% were 75 years or older. No overall differences in the safety or effectiveness were observed between these patients and younger patients.
|useInGender=Based on animal data, TABRECTA can cause malformations at doses less than the human exposure based on AUC at the 400 mg twice daily clinical dose [see Use in Specific Populations (8.1)].

'''Pregnancy Testing'''

Verify pregnancy status for females of reproductive potential prior to starting treatment with TABRECTA.

'''Contraception'''

''Females''

Advise females of reproductive potential to use effective contraception during treatment with TABRECTA and for 1 week after the last dose.

''Males''

Advise males with female partners of reproductive potential to use effective contraception during treatment with TABRECTA and for 1 week after the last dose.
|useInRenalImpair=No dosage adjustment is recommended in patients with mild (baseline creatinine clearance [CLcr] 60 to 89 mL/min by Cockcroft-Gault) or moderate renal impairment (CLcr 30 to 59 mL/min) [see Clinical Pharmacology (12.3)]. TABRECTA has not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min).
|administration=The recommended dosage of TABRECTA is 400 mg orally twice daily with or without food.

Swallow TABRECTA tablets whole. Do not break, crush or chew the tablets.

If a patient misses or vomits a dose, instruct the patient not to make up the dose, but to take the next dose at its scheduled time.
|monitoring=Monitor for new or worsening pulmonary symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold TABRECTA in patients with suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified

Monitor liver function tests (including ALT, AST, and total bilirubin) prior to the start of TABRECTA, every 2 weeks during the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop increased transaminases or bilirubin. Based on the severity of the adverse reaction, withhold, dose reduce, or permanently discontinue TABRECTA.

Monitor amylase and lipase at baseline and regularly during treatment with TABRECTA. Based on the severity of the adverse reaction, temporarily withhold, dose reduce, or permanently discontinue TABRECTA
|mechAction=Capmatinib is a kinase inhibitor that targets MET, including the mutant variant produced by exon 14 skipping. MET exon 14 skipping results in a protein with a missing regulatory domain that reduces its negative regulation leading to increased downstream MET signaling. Capmatinib inhibited cancer cell growth driven by a mutant MET variant lacking exon 14 at clinically achievable concentrations and demonstrated anti-tumor activity in murine tumor xenograft models derived from human lung tumors with either a mutation leading to MET exon 14 skipping or MET amplification. Capmatinib inhibited the phosphorylation of MET triggered by binding of hepatocyte growth factor or by MET amplification, as well as MET-mediated phosphorylation of downstream signaling proteins and proliferation and survival of MET-dependent cancer cells.
|PD='''Exposure-Response'''

Capmatinib exposure-response relationships and the time course of pharmacodynamics response are unknown.

'''Cardiac Electrophysiology'''

No large mean increase in QTc (i.e. > 20 ms) was detected following treatment with TABRECTA at the recommended dosage of 400 mg orally twice daily.
|PK=Capmatinib exposure (AUC0-12h and Cmax) increased approximately proportionally over a dose range of 200 mg (0.5 times the recommended dosage) to 400 mg. Capmatinib reached steady-state by day 3 following twice daily dosing, with a mean (% coefficient of variation [%CV]) accumulation ratio of 1.5 (41%).

'''Absorption'''

After administration of TABRECTA 400 mg orally in patients with cancer, capmatinib peak plasma concentrations (Cmax) were reached in approximately 1 to 2 hours (Tmax). The absorption of capmatinib after oral administration is estimated to be greater than 70%.

'''Effect of Food'''

A high-fat meal (containing approximately 1000 calories and 50% fat) in healthy subjects increased capmatinib AUC0-INF by 46% with no change in Cmax compared to under fasted conditions. A low-fat meal (containing approximately 300 calories and 20% fat) in healthy subjects had no clinically meaningful effect on capmatinib exposure. When capmatinib was administered at 400 mg orally twice daily in cancer patients, exposure (AUC0-12h) was similar after administration of capmatinib with food and under fasted conditions.

'''Distribution'''

Capmatinib plasma protein binding is 96%, independent of capmatinib concentration. The apparent mean volume of distribution at steady-state is 164 L.

The blood-to-plasma ratio was 1.5, but decreased at higher concentrations to 0.9.

'''Elimination'''

The effective elimination half-life of capmatinib is 6.5 hours. The mean (%CV) steady-state apparent clearance of capmatinib is 24 L/hr (82%).

'''Metabolism'''

Capmatinib is primarily metabolized by CYP3A4 and aldehyde oxidase.

'''Excretion'''

Following a single oral administration of radiolabeled-capmatinib to healthy subjects, 78% of the total radioactivity was recovered in feces with 42% as unchanged and 22% was recovered in urine with negligible as unchanged.

'''Specific Populations'''

No clinically significant effects on the pharmacokinetic parameters of capmatinib were identified for the following covariates assessed: age (26 to 90 years), sex, race (White, Asian, Native American, Black, unknown), body weight (35 to 131 kg), mild to moderate renal impairment (baseline CLcr 30 to 89 mL/min by Cockcroft-Gault) and mild, moderate or severe hepatic impairment (Child-Pugh classification). The effect of severe renal impairment (baseline CLcr 15 to 29 mL/min) on capmatinib pharmacokinetics has not been studied.

'''Drug Interaction Studies'''

'''Clinical Studies and Model-Informed Approaches'''

Strong CYP3A Inhibitors: Coadministration with itraconazole (a strong CYP3A inhibitor) increased capmatinib AUC0-INF by 42% with no change in capmatinib Cmax.

Strong CYP3A Inducers: Coadministration with rifampicin (a strong CYP3A inducer) decreased capmatinib AUC0-INF by 67% and decreased Cmax by 56%.

Moderate CYP3A Inducers: Coadministration with efavirenz (a moderate CYP3A inducer) was predicted to decrease capmatinib AUC0-12h by 44% and decrease Cmax by 34%.

Proton Pump Inhibitors: Coadministration with rabeprazole (a proton pump inhibitor) decreased capmatinib AUC0-INF by 25% and decreased Cmax by 38%.

Substrates of CYP Enzymes: Coadministration of capmatinib increased caffeine (a CYP1A2 substrate) AUC0-INF by 134% with no change in its Cmax. Coadministration of capmatinib had no clinically meaningful effect on exposure of midazolam (a CYP3A substrate).

P-gp Substrates: Coadministration of capmatinib increased digoxin (a P-gp substrate) AUC0-INF by 47% and increased Cmax by 74%.

BCRP Substrates: Coadministration of capmatinib increased rosuvastatin (a BCRP substrate) AUC0-INF by 108% and increased Cmax by 204%.

'''In Vitro Studies'''

Transporter Systems: Capmatinib is a substrate of P-gp, but not a substrate of BCRP or MRP2. Capmatinib reversibly inhibits MATE1 and MATE2K, but does not inhibit OATP1B1, OATP1B3, OCT1, OAT1, OAT3, or MRP2.
|nonClinToxic='''Carcinogenesis, Mutagenesis, Impairment of Fertility'''
Carcinogenicity studies were not conducted with capmatinib. Capmatinib was not mutagenic in an in vitro bacterial reverse mutation assay and did not cause chromosomal aberrations in an in vitro chromosome aberration assay in human peripheral blood lymphocytes. Capmatinib was not clastogenic in an in vivo bone marrow micronucleus test in rats.

Dedicated fertility studies were not conducted with capmatinib. No effects on male and female reproductive organs occurred in general toxicology studies conducted in rats and monkeys at doses resulting in exposures of up to approximately 3.6 times the human exposure based on AUC at the 400 mg twice daily clinical dose.

'''Animal Toxicology and/or Pharmacology'''
In rats, capmatinib administration resulted in vacuolation of white matter of the brain in both 4- and 13-week studies at doses ≥ 2.2 times the human exposure (AUC) at the 400 mg twice daily clinical dose. In some cases, the brain lesions were associated with early death and/or convulsions or tremors. Concentrations of capmatinib in the brain tissue of rats was approximately 9% of the corresponding concentrations in plasma.

In vitro and in vivo assays demonstrated that capmatinib has some potential for photosensitization; however, the no-observed-adverse-effect level for in vivo photosensitization was 30 mg/kg/day (Cmax of 14000 ng/mL), about 2.9 times the human Cmax at the 400 mg twice daily clinical dose.
|clinicalStudies='''Metastatic NSCLC with a Mutation that Leads to MET Exon 14 Skipping'''

The efficacy of TABRECTA was evaluated in GEOMETRY mono-1, a multicenter, non-randomized, open-label, multi-cohort study (NCT02414139). Eligible patients were required to have NSCLC with a mutation that leads to MET exon 14 skipping, epidermal growth factor receptor (EGFR) wild-type and anaplastic lymphoma kinase (ALK) negative status, and at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients with symptomatic CNS metastases, clinically significant uncontrolled cardiac disease, or who received treatment with any MET or hepatocyte growth factor (HGF) inhibitor were not eligible for the study.

Out of the first 97 patients enrolled in GEOMETRY mono-1 following the central confirmation of MET exon 14 skipping by a RNA-based clinical trial assay, 78 patient samples were retested with the FDA-approved FoundationOne® CDx (22 treatment-naïve and 56 previously treated patients) to detect mutations that lead to MET exon 14 skipping. Out of 78 samples retested with FoundationOne® CDx, 73 samples were evaluable (20 treatment-naïve and 53 previously treated patients), 72 (20 treatment-naïve and 52 previously treated patients) of which were confirmed to have a mutation that leads to MET exon 14 skipping, demonstrating an estimated positive percentage agreement of 99% (72/73) between the clinical trial assay and the FDA-approved assay.

Patients received TABRECTA 400 mg orally twice daily until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall response rate (ORR) as determined by a Blinded Independent Review Committee (BIRC) according to RECIST 1.1. An additional efficacy outcome measure was duration of response (DOR) by BIRC.

The efficacy population included 60 treatment-naïve patients and 100 previously treated patients. The median age was 71 years (range: 48 to 90 years); 61% female; 77% White; 25% had Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 and 74% had ECOG PS 1; 61% never smoked; 83% had adenocarcinoma; and 16% had CNS metastases. Among previously treated patients, 81% received one, 16% received two and 3% received three prior lines of systemic therapy. Amongst previously treated patients, 86% received prior platinum-based chemotherapy.
|howSupplied=150 mg: Pale orange brown, ovaloid, curved film-coated tablet with beveled edges, unscored, debossed with ‘DU’ on one side and ‘NVR’ on the other side: 56 Tablets per bottle

200 mg;Yellow, ovaloid, curved film-coated tablet with beveled edges, unscored, debossed with ‘LO’ on one side and ‘NVR’ on the other side.; 56 tablets per bottle.
|storage=Dispense in the original package with the desiccant cartridge. Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Protect from moisture.

Discard any unused TABRECTA remaining after 6 weeks of first opening the bottle.
|fdaPatientInfo='''Interstitial Lung Disease (ILD)/Pneumonitis'''

Inform patients of the risks of severe or fatal ILD/pneumonitis. Advise patients to immediately contact their healthcare provider for new or worsening respiratory symptoms .

'''Hepatotoxicity'''

Inform patients that they will need to undergo lab tests to monitor liver function. Advise patients to immediately contact their healthcare provider for signs and symptoms of liver dysfunction.

'''Pancreatic Toxicity'''

Inform patients that they will need to undergo lab tests to monitor pancreatic function. Advise patients to immediately contact their healthcare provider for signs and symptoms of pancreatitis.

'''Hypersensitivity Reactions'''

Inform patients that there is a risk of hypersensitivity reactions with TABRECTA. Advise patients to stop taking TABRECTA and immediately contact their healthcare provider for signs and symptoms of hypersensitivity.

'''Risk of Photosensitivity'''

Inform patients that there is a potential risk of photosensitivity reactions with TABRECTA. Advise patients to limit direct ultraviolet exposure by using sunscreen or protective clothing during treatment with TABRECTA .

'''Embryo-Fetal Toxicity'''

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6), Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment with TABRECTA and for 1 week after the last dose [see Use in Specific Populations (8.3)].

Advise males with female partners of reproductive potential to use effective contraception during treatment with TABRECTA and for 1 week after the last dose.

'''Drug Interactions'''

Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products.

'''Lactation'''

Advise women not to breastfeed during treatment with TABRECTA and for 1 week after the last dose
|alcohol=Alcohol-Capmatinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=TABRECTA
}}

Selpercatinib

2025-05-08T11:40:23Z

Alara E. Dagsali:

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=selerpcatinib
|aOrAn=a
|drugClass=kinase inhibitor with enhanced specificity for RET tyrosine kinase receptors (RTKs)
|indication='''RET Fusion-Positive Non-Small Cell Lung Cancer'''
RETEVMO® is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a rearranged during transfection (RET) gene fusion, as detected by an FDA-approved test.

'''RET-Mutant Medullary Thyroid Cancer'''
RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation, as detected by an FDA-approved test, who require systemic therapy.

'''RET Fusion-Positive Thyroid Cancer'''
RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).

'''Other RET Fusion-Positive Solid Tumors'''
RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with locally advanced or metastatic solid tumors with a RET gene fusion, as detected by an FDA-approved test, that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
|adverseReactions=*Hepatotoxicity
*Interstitial Lung Disease / Pneumonitis
*Hypertension
*QT Interval Prolongation
*Hemorrhagic Events
*Hypersensitivity
*Tumor Lysis Syndrome
*Risk of Impaired Wound Healing
*Hypothyroidism
*Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Adolescent Patients
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult='''RET Fusion-Positive Non-Small Cell Lung Cancer'''
RETEVMO® is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a rearranged during transfection (RET) gene fusion, as detected by an FDA-approved test.

'''RET-Mutant Medullary Thyroid Cancer'''
RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation, as detected by an FDA-approved test, who require systemic therapy.

'''RET Fusion-Positive Thyroid Cancer'''
RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).

'''Other RET Fusion-Positive Solid Tumors'''
RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with locally advanced or metastatic solid tumors with a RET gene fusion, as detected by an FDA-approved test, that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

'''DOSAGE'''
Adult and adolescent patients 12 years of age or older based on body weight:

*Less than 50 kg: 120 mg twice daily
*50 kg or greater: 160 mg twice daily
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Selpercatinib in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Selpercatinib in adult patients.
|fdaLIADPed=Pediatric patients 2 to less than 12 years of age based on body surface area:
*0.33 to 0.65 m2: 40 mg three times daily
*0.66 to 1.08 m2: 80 mg twice daily
*1.09 to 1.52 m2: 120 mg twice daily
*≥1.53 m2: 160 mg twice daily
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Selpercatinib in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Selpercatinib in pediatric patients.
|contraindications=None
|warnings='''Hepatotoxicity'''
Serious hepatic adverse reactions occurred in 3% of patients treated with RETEVMO. Increased AST occurred in 59% of patients, including Grade 3 or 4 events in 11% and increased ALT occurred in 55% of patients, including Grade 3 or 4 events in 12%. The median time to first onset for increased AST was 6 weeks (range: 1 day to 3.4 years) and increased ALT was 5.8 weeks (range: 1 day to 2.5 years).

Monitor ALT and AST prior to initiating RETEVMO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce the dose or permanently discontinue RETEVMO based on the severity.

'''Interstitial Lung Disease/Pneumonitis'''
Severe, life-threatening, and fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with RETEVMO. ILD/pneumonitis occurred in 1.8% of patients who received RETEVMO, including 0.3% with Grade 3 or 4 events, and 0.3% with fatal reactions.

Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Withhold RETEVMO and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Withhold, reduce the dose or permanently discontinue RETEVMO based on severity of confirmed ILD.

'''Hypertension'''
Hypertension occurred in 41% of patients, including Grade 3 hypertension in 20% and Grade 4 in one (0.1%) patient [see Adverse Reactions (6.1)]. Overall, 6.3% had their dose interrupted and 1.3% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications.

Do not initiate RETEVMO in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating RETEVMO. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce the dose, or permanently discontinue RETEVMO based on the severity.

'''QT Interval Prolongation'''
RETEVMO can cause concentration-dependent QT interval prolongation. An increase in QTcF interval to >500 ms was measured in 7% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 20% of patients. RETEVMO has not been studied in patients with clinically significant active cardiovascular disease or recent myocardial infarction.

Monitor patients who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, and severe or uncontrolled heart failure. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment, adjusting frequency based upon risk factors including diarrhea. Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiating RETEVMO and during treatment.

Monitor the QT interval more frequently when RETEVMO is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and reduce the dose or permanently discontinue RETEVMO based on the severity.

'''Hemorrhagic Events'''
Serious including fatal hemorrhagic events can occur with RETEVMO. Grade ≥3 hemorrhagic events occurred in 3.1% of patients treated with RETEVMO, including 4 (0.5%) patients with fatal hemorrhagic events, including cerebral hemorrhage (n = 2), tracheostomy site hemorrhage (n = 1), and hemoptysis (n=1).

Permanently discontinue RETEVMO in patients with severe or life-threatening hemorrhage.

'''Hypersensitivity'''
Hypersensitivity occurred in 6% of patients receiving RETEVMO, including Grade 3 hypersensitivity in 1.9%. The median time to onset was 1.9 weeks (range: 5 days to 2 years). Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis.

If hypersensitivity occurs, withhold RETEVMO and begin corticosteroids at a dose of 1 mg/kg prednisone (or equivalent). Upon resolution of the event, resume RETEVMO at a reduced dose and increase the dose of RETEVMO by 1 dose level each week as tolerated until reaching the dose taken prior to onset of hypersensitivity [see Dosage and Administration (2.5)]. Continue steroids until patient reaches target dose and then taper. Permanently discontinue RETEVMO for recurrent hypersensitivity.

'''Tumor Lysis Syndrome'''
Tumor lysis syndrome (TLS) occurred in 0.6% of patients with medullary thyroid carcinoma receiving RETEVMO [see Adverse Reactions (6.1)]. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated.

'''Risk of Impaired Wound Healing'''
Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, RETEVMO has the potential to adversely affect wound healing.

Withhold RETEVMO for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of RETEVMO after resolution of wound healing complications has not been established.

'''Hypothyroidism'''
RETEVMO can cause hypothyroidism. Hypothyroidism occurred in 13% of patients treated with RETEVMO; all reactions were Grade 1 or 2. Hypothyroidism occurred in 13% of patients (50/373) with thyroid cancer and 13% of patients (53/423) with other solid tumors including NSCLC .

Monitor thyroid function before treatment with RETEVMO and periodically during treatment. Treat with thyroid hormone replacement as clinically indicated. Withhold RETEVMO until clinically stable or permanently discontinue RETEVMO based on severity.

'''Embryo-Fetal Toxicity'''
Based on data from animal reproduction studies and its mechanism of action, RETEVMO can cause fetal harm when administered to a pregnant woman. Administration of selpercatinib to pregnant rats during organogenesis at maternal exposures that were approximately equal to those observed at the recommended human dose of 160 mg twice daily resulted in embryolethality and malformations.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose.

'''Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Pediatric Patients
Slipped capital femoral epiphysis/slipped upper femoral epiphysis (SCFE/SUFE) occurred in 1 adolescent (3.7% of 27 patients) receiving RETEVMO in LIBRETTO-121 and 1 adolescent (0.5% of 193 patients) receiving RETEVMO in LIBRETTO-531 [see Adverse Reactions (6.1)]. Monitor patients for symptoms indicative of SCFE/SUFE and treat as medically and surgically appropriate .
|clinicalTrials='''LIBRETTO-001'''

Among the 796 patients who received RETEVMO, 84% were exposed for 6 months or longer and 73% were exposed for greater than one year. Among these patients, 96% received at least one dose of RETEVMO at the recommended dosage of 160 mg orally twice daily.

The median age was 59 years (range: 15 to 92 years); 0.3% were pediatric patients 12 to 16 years of age; 51% were male; and 69% were White, 23% were Asian, and 3% were Black or African American; and 5% were Hispanic/Latino. The most common tumors were NSCLC (45%), MTC (40%), and non-medullary thyroid carcinoma (7%).

Serious adverse reactions occurred in 44% of patients who received RETEVMO. The most frequent serious adverse reactions (≥2% of patients) were pneumonia, pleural effusion, abdominal pain, hemorrhage, hypersensitivity, dyspnea, and hyponatremia. Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions included sepsis (n = 6), respiratory failure (n = 5), hemorrhage (n = 4), pneumonia (n = 3), pneumonitis (n = 2), cardiac arrest (n=2), sudden death (n = 1), and cardiac failure (n = 1).

Permanent discontinuation due to an adverse reaction occurred in 8% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation in ≥0.5% of patients included increased ALT (0.6%), fatigue (0.6%), sepsis (0.5%), and increased AST (0.5%).

Dosage interruptions due to an adverse reaction occurred in 64% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in ≥5% of patients included increased ALT, increased AST, diarrhea, and hypertension.

Dose reductions due to an adverse reaction occurred in 41% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in ≥2% of patients included increased ALT, increased AST, QT prolongation, fatigue, diarrhea, drug hypersensitivity, and edema.

The most common adverse reactions (≥25%) were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache.

The most common Grade 3 or 4 laboratory abnormalities (≥5%) were decreased lymphocytes, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), decreased sodium, and decreased calcium.

'''LIBRETTO-121'''

The safety population described below reflects exposure to RETEVMO as a single agent at 92 mg/m2 orally twice daily evaluated in 27 patients with advanced solid tumors harboring an activating RET alteration in LIBRETTO-121 [see Clinical Studies (14)]. Among the 27 pediatric and adolescent patients who received RETEVMO, 81% were exposed for 6 months or longer and 59% were exposed for greater than one year.

The median age was 13 years (range: 2 to 20 years); 22% were pediatric patients 2 to 12 years of age; 59% were male; and 52% were White, 26% were Asian, and 11% were Black or African American; and 19% were Hispanic/Latino. The most common cancers were MTC (52%), and papillary thyroid cancer (37%).

Serious adverse reactions occurred in 22% of patients who received RETEVMO. The serious adverse reactions (in 1 patient each) were abdominal infection, abdominal pain, aspiration, constipation, diarrhea, epiphysiolysis, nausea, pneumonia, pneumatosis intestinalis, rhinovirus infection, sepsis, vomiting.

Dosage interruptions due to an adverse reaction occurred in 22% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in ≥5% of patients included decreased neutrophils.

Dose reductions due to an adverse reaction occurred in 15% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in ≥2% of patients included decreased neutrophils, increased ALT, and increased weight.

The most common adverse reactions (≥25%) were musculoskeletal pain, diarrhea, headache, nausea, vomiting, coronavirus infection, abdominal pain, fatigue, pyrexia, and hemorrhage.

The most common Grade 3 or 4 laboratory abnormalities (≥5%) were decreased calcium, decreased hemoglobin, and decreased neutrophils.

'''LIBRETTO-431'''

The safety population described below reflects exposure to RETEVMO as a single agent administered at 160 mg orally twice daily evaluated in 158 patients with unresectable locally advanced or metastatic RET fusion-positive NSCLC in LIBRETTO-431. Among the 158 patients who received RETEVMO, the median duration of exposure was 16.7 months (range: 5 days to 37.9 months); 87% were exposed for 6 months or longer and 70% were exposed for one year or longer.

The median age was 61 years (range: 31 to 87 years); 46% were male; and 36% were White, 58% were Asian, 1.3% were Black or African American, 1.3% were American Indian or Alaska Native, and 3.2% were missing.

Serious adverse reactions occurred in 35% of patients who received RETEVMO. The most frequent serious adverse reactions (≥2% of patients) were pleural effusion, and abnormal hepatic function. Fatal adverse reactions occurred in 4.4% of patients who received RETEVMO; fatal adverse reactions included myocardial infarction (n = 2), respiratory failure (n = 2), cardiac arrest, malnutrition, and sudden death (n = 1, each).

Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation in ≥1% of patients included increased ALT (1.3%), and myocardial infarction (1.3%).

Dosage interruptions due to an adverse reaction occurred in 72% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in ≥5% of patients included increased ALT, hypertension, increased AST, QT prolongation, diarrhea, and COVID-19 infection.

Dose reductions due to an adverse reaction occurred in 51% of patients who received RETEVMO. Adverse reactions requiring dose reductions in ≥5% of patients included increased ALT, increased AST, QT prolongation.

The most common adverse reactions (≥25%) in patients who received RETEVMO were hypertension, diarrhea, edema, dry mouth, rash, fatigue, abdominal pain, and musculoskeletal pain.

The most common Grade 3 or 4 laboratory abnormalities (≥5%) in patients who received RETEVMO were increased ALT, increased AST, and decreased lymphocytes.
|drugInteractions='''Effects of Other Drugs on RETEVMO'''
Acid-Reducing Agents

Concomitant use of RETEVMO with acid-reducing agents decreases selpercatinib plasma concentrations, which may reduce RETEVMO anti-tumor activity.

Avoid concomitant use of PPIs, H2 receptor antagonists, and locally-acting antacids with RETEVMO. If coadministration cannot be avoided, take RETEVMO with food (with a PPI) or modify its administration time (with a H2 receptor antagonist or a locally-acting antacid) .

'''Strong and Moderate CYP3A Inhibitors'''

Concomitant use of RETEVMO with a strong or moderate CYP3A inhibitor increases selpercatinib plasma concentrations, which may increase the risk of RETEVMO adverse reactions, including QTc interval prolongation.

Avoid concomitant use of strong and moderate CYP3A inhibitors with RETEVMO. If concomitant use of strong and moderate CYP3A inhibitors cannot be avoided, reduce the RETEVMO dosage and monitor the QT interval with ECGs more frequently.

'''Strong and Moderate CYP3A Inducers'''

Concomitant use of RETEVMO with a strong or moderate CYP3A inducer decreases selpercatinib plasma concentrations, which may reduce RETEVMO anti-tumor activity.

Avoid coadministration of strong or moderate CYP3A inducers with RETEVMO.

'''Effects of RETEVMO on Other Drugs'''
CYP2C8 and CYP3A Substrates

RETEVMO is a moderate CYP2C8 inhibitor and a weak CYP3A inhibitor. Concomitant use of RETEVMO with CYP2C8 and CYP3A substrates increases their plasma concentrations, which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with CYP2C8 and CYP3A substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling.

'''Certain P-gp and BCRP Substrates'''

RETEVMO is a P-gp and BCRP inhibitor. Concomitant use of RETEVMO with P-gp or BCRP substrates increases their plasma concentrations, which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with P-gp or BCRP substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for P-gp and BCRP substrates provided in their approved product labeling.

'''Drugs that Prolong QT Interval'''
RETEVMO is associated with QTc interval prolongation. Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.
|useInLaborDelivery=Based on findings from animal studies, and its mechanism of action [see Clinical Pharmacology (12.1)], RETEVMO can cause fetal harm when administered to a pregnant woman. There are no available data on RETEVMO use in pregnant women to inform drug-associated risk. Administration of selpercatinib to pregnant rats during the period of organogenesis resulted in embryolethality and malformations at maternal exposures that were approximately equal to the human exposure at the clinical dose of 160 mg twice daily. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
|useInNursing=There are no data on the presence of selpercatinib or its metabolites in human milk or on their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with RETEVMO and for 1 week after the last dose.
|useInPed=The safety and effectiveness of RETEVMO have been established in pediatric patients 2 years of age and older for the treatment of:

advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation who require systemic therapy
advanced or metastatic thyroid cancer with a RET gene fusion who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate)
locally advanced or metastatic solid tumors with a RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.
Use of RETEVMO for these indications is supported by evidence from adequate and well-controlled studies in adult and pediatric patients with additional pharmacokinetic and safety data in pediatric patients 2 years of age and older. The predicted exposures of selpercatinib in pediatric patients at the recommended dosages were within the range of values predicted in patients ≥ 12 years and ≥ 50 kg in body weight receiving the approved recommended dosage of 160 mg twice daily.

The safety and effectiveness of RETEVMO have not been established in these indications in patients less than 2 years of age.

The safety and effectiveness of RETEVMO have not been established in pediatric patients for other indications .

Juvenile Animal Toxicity Data
|useInGeri=Of 796 patients who received RETEVMO, 34% (268 patients) were ≥65 years of age and 9% (74 patients) were ≥75 years of age. No overall differences were observed in the safety or effectiveness of RETEVMO between patients who were ≥65 years of age and younger patients.
|useInGender=Based on animal data, RETEVMO can cause embryolethality and malformations at doses resulting in exposures less than or equal to the human exposure at the clinical dose of 160 mg twice daily.

'''Pregnancy Testing'''

Verify pregnancy status in females of reproductive potential prior to initiating RETEVMO .

'''Contraception'''

''Females''

Advise female patients of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose.

''Males''

Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose.

'''Infertility'''

RETEVMO may impair fertility in females and males of reproductive potential.
|useInRenalImpair=No dosage modification is recommended for patients with mild to severe renal impairment [estimated Glomerular Filtration Rate (eGFR) ≥15 to 89 mL/min, estimated by Modification of Diet in Renal Disease (MDRD) equation]. The recommended dosage has not been established for patients with end-stage renal disease (ESRD)
|useInHepaticImpair=Reduce the dose when administering RETEVMO to patients with severe [total bilirubin greater than 3 to 10 times upper limit of normal (ULN) and any AST] hepatic impairment . No dosage modification is recommended for patients with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST) or moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST) hepatic impairment. Monitor for RETEVMO-related adverse reactions in patients with hepatic impairment .
|administration=Adult and adolescent patients 12 years of age or older based on body weight:

*Less than 50 kg: 120 mg twice daily
*50 kg or greater: 160 mg twice daily

Pediatric patients 2 to less than 12 years of age based on body surface area:
*0.33 to 0.65 m2: 40 mg three times daily
*0.66 to 1.08 m2: 80 mg twice daily
*1.09 to 1.52 m2: 120 mg twice daily
*≥1.53 m2: 160 mg twice daily
|mechAction=Selpercatinib is a kinase inhibitor. Selpercatinib inhibited wild-type RET and multiple mutated RET isoforms as well as VEGFR1 and VEGFR3 with IC50 values ranging from 0.92 nM to 67.8 nM. In other enzyme assays, selpercatinib also inhibited FGFR 1, 2, and 3 at higher concentrations that were still clinically achievable. In cellular assays, selpercatinib inhibited RET at approximately 60-fold lower concentrations than FGFR1 and 2 and approximately 8-fold lower concentration than VEGFR3.

Certain point mutations in RET or chromosomal rearrangements involving in-frame fusions of RET with various partners can result in constitutively activated chimeric RET fusion proteins that can act as oncogenic drivers by promoting cell proliferation of tumor cell lines. In in vitro and in vivo tumor models, selpercatinib demonstrated anti-tumor activity in cells harboring constitutive activation of RET proteins resulting from gene fusions and mutations, including CCDC6-RET, KIF5B-RET, RET V804M, and RET M918T. In addition, selpercatinib showed anti-tumor activity in mice intracranially implanted with a patient-derived RET fusion positive tumor.
|PD='''Exposure-Response Relationship'''

Selpercatinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.

'''Cardiac Electrophysiology'''

The effect of RETEVMO on the QTc interval was evaluated in a thorough QT study in healthy subjects. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state maximum concentration (Cmax) observed in patients after administration of 160 mg twice daily. The increase in QTc was concentration-dependent.
|PK=The pharmacokinetics of selpercatinib capsules were evaluated in patients with locally advanced or metastatic solid tumors administered 160 mg twice daily unless otherwise specified. The capsule and tablet dosage forms of selpercatinib are bioequivalent. Steady state selpercatinib AUC and Cmax increased in a slightly greater than dose proportional manner over the dose range of 20 mg once daily to 240 mg twice daily [0.06 to 1.5 times the maximum recommended total daily dosage].

Steady-state was reached by approximately 7 days and the median accumulation ratio after administration of 160 mg twice daily was 3.4-fold. Mean steady-state selpercatinib [coefficient of variation (CV%)] Cmax was 2,980 (53%) ng/mL and AUC0-24h was 51,600 (58%) ng*h/mL.

'''Absorption'''

The median tmax of selpercatinib is 2 hours. The mean absolute bioavailability of RETEVMO capsules is 73% (60% to 82%) in healthy subjects.

'''Effect of Food'''

For both the capsule and tablet dosage forms no clinically significant differences in selpercatinib AUC or Cmax were observed following administration of a high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) in healthy subjects.

'''Distribution'''

The apparent volume of distribution (Vss/F) of selpercatinib is 203 L.

Protein binding of selpercatinib is 96% in vitro and is independent of concentration. The blood-to-plasma concentration ratio is 0.7.

'''Elimination'''

The apparent clearance (CL/F) of selpercatinib is 6 L/h in patients and the half-life is 32 hours following oral administration of RETEVMO in healthy subjects.

'''Metabolism'''

Selpercatinib is metabolized predominantly by CYP3A4. Following oral administration of a single radiolabeled 160 mg dose of selpercatinib to healthy subjects, unchanged selpercatinib constituted 86% of the radioactive drug components in plasma.

'''Excretion'''

Following oral administration of a single radiolabeled 160 mg dose of selpercatinib to healthy subjects, 69% of the administered dose was recovered in feces (14% unchanged) and 24% in urine (12% unchanged).

Specific Populations

The apparent volume of distribution and clearance of selpercatinib increase with increasing body weight (9.6 kg to 179 kg).

No clinically significant differences in the pharmacokinetics of selpercatinib were observed based on age (2 years to 92 years), sex, or mild, moderate, or severe renal impairment (eGFR ≥15 to 89 mL/min). The effect of ESRD on selpercatinib pharmacokinetics has not been studied.

Pediatric patients

The exposures of selpercatinib in pediatric patients are predicted to be comparable to those in adult patients administered at the recommended dosages.

Patients with Hepatic Impairment

The selpercatinib AUC0-INF increased 1.1-fold in subjects with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST), 1.3-fold in subjects with moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST), and 1.8-fold in subjects with severe (total bilirubin greater than 3 to 10 times ULN and any AST) hepatic impairment, compared to subjects with normal hepatic function.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Proton-Pump Inhibitors (PPI): Coadministration with multiple daily doses of omeprazole (PPI) decreased selpercatinib AUC0-INF and Cmax when RETEVMO was administered fasting. Coadministration with multiple daily doses of omeprazole did not significantly change the selpercatinib AUC0-INF and Cmax when RETEVMO was administered with food
|nonClinToxic=Selpercatinib was not carcinogenic in a 2-year study in rats when administered by daily oral gavage at doses up to 20 mg/kg in males or 40 mg/kg in females (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). Selpercatinib was not carcinogenic in a 6-month study in rasH2 transgenic mice when administered by daily oral gavage at doses of up to 60 mg/kg.

Selpercatinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assays, with or without metabolic activation, or clastogenic in the in vitro micronucleus assay in human peripheral lymphocytes, with or without metabolic activation. Selpercatinib was positive in the in vivo micronucleus assay in rats at concentrations >7 times the Cmax at the human dose of 160 mg twice daily.

In general toxicology studies, male rats and minipigs exhibited testicular degeneration which was associated with luminal cell debris and/or reduced luminal sperm in the epididymis at selpercatinib exposures approximately 0.4 (rat) and 0.1 (minipig) times the clinical exposure by AUC at the 160 mg twice daily clinical dose. In a dedicated fertility study in male rats, administration of selpercatinib at doses up to 30 mg/kg/day (approximately twice the clinical exposure by AUC at the 160 twice daily clinical dose) for 28 days prior to cohabitation with untreated females did not affect mating or have clear effects on fertility. Males did, however, display a dose-dependent increase in testicular germ cell depletion and spermatid retention at doses ≥3 mg/kg (~0.2 times the clinical exposure by AUC at the 160 twice daily clinical dose) accompanied by altered sperm morphology at 30 mg/kg.

In a dedicated fertility study in female rats treated with selpercatinib for 15 days before mating to Gestational Day 7, there were decreases in the number of estrous cycles at a dose of 75 mg/kg (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). While selpercatinib did not have clear effects on mating performance or ability to become pregnant at any dose level, half of females at the 75 mg/kg dose level had 100% nonviable embryos. At the same dose level in females with some viable embryos there were increases in post-implantation loss. In a 3-month general toxicology study in minipigs, there were findings of decreased or absent corpora lutea at a selpercatinib dose of 15 mg/kg (approximately 0.3 times to the human exposure by AUC at the 160 mg twice daily clinical dose). Corpora luteal cysts were present in the minipig at selpercatinib doses ≥2 mg/kg (approximately 0.07 times the human exposure by AUC at the 160 mg twice daily clinical dose).
|clinicalStudies='''LIBRETTO-001'''

The efficacy of RETEVMO was evaluated in patients with advanced RET fusion-positive NSCLC enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). The study enrolled patients with advanced or metastatic RET fusion-positive NSCLC who had progressed on platinum-based chemotherapy and patients with locally advanced (stage III who were not candidates for surgical resection or definitive chemoradiation) or metastatic NSCLC without prior systemic therapy in separate cohorts. Identification of a RET gene alteration was prospectively determined in local laboratories using next generation sequencing (NGS), polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH) or other local testing methods. Adult patients received RETEVMO 160 mg orally twice daily until unacceptable toxicity or disease progression; patients enrolled in the dose escalation phase were permitted to adjust their dose to 160 mg twice daily. The major efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR), as determined by a blinded independent review committee (BIRC) according to RECIST v1.1.

'''RET Fusion-Positive NSCLC Previously Treated with Platinum Chemotherapy'''

Efficacy was evaluated in 247 patients with RET fusion-positive NSCLC previously treated with platinum chemotherapy enrolled into a cohort of LIBRETTO-001.

The median age was 61 years (range: 23 to 81); 57% were female; 44% were White, 48% were Asian, 4.9% were Black or African American; and 2.8% were Hispanic/Latino. ECOG performance status was 0-1 (97%) or 2 (3%) and 97% of patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range 1–15); 58% had prior anti-PD1/PD-L1 therapy. RET fusions were detected in 94% of patients using NGS (84.6% tumor samples; 9.3% blood or plasma samples), 4.0% using FISH, 1.6% using PCR and 0.4% by other local testing methods.

'''LIBRETTO-431'''

The efficacy of RETEVMO was evaluated in patients with unresectable, locally advanced or metastatic, RET fusion-positive NSCLC enrolled in a multicenter, open-label, active-controlled, randomized trial (LIBRETTO-431, NCT04194944). The trial evaluated RETEVMO compared to platinum-based and pemetrexed chemotherapy with or without pembrolizumab in patients with RET fusion-positive, unresectable locally advanced or metastatic NSCLC with no previous systemic therapy for metastatic disease.

Patients (N=261) were randomized to receive either RETEVMO (160 mg orally twice daily) in continuous 21-day cycles or pemetrexed intravenously (IV) (500 mg per square meter of body-surface area) along with the investigator’s choice of platinum therapy (carboplatin IV [AUC 5, maximum dose 750 mg] or cisplatin IV [75 mg per square meter]) with or without pembrolizumab IV (200 mg) every 21 days. Treatment continued until disease progression or unacceptable toxicity. Crossover from the control arm to RETEVMO was permitted following disease progression. Patients were stratified according to geographic region (East Asia vs. elsewhere), brain metastases at baseline (presence vs. absence or unknown), and the investigator’s intent (before randomization) to treat the patient with or without pembrolizumab. Tumor assessments were performed every 6 weeks for two assessments, then every 9 weeks for four assessments, and then every 12 weeks thereafter.

The major efficacy outcome measure was progression-free survival (PFS) in patients intended to be treated with chemotherapy in combination with pembrolizumab and in the overall study population as determined by a blinded independent review committee (BIRC) according to RECIST v1.1. Other efficacy outcome measures included overall survival (OS) and overall response rate (ORR).

A total of 212 patients were enrolled in LIBRETTO-431 with an intent to treat with pembrolizumab if randomized to the control arm (129 into RETEVMO arm and 83 into chemotherapy with pembrolizumab arm). The median age was 61.5 years (range: 31 to 84 years); 47% were male; 41% White, 55% Asian, and 0.9% Black or African American, 1.4% American Indian or Alaska Native, 1.9% were race not reported; ethnicity was not reported in 96% of patients. ECOG performance status was 0-1 (97%) or 2 (3%), 68% were never smokers, 93% of patients had metastatic disease, and 14% had measurable intracranial metastases at baseline, as determined by a neuroradiologic BIRC. RET fusions were detected in 60% of patients using NGS and 40% using PCR (89% tumor samples; 11% in blood
|howSupplied=40 mg; Gray opaque, imprinted with “Lilly”, “3977” and “40 mg” in black ink; 60 count bottle
80 mg; Blue opaque, imprinted with “Lilly”, “2980” and “80 mg” in black ink; 60-120 count bottle
|storage=Store at 20°C to 25°C (68°F to 77°F); excursions between 15°C and 30°C (59°F to 86°F) are permitted .
|fdaPatientInfo=Advise the patient to read the FDA-approved patient labeling (Patient Information).

'''Hepatotoxicity'''

Advise patients that hepatotoxicity can occur and to immediately contact their healthcare provider for signs or symptoms of hepatotoxicity.

'''Interstitial Lung Disease (ILD)/Pneumonitis'''

Advise patients that ILD/ pneumonitis can occur and to contact their healthcare provider immediately for signs or symptoms of ILD including new or worsening cough or shortness of breath.

'''Hypertension'''

Advise patients that they will require regular blood pressure monitoring and to contact their healthcare provider if they experience symptoms of increased blood pressure or elevated readings .

'''QT Prolongation'''

Advise patients that RETEVMO can cause QTc interval prolongation and to inform their healthcare provider if they have any QTc interval prolongation symptoms, such as syncope.

'''Hemorrhagic Events'''

Advise patients that RETEVMO may increase the risk for bleeding and to contact their healthcare provider if they experience any signs or symptoms of bleeding.

'''Hypersensitivity Reactions'''

Advise patients to monitor for signs and symptoms of hypersensitivity reactions, particularly during the first month of treatment.
.

''Tumor Lysis Syndrome'''

Advise patients to contact their healthcare provider promptly to report any signs and symptoms of TLS.

'''Risk of Impaired Wound Healing'''

Advise patients that RETEVMO may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure.

'''Hypothyroidism'''

Advise patients that RETEVMO can cause hypothyroidism and to immediately contact their healthcare provider for signs or symptoms of hypothyroidism.

'''Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis'''

Advise pediatric patients and caregivers to contact their healthcare provider promptly to report any signs and symptoms indicative of slipped capital femoral epiphysis/slipped upper femoral epiphysis.

'''Embryo-Fetal Toxicity'''

Advise pregnant women and females of reproductive potential of the possible risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.

Advise females of reproductive potential to use effective contraception during the treatment with RETEVMO and for 1 week after the last dose .

Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose [see Use in Specific Populations (8.3)].

'''Lactation'''

Advise women not to breastfeed during treatment with RETEVMO and for 1 week after the last dose.

'''Infertility'''

Advise males and females of reproductive potential that RETEVMO may impair fertility .

'''Drug Interactions'''

Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid St. John's wort, proton pump inhibitors, H2 receptor antagonists, and antacids while taking RETEVMO.

If PPIs are required, instruct patients to take RETEVMO with food. If H2 receptor antagonists are required, instruct patients to take RETEVMO 2 hours before or 10 hours after the H2 receptor antagonist. If locally-acting antacids are required, instruct patients to take RETEVMO 2 hours before or 2 hours after the locally-acting antacid .
|alcohol=Alcohol-Selpercatinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=RETEVMO
}}

Selpercatinib

2025-05-08T11:21:32Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=selerpcatinib |aOrAn=a |drugClass=kinase inhibitor with enhanced specificity for RET tyrosine kinase receptors (RTKs) |indication='''RET Fusion-Positive Non-Small Cell Lung Cancer''' RETEVMO® is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a rearranged during transfection (RET) gene fusion, as detected b..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=selerpcatinib
|aOrAn=a
|drugClass=kinase inhibitor with enhanced specificity for RET tyrosine kinase receptors (RTKs)
|indication='''RET Fusion-Positive Non-Small Cell Lung Cancer'''
RETEVMO® is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a rearranged during transfection (RET) gene fusion, as detected by an FDA-approved test.

'''RET-Mutant Medullary Thyroid Cancer'''
RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation, as detected by an FDA-approved test, who require systemic therapy.

'''RET Fusion-Positive Thyroid Cancer'''
RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).

'''Other RET Fusion-Positive Solid Tumors'''
RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with locally advanced or metastatic solid tumors with a RET gene fusion, as detected by an FDA-approved test, that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
|adverseReactions=*Hepatotoxicity
*Interstitial Lung Disease / Pneumonitis
*Hypertension
*QT Interval Prolongation
*Hemorrhagic Events
*Hypersensitivity
*Tumor Lysis Syndrome
*Risk of Impaired Wound Healing
*Hypothyroidism
*Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Adolescent Patients
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult='''RET Fusion-Positive Non-Small Cell Lung Cancer'''
RETEVMO® is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a rearranged during transfection (RET) gene fusion, as detected by an FDA-approved test.

'''RET-Mutant Medullary Thyroid Cancer'''
RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation, as detected by an FDA-approved test, who require systemic therapy.

'''RET Fusion-Positive Thyroid Cancer'''
RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).

'''Other RET Fusion-Positive Solid Tumors'''
RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with locally advanced or metastatic solid tumors with a RET gene fusion, as detected by an FDA-approved test, that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

'''DOSAGE'''
Adult and adolescent patients 12 years of age or older based on body weight:

*Less than 50 kg: 120 mg twice daily
*50 kg or greater: 160 mg twice daily
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Selpercatinib in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Selpercatinib in adult patients.
|fdaLIADPed=Pediatric patients 2 to less than 12 years of age based on body surface area:
*0.33 to 0.65 m2: 40 mg three times daily
*0.66 to 1.08 m2: 80 mg twice daily
*1.09 to 1.52 m2: 120 mg twice daily
*≥1.53 m2: 160 mg twice daily
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Selpercatinib in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Selpercatinib in pediatric patients.
|contraindications=None
|warnings='''Hepatotoxicity'''
Serious hepatic adverse reactions occurred in 3% of patients treated with RETEVMO. Increased AST occurred in 59% of patients, including Grade 3 or 4 events in 11% and increased ALT occurred in 55% of patients, including Grade 3 or 4 events in 12%. The median time to first onset for increased AST was 6 weeks (range: 1 day to 3.4 years) and increased ALT was 5.8 weeks (range: 1 day to 2.5 years).

Monitor ALT and AST prior to initiating RETEVMO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce the dose or permanently discontinue RETEVMO based on the severity.

'''Interstitial Lung Disease/Pneumonitis'''
Severe, life-threatening, and fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with RETEVMO. ILD/pneumonitis occurred in 1.8% of patients who received RETEVMO, including 0.3% with Grade 3 or 4 events, and 0.3% with fatal reactions.

Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Withhold RETEVMO and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Withhold, reduce the dose or permanently discontinue RETEVMO based on severity of confirmed ILD.

'''Hypertension'''
Hypertension occurred in 41% of patients, including Grade 3 hypertension in 20% and Grade 4 in one (0.1%) patient [see Adverse Reactions (6.1)]. Overall, 6.3% had their dose interrupted and 1.3% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications.

Do not initiate RETEVMO in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating RETEVMO. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce the dose, or permanently discontinue RETEVMO based on the severity.

'''QT Interval Prolongation'''
RETEVMO can cause concentration-dependent QT interval prolongation. An increase in QTcF interval to >500 ms was measured in 7% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 20% of patients. RETEVMO has not been studied in patients with clinically significant active cardiovascular disease or recent myocardial infarction.

Monitor patients who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, and severe or uncontrolled heart failure. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment, adjusting frequency based upon risk factors including diarrhea. Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiating RETEVMO and during treatment.

Monitor the QT interval more frequently when RETEVMO is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and reduce the dose or permanently discontinue RETEVMO based on the severity.

'''Hemorrhagic Events'''
Serious including fatal hemorrhagic events can occur with RETEVMO. Grade ≥3 hemorrhagic events occurred in 3.1% of patients treated with RETEVMO, including 4 (0.5%) patients with fatal hemorrhagic events, including cerebral hemorrhage (n = 2), tracheostomy site hemorrhage (n = 1), and hemoptysis (n=1).

Permanently discontinue RETEVMO in patients with severe or life-threatening hemorrhage.

'''Hypersensitivity'''
Hypersensitivity occurred in 6% of patients receiving RETEVMO, including Grade 3 hypersensitivity in 1.9%. The median time to onset was 1.9 weeks (range: 5 days to 2 years). Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis.

If hypersensitivity occurs, withhold RETEVMO and begin corticosteroids at a dose of 1 mg/kg prednisone (or equivalent). Upon resolution of the event, resume RETEVMO at a reduced dose and increase the dose of RETEVMO by 1 dose level each week as tolerated until reaching the dose taken prior to onset of hypersensitivity [see Dosage and Administration (2.5)]. Continue steroids until patient reaches target dose and then taper. Permanently discontinue RETEVMO for recurrent hypersensitivity.

'''Tumor Lysis Syndrome'''
Tumor lysis syndrome (TLS) occurred in 0.6% of patients with medullary thyroid carcinoma receiving RETEVMO [see Adverse Reactions (6.1)]. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated.

'''Risk of Impaired Wound Healing'''
Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, RETEVMO has the potential to adversely affect wound healing.

Withhold RETEVMO for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of RETEVMO after resolution of wound healing complications has not been established.

'''Hypothyroidism'''
RETEVMO can cause hypothyroidism. Hypothyroidism occurred in 13% of patients treated with RETEVMO; all reactions were Grade 1 or 2. Hypothyroidism occurred in 13% of patients (50/373) with thyroid cancer and 13% of patients (53/423) with other solid tumors including NSCLC .

Monitor thyroid function before treatment with RETEVMO and periodically during treatment. Treat with thyroid hormone replacement as clinically indicated. Withhold RETEVMO until clinically stable or permanently discontinue RETEVMO based on severity.

'''Embryo-Fetal Toxicity'''
Based on data from animal reproduction studies and its mechanism of action, RETEVMO can cause fetal harm when administered to a pregnant woman. Administration of selpercatinib to pregnant rats during organogenesis at maternal exposures that were approximately equal to those observed at the recommended human dose of 160 mg twice daily resulted in embryolethality and malformations.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose.

'''Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Pediatric Patients
Slipped capital femoral epiphysis/slipped upper femoral epiphysis (SCFE/SUFE) occurred in 1 adolescent (3.7% of 27 patients) receiving RETEVMO in LIBRETTO-121 and 1 adolescent (0.5% of 193 patients) receiving RETEVMO in LIBRETTO-531 [see Adverse Reactions (6.1)]. Monitor patients for symptoms indicative of SCFE/SUFE and treat as medically and surgically appropriate .
|clinicalTrials='''LIBRETTO-001'''

Among the 796 patients who received RETEVMO, 84% were exposed for 6 months or longer and 73% were exposed for greater than one year. Among these patients, 96% received at least one dose of RETEVMO at the recommended dosage of 160 mg orally twice daily.

The median age was 59 years (range: 15 to 92 years); 0.3% were pediatric patients 12 to 16 years of age; 51% were male; and 69% were White, 23% were Asian, and 3% were Black or African American; and 5% were Hispanic/Latino. The most common tumors were NSCLC (45%), MTC (40%), and non-medullary thyroid carcinoma (7%).

Serious adverse reactions occurred in 44% of patients who received RETEVMO. The most frequent serious adverse reactions (≥2% of patients) were pneumonia, pleural effusion, abdominal pain, hemorrhage, hypersensitivity, dyspnea, and hyponatremia. Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions included sepsis (n = 6), respiratory failure (n = 5), hemorrhage (n = 4), pneumonia (n = 3), pneumonitis (n = 2), cardiac arrest (n=2), sudden death (n = 1), and cardiac failure (n = 1).

Permanent discontinuation due to an adverse reaction occurred in 8% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation in ≥0.5% of patients included increased ALT (0.6%), fatigue (0.6%), sepsis (0.5%), and increased AST (0.5%).

Dosage interruptions due to an adverse reaction occurred in 64% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in ≥5% of patients included increased ALT, increased AST, diarrhea, and hypertension.

Dose reductions due to an adverse reaction occurred in 41% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in ≥2% of patients included increased ALT, increased AST, QT prolongation, fatigue, diarrhea, drug hypersensitivity, and edema.

The most common adverse reactions (≥25%) were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache.

The most common Grade 3 or 4 laboratory abnormalities (≥5%) were decreased lymphocytes, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), decreased sodium, and decreased calcium.

'''LIBRETTO-121'''

The safety population described below reflects exposure to RETEVMO as a single agent at 92 mg/m2 orally twice daily evaluated in 27 patients with advanced solid tumors harboring an activating RET alteration in LIBRETTO-121 [see Clinical Studies (14)]. Among the 27 pediatric and adolescent patients who received RETEVMO, 81% were exposed for 6 months or longer and 59% were exposed for greater than one year.

The median age was 13 years (range: 2 to 20 years); 22% were pediatric patients 2 to 12 years of age; 59% were male; and 52% were White, 26% were Asian, and 11% were Black or African American; and 19% were Hispanic/Latino. The most common cancers were MTC (52%), and papillary thyroid cancer (37%).

Serious adverse reactions occurred in 22% of patients who received RETEVMO. The serious adverse reactions (in 1 patient each) were abdominal infection, abdominal pain, aspiration, constipation, diarrhea, epiphysiolysis, nausea, pneumonia, pneumatosis intestinalis, rhinovirus infection, sepsis, vomiting.

Dosage interruptions due to an adverse reaction occurred in 22% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in ≥5% of patients included decreased neutrophils.

Dose reductions due to an adverse reaction occurred in 15% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in ≥2% of patients included decreased neutrophils, increased ALT, and increased weight.

The most common adverse reactions (≥25%) were musculoskeletal pain, diarrhea, headache, nausea, vomiting, coronavirus infection, abdominal pain, fatigue, pyrexia, and hemorrhage.

The most common Grade 3 or 4 laboratory abnormalities (≥5%) were decreased calcium, decreased hemoglobin, and decreased neutrophils.

'''LIBRETTO-431'''

The safety population described below reflects exposure to RETEVMO as a single agent administered at 160 mg orally twice daily evaluated in 158 patients with unresectable locally advanced or metastatic RET fusion-positive NSCLC in LIBRETTO-431. Among the 158 patients who received RETEVMO, the median duration of exposure was 16.7 months (range: 5 days to 37.9 months); 87% were exposed for 6 months or longer and 70% were exposed for one year or longer.

The median age was 61 years (range: 31 to 87 years); 46% were male; and 36% were White, 58% were Asian, 1.3% were Black or African American, 1.3% were American Indian or Alaska Native, and 3.2% were missing.

Serious adverse reactions occurred in 35% of patients who received RETEVMO. The most frequent serious adverse reactions (≥2% of patients) were pleural effusion, and abnormal hepatic function. Fatal adverse reactions occurred in 4.4% of patients who received RETEVMO; fatal adverse reactions included myocardial infarction (n = 2), respiratory failure (n = 2), cardiac arrest, malnutrition, and sudden death (n = 1, each).

Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation in ≥1% of patients included increased ALT (1.3%), and myocardial infarction (1.3%).

Dosage interruptions due to an adverse reaction occurred in 72% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in ≥5% of patients included increased ALT, hypertension, increased AST, QT prolongation, diarrhea, and COVID-19 infection.

Dose reductions due to an adverse reaction occurred in 51% of patients who received RETEVMO. Adverse reactions requiring dose reductions in ≥5% of patients included increased ALT, increased AST, QT prolongation.

The most common adverse reactions (≥25%) in patients who received RETEVMO were hypertension, diarrhea, edema, dry mouth, rash, fatigue, abdominal pain, and musculoskeletal pain.

The most common Grade 3 or 4 laboratory abnormalities (≥5%) in patients who received RETEVMO were increased ALT, increased AST, and decreased lymphocytes.
|drugInteractions='''Effects of Other Drugs on RETEVMO'''
Acid-Reducing Agents

Concomitant use of RETEVMO with acid-reducing agents decreases selpercatinib plasma concentrations, which may reduce RETEVMO anti-tumor activity.

Avoid concomitant use of PPIs, H2 receptor antagonists, and locally-acting antacids with RETEVMO. If coadministration cannot be avoided, take RETEVMO with food (with a PPI) or modify its administration time (with a H2 receptor antagonist or a locally-acting antacid) .

'''Strong and Moderate CYP3A Inhibitors'''

Concomitant use of RETEVMO with a strong or moderate CYP3A inhibitor increases selpercatinib plasma concentrations, which may increase the risk of RETEVMO adverse reactions, including QTc interval prolongation.

Avoid concomitant use of strong and moderate CYP3A inhibitors with RETEVMO. If concomitant use of strong and moderate CYP3A inhibitors cannot be avoided, reduce the RETEVMO dosage and monitor the QT interval with ECGs more frequently.

'''Strong and Moderate CYP3A Inducers'''

Concomitant use of RETEVMO with a strong or moderate CYP3A inducer decreases selpercatinib plasma concentrations, which may reduce RETEVMO anti-tumor activity.

Avoid coadministration of strong or moderate CYP3A inducers with RETEVMO.

'''Effects of RETEVMO on Other Drugs'''
CYP2C8 and CYP3A Substrates

RETEVMO is a moderate CYP2C8 inhibitor and a weak CYP3A inhibitor. Concomitant use of RETEVMO with CYP2C8 and CYP3A substrates increases their plasma concentrations, which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with CYP2C8 and CYP3A substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling.

'''Certain P-gp and BCRP Substrates'''

RETEVMO is a P-gp and BCRP inhibitor. Concomitant use of RETEVMO with P-gp or BCRP substrates increases their plasma concentrations, which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with P-gp or BCRP substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for P-gp and BCRP substrates provided in their approved product labeling.

'''Drugs that Prolong QT Interval'''
RETEVMO is associated with QTc interval prolongation. Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.
|useInLaborDelivery=Based on findings from animal studies, and its mechanism of action [see Clinical Pharmacology (12.1)], RETEVMO can cause fetal harm when administered to a pregnant woman. There are no available data on RETEVMO use in pregnant women to inform drug-associated risk. Administration of selpercatinib to pregnant rats during the period of organogenesis resulted in embryolethality and malformations at maternal exposures that were approximately equal to the human exposure at the clinical dose of 160 mg twice daily. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
|useInNursing=There are no data on the presence of selpercatinib or its metabolites in human milk or on their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with RETEVMO and for 1 week after the last dose.
|useInPed=The safety and effectiveness of RETEVMO have been established in pediatric patients 2 years of age and older for the treatment of:

advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation who require systemic therapy
advanced or metastatic thyroid cancer with a RET gene fusion who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate)
locally advanced or metastatic solid tumors with a RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.
Use of RETEVMO for these indications is supported by evidence from adequate and well-controlled studies in adult and pediatric patients with additional pharmacokinetic and safety data in pediatric patients 2 years of age and older. The predicted exposures of selpercatinib in pediatric patients at the recommended dosages were within the range of values predicted in patients ≥ 12 years and ≥ 50 kg in body weight receiving the approved recommended dosage of 160 mg twice daily.

The safety and effectiveness of RETEVMO have not been established in these indications in patients less than 2 years of age.

The safety and effectiveness of RETEVMO have not been established in pediatric patients for other indications .

Juvenile Animal Toxicity Data
|useInGeri=Of 796 patients who received RETEVMO, 34% (268 patients) were ≥65 years of age and 9% (74 patients) were ≥75 years of age. No overall differences were observed in the safety or effectiveness of RETEVMO between patients who were ≥65 years of age and younger patients.
|useInGender=Based on animal data, RETEVMO can cause embryolethality and malformations at doses resulting in exposures less than or equal to the human exposure at the clinical dose of 160 mg twice daily.

'''Pregnancy Testing'''

Verify pregnancy status in females of reproductive potential prior to initiating RETEVMO .

'''Contraception'''

''Females''

Advise female patients of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose.

''Males''

Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose.

'''Infertility'''

RETEVMO may impair fertility in females and males of reproductive potential.
|useInRenalImpair=No dosage modification is recommended for patients with mild to severe renal impairment [estimated Glomerular Filtration Rate (eGFR) ≥15 to 89 mL/min, estimated by Modification of Diet in Renal Disease (MDRD) equation]. The recommended dosage has not been established for patients with end-stage renal disease (ESRD)
|useInHepaticImpair=Reduce the dose when administering RETEVMO to patients with severe [total bilirubin greater than 3 to 10 times upper limit of normal (ULN) and any AST] hepatic impairment . No dosage modification is recommended for patients with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST) or moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST) hepatic impairment. Monitor for RETEVMO-related adverse reactions in patients with hepatic impairment .
|administration=Adult and adolescent patients 12 years of age or older based on body weight:

*Less than 50 kg: 120 mg twice daily
*50 kg or greater: 160 mg twice daily

Pediatric patients 2 to less than 12 years of age based on body surface area:
*0.33 to 0.65 m2: 40 mg three times daily
*0.66 to 1.08 m2: 80 mg twice daily
*1.09 to 1.52 m2: 120 mg twice daily
*≥1.53 m2: 160 mg twice daily
|mechAction=Selpercatinib is a kinase inhibitor. Selpercatinib inhibited wild-type RET and multiple mutated RET isoforms as well as VEGFR1 and VEGFR3 with IC50 values ranging from 0.92 nM to 67.8 nM. In other enzyme assays, selpercatinib also inhibited FGFR 1, 2, and 3 at higher concentrations that were still clinically achievable. In cellular assays, selpercatinib inhibited RET at approximately 60-fold lower concentrations than FGFR1 and 2 and approximately 8-fold lower concentration than VEGFR3.

Certain point mutations in RET or chromosomal rearrangements involving in-frame fusions of RET with various partners can result in constitutively activated chimeric RET fusion proteins that can act as oncogenic drivers by promoting cell proliferation of tumor cell lines. In in vitro and in vivo tumor models, selpercatinib demonstrated anti-tumor activity in cells harboring constitutive activation of RET proteins resulting from gene fusions and mutations, including CCDC6-RET, KIF5B-RET, RET V804M, and RET M918T. In addition, selpercatinib showed anti-tumor activity in mice intracranially implanted with a patient-derived RET fusion positive tumor.
|PD='''Exposure-Response Relationship'''

Selpercatinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.

'''Cardiac Electrophysiology'''

The effect of RETEVMO on the QTc interval was evaluated in a thorough QT study in healthy subjects. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state maximum concentration (Cmax) observed in patients after administration of 160 mg twice daily. The increase in QTc was concentration-dependent.
|PK=The pharmacokinetics of selpercatinib capsules were evaluated in patients with locally advanced or metastatic solid tumors administered 160 mg twice daily unless otherwise specified. The capsule and tablet dosage forms of selpercatinib are bioequivalent. Steady state selpercatinib AUC and Cmax increased in a slightly greater than dose proportional manner over the dose range of 20 mg once daily to 240 mg twice daily [0.06 to 1.5 times the maximum recommended total daily dosage].

Steady-state was reached by approximately 7 days and the median accumulation ratio after administration of 160 mg twice daily was 3.4-fold. Mean steady-state selpercatinib [coefficient of variation (CV%)] Cmax was 2,980 (53%) ng/mL and AUC0-24h was 51,600 (58%) ng*h/mL.

'''Absorption'''

The median tmax of selpercatinib is 2 hours. The mean absolute bioavailability of RETEVMO capsules is 73% (60% to 82%) in healthy subjects.

'''Effect of Food'''

For both the capsule and tablet dosage forms no clinically significant differences in selpercatinib AUC or Cmax were observed following administration of a high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) in healthy subjects.

'''Distribution'''

The apparent volume of distribution (Vss/F) of selpercatinib is 203 L.

Protein binding of selpercatinib is 96% in vitro and is independent of concentration. The blood-to-plasma concentration ratio is 0.7.

'''Elimination'''

The apparent clearance (CL/F) of selpercatinib is 6 L/h in patients and the half-life is 32 hours following oral administration of RETEVMO in healthy subjects.

'''Metabolism'''

Selpercatinib is metabolized predominantly by CYP3A4. Following oral administration of a single radiolabeled 160 mg dose of selpercatinib to healthy subjects, unchanged selpercatinib constituted 86% of the radioactive drug components in plasma.

'''Excretion'''

Following oral administration of a single radiolabeled 160 mg dose of selpercatinib to healthy subjects, 69% of the administered dose was recovered in feces (14% unchanged) and 24% in urine (12% unchanged).

Specific Populations

The apparent volume of distribution and clearance of selpercatinib increase with increasing body weight (9.6 kg to 179 kg).

No clinically significant differences in the pharmacokinetics of selpercatinib were observed based on age (2 years to 92 years), sex, or mild, moderate, or severe renal impairment (eGFR ≥15 to 89 mL/min). The effect of ESRD on selpercatinib pharmacokinetics has not been studied.

Pediatric patients

The exposures of selpercatinib in pediatric patients are predicted to be comparable to those in adult patients administered at the recommended dosages.

Patients with Hepatic Impairment

The selpercatinib AUC0-INF increased 1.1-fold in subjects with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST), 1.3-fold in subjects with moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST), and 1.8-fold in subjects with severe (total bilirubin greater than 3 to 10 times ULN and any AST) hepatic impairment, compared to subjects with normal hepatic function.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Proton-Pump Inhibitors (PPI): Coadministration with multiple daily doses of omeprazole (PPI) decreased selpercatinib AUC0-INF and Cmax when RETEVMO was administered fasting. Coadministration with multiple daily doses of omeprazole did not significantly change the selpercatinib AUC0-INF and Cmax when RETEVMO was administered with food
|nonClinToxic=Selpercatinib was not carcinogenic in a 2-year study in rats when administered by daily oral gavage at doses up to 20 mg/kg in males or 40 mg/kg in females (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). Selpercatinib was not carcinogenic in a 6-month study in rasH2 transgenic mice when administered by daily oral gavage at doses of up to 60 mg/kg.

Selpercatinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assays, with or without metabolic activation, or clastogenic in the in vitro micronucleus assay in human peripheral lymphocytes, with or without metabolic activation. Selpercatinib was positive in the in vivo micronucleus assay in rats at concentrations >7 times the Cmax at the human dose of 160 mg twice daily.

In general toxicology studies, male rats and minipigs exhibited testicular degeneration which was associated with luminal cell debris and/or reduced luminal sperm in the epididymis at selpercatinib exposures approximately 0.4 (rat) and 0.1 (minipig) times the clinical exposure by AUC at the 160 mg twice daily clinical dose. In a dedicated fertility study in male rats, administration of selpercatinib at doses up to 30 mg/kg/day (approximately twice the clinical exposure by AUC at the 160 twice daily clinical dose) for 28 days prior to cohabitation with untreated females did not affect mating or have clear effects on fertility. Males did, however, display a dose-dependent increase in testicular germ cell depletion and spermatid retention at doses ≥3 mg/kg (~0.2 times the clinical exposure by AUC at the 160 twice daily clinical dose) accompanied by altered sperm morphology at 30 mg/kg.

In a dedicated fertility study in female rats treated with selpercatinib for 15 days before mating to Gestational Day 7, there were decreases in the number of estrous cycles at a dose of 75 mg/kg (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). While selpercatinib did not have clear effects on mating performance or ability to become pregnant at any dose level, half of females at the 75 mg/kg dose level had 100% nonviable embryos. At the same dose level in females with some viable embryos there were increases in post-implantation loss. In a 3-month general toxicology study in minipigs, there were findings of decreased or absent corpora lutea at a selpercatinib dose of 15 mg/kg (approximately 0.3 times to the human exposure by AUC at the 160 mg twice daily clinical dose). Corpora luteal cysts were present in the minipig at selpercatinib doses ≥2 mg/kg (approximately 0.07 times the human exposure by AUC at the 160 mg twice daily clinical dose).
|clinicalStudies='''LIBRETTO-001'''

The efficacy of RETEVMO was evaluated in patients with advanced RET fusion-positive NSCLC enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). The study enrolled patients with advanced or metastatic RET fusion-positive NSCLC who had progressed on platinum-based chemotherapy and patients with locally advanced (stage III who were not candidates for surgical resection or definitive chemoradiation) or metastatic NSCLC without prior systemic therapy in separate cohorts. Identification of a RET gene alteration was prospectively determined in local laboratories using next generation sequencing (NGS), polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH) or other local testing methods. Adult patients received RETEVMO 160 mg orally twice daily until unacceptable toxicity or disease progression; patients enrolled in the dose escalation phase were permitted to adjust their dose to 160 mg twice daily. The major efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR), as determined by a blinded independent review committee (BIRC) according to RECIST v1.1.

'''RET Fusion-Positive NSCLC Previously Treated with Platinum Chemotherapy'''

Efficacy was evaluated in 247 patients with RET fusion-positive NSCLC previously treated with platinum chemotherapy enrolled into a cohort of LIBRETTO-001.

The median age was 61 years (range: 23 to 81); 57% were female; 44% were White, 48% were Asian, 4.9% were Black or African American; and 2.8% were Hispanic/Latino. ECOG performance status was 0-1 (97%) or 2 (3%) and 97% of patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range 1–15); 58% had prior anti-PD1/PD-L1 therapy. RET fusions were detected in 94% of patients using NGS (84.6% tumor samples; 9.3% blood or plasma samples), 4.0% using FISH, 1.6% using PCR and 0.4% by other local testing methods.

'''LIBRETTO-431'''

The efficacy of RETEVMO was evaluated in patients with unresectable, locally advanced or metastatic, RET fusion-positive NSCLC enrolled in a multicenter, open-label, active-controlled, randomized trial (LIBRETTO-431, NCT04194944). The trial evaluated RETEVMO compared to platinum-based and pemetrexed chemotherapy with or without pembrolizumab in patients with RET fusion-positive, unresectable locally advanced or metastatic NSCLC with no previous systemic therapy for metastatic disease.

Patients (N=261) were randomized to receive either RETEVMO (160 mg orally twice daily) in continuous 21-day cycles or pemetrexed intravenously (IV) (500 mg per square meter of body-surface area) along with the investigator’s choice of platinum therapy (carboplatin IV [AUC 5, maximum dose 750 mg] or cisplatin IV [75 mg per square meter]) with or without pembrolizumab IV (200 mg) every 21 days. Treatment continued until disease progression or unacceptable toxicity. Crossover from the control arm to RETEVMO was permitted following disease progression. Patients were stratified according to geographic region (East Asia vs. elsewhere), brain metastases at baseline (presence vs. absence or unknown), and the investigator’s intent (before randomization) to treat the patient with or without pembrolizumab. Tumor assessments were performed every 6 weeks for two assessments, then every 9 weeks for four assessments, and then every 12 weeks thereafter.

The major efficacy outcome measure was progression-free survival (PFS) in patients intended to be treated with chemotherapy in combination with pembrolizumab and in the overall study population as determined by a blinded independent review committee (BIRC) according to RECIST v1.1. Other efficacy outcome measures included overall survival (OS) and overall response rate (ORR).

A total of 212 patients were enrolled in LIBRETTO-431 with an intent to treat with pembrolizumab if randomized to the control arm (129 into RETEVMO arm and 83 into chemotherapy with pembrolizumab arm). The median age was 61.5 years (range: 31 to 84 years); 47% were male; 41% White, 55% Asian, and 0.9% Black or African American, 1.4% American Indian or Alaska Native, 1.9% were race not reported; ethnicity was not reported in 96% of patients. ECOG performance status was 0-1 (97%) or 2 (3%), 68% were never smokers, 93% of patients had metastatic disease, and 14% had measurable intracranial metastases at baseline, as determined by a neuroradiologic BIRC. RET fusions were detected in 60% of patients using NGS and 40% using PCR (89% tumor samples; 11% in blood
|howSupplied=40 mg; Gray opaque, imprinted with “Lilly”, “3977” and “40 mg” in black ink; 60 count bottle
80 mg; Blue opaque, imprinted with “Lilly”, “2980” and “80 mg” in black ink; 60-120 count bottle
|storage=Store at 20°C to 25°C (68°F to 77°F); excursions between 15°C and 30°C (59°F to 86°F) are permitted [see USP Controlled Room Temperature].
|fdaPatientInfo=Advise the patient to read the FDA-approved patient labeling (Patient Information).

Hepatotoxicity

Advise patients that hepatotoxicity can occur and to immediately contact their healthcare provider for signs or symptoms of hepatotoxicity [see Warnings and Precautions (5.1)].

Interstitial Lung Disease (ILD)/Pneumonitis

Advise patients that ILD/ pneumonitis can occur and to contact their healthcare provider immediately for signs or symptoms of ILD including new or worsening cough or shortness of breath [see Warnings and Precautions (5.2)].

Hypertension

Advise patients that they will require regular blood pressure monitoring and to contact their healthcare provider if they experience symptoms of increased blood pressure or elevated readings [see Warnings and Precautions (5.3)].

QT Prolongation

Advise patients that RETEVMO can cause QTc interval prolongation and to inform their healthcare provider if they have any QTc interval prolongation symptoms, such as syncope [see Warnings and Precautions (5.4)].

Hemorrhagic Events

Advise patients that RETEVMO may increase the risk for bleeding and to contact their healthcare provider if they experience any signs or symptoms of bleeding [see Warnings and Precautions (5.5)].

Hypersensitivity Reactions

Advise patients to monitor for signs and symptoms of hypersensitivity reactions, particularly during the first month of treatment [see Warnings and Precautions (5.6)].

Tumor Lysis Syndrome

Advise patients to contact their healthcare provider promptly to report any signs and symptoms of TLS [see Warnings and Precautions (5.7)].

Risk of Impaired Wound Healing

Advise patients that RETEVMO may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see Warnings and Precautions (5.8)].

Hypothyroidism

Advise patients that RETEVMO can cause hypothyroidism and to immediately contact their healthcare provider for signs or symptoms of hypothyroidism [see Warnings and Precautions (5.9)].

Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis

Advise pediatric patients and caregivers to contact their healthcare provider promptly to report any signs and symptoms indicative of slipped capital femoral epiphysis/slipped upper femoral epiphysis [see Warnings and Precautions (5.11)].

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the possible risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.10), Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during the treatment with RETEVMO and for 1 week after the last dose [see Use in Specific Populations (8.3)].

Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with RETEVMO and for 1 week after the last dose [see Use in Specific Populations (8.2)].

Infertility

Advise males and females of reproductive potential that RETEVMO may impair fertility [see Use in Specific Populations (8.4), Nonclinical Toxicology (13.1)].

Drug Interactions

Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid St. John's wort, proton pump inhibitors, H2 receptor antagonists, and antacids while taking RETEVMO.

If PPIs are required, instruct patients to take RETEVMO with food. If H2 receptor antagonists are required, instruct patients to take RETEVMO 2 hours before or 10 hours after the H2 receptor antagonist. If locally-acting antacids are required, instruct patients to take RETEVMO 2 hours before or 2 hours after the locally-acting antacid [see Drug Interactions (7.1, 7.2)].
|alcohol=Alcohol-Selpercatinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=RETEVMO
}}

Fluoroestradiol f 18

2025-05-04T11:45:33Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=fluoroestradiol f 18 |drugClass=used to detect estrogen receptor-positive breast cancer lesions |indication=CERIANNA is indicated for use with positron emission tomography (PET) imaging for the detection of estrogen receptor (ER)-positive lesions as an adjunct to biopsy in patients with recurrent or metastatic breast cancer. |blackBoxWarningTitle='''TIT..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=fluoroestradiol f 18
|drugClass=used to detect estrogen receptor-positive breast cancer lesions
|indication=CERIANNA is indicated for use with positron emission tomography (PET) imaging for the detection of estrogen receptor (ER)-positive lesions as an adjunct to biopsy in patients with recurrent or metastatic breast cancer.
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=CERIANNA is indicated for use with positron emission tomography (PET) imaging for the detection of estrogen receptor (ER)-positive lesions as an adjunct to biopsy in patients with recurrent or metastatic breast cancer.

'''DOSAGE'''
Injection: clear, colorless solution in a multiple-dose vial containing 148 MBq/mL to 3,700 MBq/mL (4 mCi/mL to 100 mCi/mL) of fluoroestradiol F 18 at end of synthesis.

The recommended amount of radioactivity to be administered for PET imaging is 222 MBq (6 mCi), with a range of 111 MBq to 222 MBq (3 mCi to 6 mCi), administered as a single intravenous injection of 10 mL or less over 1 to 2 minutes.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Fluoroestradiol f 18 in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Fluoroestradiol f 18 in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Fluoroestradiol f 18 in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Fluoroestradiol f 18 in pediatric patients.
|contraindications=None
|warnings='''Risk of Misdiagnosis'''
''Inadequate Tumor Characterization and Other ER-Positive Pathology''

Breast cancer may be heterogeneous within patients and across time. CERIANNA images ER and is not useful for imaging other receptors such as HER2 and PR. The uptake of fluoroestradiol F 18 is not specific for breast cancer and may occur in a variety of ER-positive tumors that arise outside of the breast, including from the uterus and ovaries. Do not use CERIANNA in lieu of biopsy when biopsy is indicated in patients with recurrent or metastatic breast cancer.

''False Negative CERIANNA Scan''

A negative CERIANNA scan does not rule out ER-positive breast cancer [see Clinical Studies (14)]. Pathology or clinical characteristics that suggest a patient may benefit from systemic hormone therapy should take precedence over a discordant negative CERIANNA scan.

'''Radiation Risks'''
Diagnostic radiopharmaceuticals, including CERIANNA, expose patients to radiation. Radiation exposure is associated with a dose-dependent increased risk of cancer. Ensure safe drug handling and patient preparation procedures to protect patients and health care providers from unintentional radiation exposure.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of CERIANNA was evaluated from published clinical studies of 1,207 patients with breast cancer receiving at least one fluoroestradiol F 18 administration. The following adverse reactions occurred at a rate < 1%:

*General disorders: injection-site pain
*Neurological and gastrointestinal disorders: dysgeusia
|drugInteractions=Drugs that bind to the estrogen receptor (ER) may compete with the binding of fluoroestradiol F 18 and may reduce the detection of ER-positive lesions with CERIANNA.

Before administering CERIANNA, discontinue drugs that bind to the ER, such as SERMs and SERDs, for at least 5 biological half-lives (e.g., elacestrant for 11 days, tamoxifen for 8 weeks, and fulvestrant for 28 weeks)
|useInLaborDelivery=All radiopharmaceuticals, including CERIANNA, have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of radiation dose. Advise a pregnant woman of the potential risks of fetal exposure to radiation from administration of CERIANNA.

There are no available data on CERIANNA use in pregnant women. No animal reproduction studies using fluoroestradiol F 18 have been conducted to evaluate its effect on female reproduction and embryo-fetal development.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
|useInNursing=There are no data on the presence of fluoroestradiol F 18 in human milk, or its effects on the breastfed infant or milk production. Lactation studies have not been conducted in animals. Advise a lactating woman to avoid breastfeeding for 4 hours after CERIANNA administration in order to minimize radiation exposure to a breastfed infant.
|useInPed=The safety and effectiveness of CERIANNA in pediatric patients have not been established.
|useInGeri=Clinical studies of fluoroestradiol F 18 injection did not reveal any difference in pharmacokinetics or biodistribution in patients aged 65 and over.
|administration='''For patient preparation instructions''':

*Use aseptic technique and radiation shielding when withdrawing and administering CERIANNA.
*Visually inspect the radiopharmaceutical solution. Do not use if it contains particulate matter or if it is cloudy or discolored (CERIANNA is a clear, colorless solution).
*CERIANNA may be diluted with 0.9% Sodium Chloride Injection, USP.
*Assay the dose in a suitable dose calibrator prior to administration.

'''Post-Administration Instructions''':

*Follow the CERIANNA injection with an intravenous flush of 0.9% Sodium Chloride injection, USP.
*Dispose of any unused CERIANNA in compliance with applicable regulations.
|mechAction=Fluoroestradiol F 18 binds ER. The following binding affinity: Kd = 0.13 ± 0.02 nM, Bmax = 1901 ± 89 fmol/mg, and IC50 = 0.085 nM, was determined in an ER-positive human breast cancer cell line (MCF-7).
|PD=The relationship between fluoroestradiol F18 plasma concentrations and image interpretation has not been studied. Fluoroestradiol F18 uptake measured by PET in human tumors is directly proportional to tumor ER expression measured by in vitro assays.
|PK='''Distribution'''

After intravenous injection, 95% of fluoroestradiol F 18 is bound to plasma proteins. Fluoroestradiol F 18 distributes primarily to hepatobiliary system, and also to small and large intestines, heart wall, blood, kidney, uterus and bladder.

'''Metabolism'''

Fluoroestradiol F 18 is metabolized in the liver. At 20 minutes after injection, approximately 20% of circulating radioactivity in the plasma is in the form of non-metabolized fluoroestradiol F 18. At 2 hours after injection, circulating fluoroestradiol F 18 levels are less than 5% of peak concentration.

'''Excretion'''

Elimination is by biliary and urinary excretion.
|nonClinToxic='''Carcinogenesis'''

No long-term studies in animals were performed to evaluate the carcinogenic potential of CERIANNA.

'''Mutagenesis'''

Fluoroestradiol was evaluated by in vitro bacterial reverse mutation assay (Ames test) and in vitro L5178Y/TK+/- mouse lymphoma mutagenesis assay. Fluoroestradiol was negative for genotoxicity by Ames test at up to 1.25 µg per plate for 5 tester strains (Salmonella typhimurium tester strains TA98, TA100, TA1535 and TA1537 and Escherichia Coli tester strain WP2 uvrA) in the presence or absence of S9 metabolic activation. Fluoroestradiol was negative for genotoxicity by L5178Y/TK+/- mouse lymphoma mutagenesis assay at up to 8 ng/mL in the absence or presence of S9 metabolic activation.

Potential in vivo genotoxicity of fluoroestradiol was evaluated in a rat micronucleus assay. In this assay, fluoroestradiol did not increase the number of micronucleated polychromatic erythrocytes (MN-PCEs) at 51 µg/kg/day, when given for 14 consecutive days. However, CERIANNA has the potential to be mutagenic because of the F 18 radioisotope.

'''Impairment of Fertility'''

No studies in animals have been performed to evaluate potential impairment of fertility in males or females.
|clinicalStudies=The effectiveness of CERIANNA for detecting ER-positive non-primary breast cancer lesions was evaluated based on published study reports of fluoroestradiol F 18. Study 1 (NCT01986569) enrolled 90 women (median age 55 years, 39% premenopausal) with histologically confirmed invasive breast cancer. The patients had first known or suspected recurrence of treated breast cancer or stage IV metastatic breast cancer. Recent biopsy of lesions outside of bone and areas with high physiologic fluoroestradiol F 18 uptake was also required. Patients concurrently using estrogen receptor modulators or fulvestrant discontinued them 60 days prior to fluoroestradiol F 18 administration. Concurrent use of aromatase inhibitors was permitted. Three image readers were blinded to all clinical information, except for the location of the largest biopsied lesion, for which pathologists independently provided an Allred score (0 to 8). The image readers scored the intensity of FES uptake on a three-point scale relative to normal biodistribution as either "decreased," "equivocal," or "increased" (1 to 3).

Image reader performance for distinguishing between ER-positive and ER-negative fluoroestradiol F 18 uptake was compared to biopsy in 85 patients. Of the 47 patients with positive biopsy (Allred score ≥ 3), 36 were positive on imaging (majority reader score = 3). Ten of 11 patients with false negative imaging had Allred scores between 3 and 6 [see Warnings and Precautions (5.1)]. Of the 38 patients with negative biopsy, all 38 were negative on imaging.

Study 2 (NCT00602043) in 13 patients showed similar results.
|howSupplied=CERIANNA is supplied in a 50 mL multiple-dose glass vial (NDC 72874-001-01) containing a clear, colorless injection solution at a strength of 148 MBq/mL to 3,700 MBq/mL (4 mCi/mL to 100 mCi/mL) fluoroestradiol F 18 at the end of synthesis. Each vial contains multiple doses and is enclosed in a shield container to minimize external radiation exposure.
|storage=Store CERIANNA at controlled room temperature (USP) 20°C to 25°C (68°F to 77°F). Store CERIANNA upright in the original container with radiation shielding. The expiration date and time are provided on the container label. Use CERIANNA within 12 hours from the time of the end of synthesis.
|fdaPatientInfo='''Radiation Risks'''

Advise patients of the radiation risks of CERIANNA. Instruct patients to drink water to ensure adequate hydration prior to administration of CERIANNA and to continue drinking and voiding frequently during the first hours following administration to reduce radiation exposure.

'''Pregnancy'''

Advise a pregnant woman of the potential risks of fetal exposure to radiation doses with CERIANNA.

'''Lactation'''

Advise a lactating woman to avoid breastfeeding for 4 hours after CERIANNA administration in order to minimize radiation exposure to a breastfed infant
|alcohol=Alcohol-Fluoroestradiol f 18 interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=CERIANNA
}}

Flortaucipir F18

2025-05-04T08:48:06Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=flortaucipir f-18 injection |drugClass=specifically bind to misfolded tau proteins in the brain |indicationType=treatment |indication=TAUVID is indicated for use with positron emission tomography (PET) imaging of the brain to estimate the density and distribution of aggregated tau neurofibrillary tangles (NFTs) in adult patients with cognitive impairment who are being evaluated for..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=flortaucipir f-18 injection
|drugClass=specifically bind to misfolded tau proteins in the brain
|indicationType=treatment
|indication=TAUVID is indicated for use with positron emission tomography (PET) imaging of the brain to estimate the density and distribution of aggregated tau neurofibrillary tangles (NFTs) in adult patients with cognitive impairment who are being evaluated for Alzheimer's disease (AD).

'''Limitations of Use'''

TAUVID is not indicated for use in the evaluation of patients for chronic traumatic encephalopathy (CTE)
|adverseReactions=*Headache
*Injection site pain
*Increased blood pressure
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=TAUVID is indicated for use with positron emission tomography (PET) imaging of the brain to estimate the density and distribution of aggregated tau neurofibrillary tangles (NFTs) in adult patients with cognitive impairment who are being evaluated for Alzheimer's disease (AD).

'''Limitations of Use'''

TAUVID is not indicated for use in the evaluation of patients for chronic traumatic encephalopathy (CTE)

'''DOSAGE'''
The recommended amount of radioactivity to be administered for PET imaging is 370 MBq (10 mCi), administered as an intravenous bolus injection in a total volume of 10 mL or less.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Flortaucipir F18 in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Flortaucipir F18 in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Flortaucipir F18 in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Flortaucipir F18 in pediatric patients.
|contraindications=None
|warnings='''Risk of Misdiagnosis in Patients Evaluated for Alzheimer's disease'''

TAUVID does not target β-amyloid, one of two required components of the neuropathological diagnosis of AD.

TAUVID performance for detecting tau pathology was assessed in terminally ill patients, the majority of whom had AD dementia with B3 level NFT pathology. TAUVID performance for detecting tau pathology may be lower in patients in earlier stages of the pathological spectrum.

'''Negative TAUVID Scan'''

NFTs may be present at levels that qualify for the neuropathological diagnosis of AD (B2 tau pathology in the presence of at least moderate levels of cortical amyloid pathology) in patients with a negative TAUVID scan. Consider additional evaluation to confirm the absence of AD pathology in patients with a negative TAUVID scan.

'''False Positive TAUVID Scan'''

Small foci of noncontiguous tracer uptake may lead to a false positive TAUVID scan. Only uptake of tracer in the neocortex should contribute to the interpretation of a positive TAUVID scan.

'''Risk of Chronic Traumatic Encephalopathy Misdiagnosis'''
The safety and effectiveness of TAUVID have not been established for patients being evaluated for CTE. Preliminary non-clinical and clinical investigations suggest differences in tau conformation and distribution may limit flortaucipir F 18 binding. Therefore, TAUVID is not indicated for detection of CTE.

'''Radiation Risk'''
Diagnostic radiopharmaceuticals, including TAUVID, expose patients to radiation. Radiation exposure is associated with a dose-dependent increased risk of cancer. Ensure safe handling and preparation procedures to protect patients and health care workers from unintentional radiation exposure
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical studies, 1,921 study participants were exposed to TAUVID. In these studies, 885 study participants received 240 MBq of TAUVID (about 65% of the recommended dose) and 1,036 study participants received 370 MBq of TAUVID (the recommended dose).

Adverse reactions with a frequency <0.5% in adults who received TAUVID in clinical trials include:

Nervous system disorders: dysgeusia
|useInLaborDelivery=All radiopharmaceuticals, including TAUVID, have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of radiation dose. Advise a pregnant woman of the potential risks of fetal exposure to radiation doses with administration of TAUVID. TAUVID is not likely to be used in females of reproductive age.

There are no available data on TAUVID use in pregnant women. No animal reproduction studies using flortaucipir F 18 have been conducted to evaluate its effect on female reproduction and embryo-fetal development.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
|useInNursing=There are no data on the presence of flortaucipir F 18 in human milk, or its effects on the breastfed infant or milk production. Lactation studies have not been conducted in animals. Advise a lactating woman to avoid breastfeeding for 4 hours after TAUVID administration in order to minimize radiation exposure to a breastfed infant.
|useInPed=The safety and effectiveness of TAUVID in pediatric patients have not been established.
|useInGeri=Of 1,921 study participants in completed clinical studies of TAUVID, 1,544 (80%) TAUVID-treated subjects were ≥ 65 years old, while 839 (44%) were ≥ 75 years old. No overall differences in safety or effectiveness of TAUVID were observed between subjects ≥ 65 years old and younger adult subjects, and other reported clinical experience has not identified differences in safety or effectiveness between elderly and younger patients.
|administration=*Assessment of pregnancy status is recommended in females of reproductive potential before administering TAUVID.
*Use aseptic technique and radiation shielding during the preparation and administration of TAUVID.
*Visually inspect the radiopharmaceutical solution prior to administration. Do not use it if it contains particulate matter or if it is discolored (TAUVID is a clear, colorless solution).
*TAUVID may be diluted aseptically with 0.9% Sodium Chloride Injection to a maximum dilution of 1:5 by the end-user. Diluted product should be used within 4 hours of dilution and prior to product expiry.
*Assay the dose in a suitable dose calibrator prior to administration.
|mechAction=Flortaucipir F 18 binds to aggregated tau protein. In the brains of patients with AD, tau aggregates combine to form NFTs, one of two components required for the neuropathological diagnosis of AD. In vitro, flortaucipir F 18 binds to paired helical filament (PHF) tau purified from brain homogenates of donors with AD. The dissociation constant (Kd) of flortaucipir F 18 binding to PHFs is 0.57 nM. In vivo, flortaucipir F 18 is differentially retained in neocortical areas that contain aggregated tau. In vitro, tritiated flortaucipir has been reported to bind with low nanomolar affinity to monoamine oxidase-A and monoamine oxidase-B, which could contribute to off target binding.
|PD=The relationship between flortaucipir F 18 plasma concentrations and image interpretation was not explored in clinical trials.

'''Effect of MAO Inhibitors on Flortaucipir Binding in AD Patients'''

TAUVID PET signal was slightly reduced by rasagiline, a MAO-B inhibitor, in vivo in low tau, high MAO-B areas of the brain such as the nucleus accumbens, putamen, and caudate. However, there is little potential for MAO binding to affect TAUVID scan interpretation in neocortical areas.
|PK=After intravenous administration of TAUVID, flortaucipir F 18 was distributed throughout the body with less than 10% of the injected F 18 radioactivity present in the blood by 5 minutes following administration, and less than 5% present in the blood by 10 minutes after administration. The residual F 18 in circulation during the 80-minute to 100-minute imaging window was approximately 28% to 34% parent, with the remainder being metabolites.

Clearance occurs primarily by hepatobiliary and renal excretion.
|nonClinToxic=Animal studies to assess the carcinogenicity or reproductive toxicity potentials of flortaucipir F 18 have not been conducted.

In an in vitro bacterial reverse mutation assay (Ames test), increases in the number of revertant colonies were observed in 4 of the 5 strains exposed to flortaucipir F 19. In a chromosomal aberration in vitro study with Chinese hamster ovary (CHO) cells, flortaucipir F 19 increased the percent of cells with structural aberrations with 3 hour exposure with or without S9 metabolic activation. Twenty hour exposure without activation produced an increase in structural aberrations at all tested concentrations.

Flortaucipir F 19 was evaluated in a rat micronucleus study and showed no genotoxicity. In this study, flortaucipir F 19 did not increase the number of micronucleated polychromatic erythrocytes at the highest achievable dose level, 1600 μg/kg/day, when given for two consecutive days.
|clinicalStudies=The performance of TAUVID imaging to estimate the density and distribution of aggregated tau neurofibrillary tangles (NFTs) was evaluated in two clinical studies: Study 1 (NCT02516046) and Study 2 (NCT03901092). In each study, TAUVID imaging was interpreted by 5 independent readers who were blinded to clinical information. Readers interpreted TAUVID imaging as positive or negative.

Study 1 enrolled 156 terminally ill patients who agreed to undergo TAUVID imaging and to participate in a postmortem brain donation program. In 64 of these patients, reader interpretation of the TAUVID scan was compared to tau pathology based on scoring provided by independent pathologists, who evaluated the density and distribution of NFTs in the post-mortem brain. Of the 64 patients, the mean age was 83 years (range 55 to 100); 34 were female; 49 had dementia, 1 had mild cognitive impairment, and 14 had no cognitive impairment on clinical evaluation around the time of TAUVID imaging.

The performance of the five TAUVID readers for sensitivity (95% CI) ranged from 92% (80, 97) to 100% (91, 100) and for specificity (95% CI) ranged from 52% (34, 70) to 92% (75, 98). Exploratory analysis evaluated how the same TAUVID interpretations distinguished B2-B3 from B0-B1 tau pathology, a threshold used in integrating tau and amyloid pathology for the neuropathological diagnosis of AD. In this analysis, the performance of the five TAUVID readers for sensitivity (95% CI) ranged from 68% (55, 79) to 86% (74, 93) and for specificity (95% CI) ranged from 63% (31, 86) to 100% (68, 100).

Study 2 included the same terminally ill patients as in Study 1 (plus 18 additional terminally ill patients) and 159 patients with cognitive impairment being evaluated for AD (the indicated population). Inter-reader agreement for five new TAUVID readers was evaluated using Fleiss' kappa statistic (95% CI) and found to be 0.87 (0.83, 0.91) across all 241 patients. Exploratory analysis evaluated inter-reader agreement in two subgroups. In this analysis, Fleiss' kappa (95% CI) was 0.82 (0.75, 0.88) in the terminally ill patients and 0.90 (0.85, 0.95) in the indicated population.
|howSupplied=TAUVID injection is supplied in a 50 mL or 100 mL multiple-dose vial containing a clear, colorless solution free of visible particulate matter at a strength of 300 MBq/mL to 3,700 MBq/mL (8.1 mCi/mL to 100 mCi/mL) flortaucipir F 18 at end of synthesis. Each vial contains multiple doses and is enclosed in a shield container to minimize external radiation exposure.
|storage=Store TAUVID at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). TAUVID does not contain a preservative. Store TAUVID upright in a shielding container. The expiration date and time are provided on the container label. Use TAUVID within the labeled expiration.
|fdaPatientInfo='''Radiation Risk'''

Advise patients of the radiation risk of TAUVID.

'''Pregnancy'''

Advise a pregnant woman of the potential risks of fetal exposure to radiation doses with TAUVID.

'''Lactation'''

Advise a lactating woman to avoid breastfeeding for 4 hours after TAUVID administration in order to minimize radiation exposure to a breastfed infant.
|alcohol=Alcohol-Flortaucipir F18 interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=Tauvid
}}

Inebilizumab-cdon

2025-05-04T08:21:36Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=inebilizumab |aOrAn=a |drugClass=humanized monoclonal antibody against CD19 |indicationType=treatment |indication='''Neuromyelitis Optica Spectrum Disorder (NMOSD)''' UPLIZNA is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. '''Immunoglobulin G4-Related Disease (IgG4-RD)''' UPLI..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=inebilizumab
|aOrAn=a
|drugClass=humanized monoclonal antibody against CD19
|indicationType=treatment
|indication='''Neuromyelitis Optica Spectrum Disorder (NMOSD)'''
UPLIZNA is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.

'''Immunoglobulin G4-Related Disease (IgG4-RD)'''
UPLIZNA is indicated for the treatment of Immunoglobulin G4-related disease (IgG4-RD) in adult patients.
|adverseReactions=The following clinically significant adverse reactions are described elsewhere in the labeling:

*Infusion Reactions
*Infections
*Reduction in Immunoglobulins
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult='''Neuromyelitis Optica Spectrum Disorder (NMOSD)'''
UPLIZNA is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.

'''Immunoglobulin G4-Related Disease (IgG4-RD)'''
UPLIZNA is indicated for the treatment of Immunoglobulin G4-related disease (IgG4-RD) in adult patients.

'''DOSAGE'''
Injection: 100 mg/10 mL (10 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in a single-dose vial.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Inebilizumab-cdon in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Inebilizumab-cdon in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Inebilizumab-cdon in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Inebilizumab-cdon in pediatric patients.
|contraindications=UPLIZNA is contraindicated in patients with:

*A history of a life-threatening infusion reaction to UPLIZNA
*Active hepatitis B infection
*Active or untreated latent tuberculosis
|warnings='''Infusion Reactions'''
UPLIZNA can cause infusion reactions, including anaphylaxis. Symptoms can include headache, nausea, somnolence, dyspnea, fever, myalgia, rash, or palpitations. During the randomized clinical trial period, infusion reactions were observed with the first course of UPLIZNA in 9.3% of NMOSD patients. Infusion reactions of UPLIZNA were observed in 7.4% of IgG4-RD patients during the randomized controlled period. Infusion reactions were most common with the first infusion but were also observed during subsequent infusions.

Reducing the Risk of Infusion Reactions and Managing Infusion Reactions

Administer pre-medication with a corticosteroid, an antihistamine, and an antipyretic.

Management recommendations for infusion reactions depend on the type and severity of the reaction. For life-threatening infusion reactions, immediately and permanently stop UPLIZNA and administer appropriate supportive treatment. For less severe infusion reactions, management may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment.

'''Infections'''
An increased risk of infections has been observed with other B-cell depleting therapies. The most common infections reported by UPLIZNA-treated patients in the randomized and open-label clinical trial periods for NMOSD included urinary tract infection (20%), nasopharyngitis (13%), upper respiratory tract infection (8%), and influenza (7%). In the IgG4-RD randomized controlled and open-label periods, the most common infections reported by UPLIZNA-treated patients were upper respiratory tract infection (11%), nasopharyngitis (10%), urinary tract infection (9%), and influenza (6%). Delay UPLIZNA administration in patients with an active infection until the infection is resolved.

Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants

UPLIZNA has not been studied in combination with other immunosuppressants. If combining UPLIZNA with another immunosuppressive therapy, consider the potential for increased immunosuppressive effects.

'''Hepatitis B Virus (HBV) Reactivation'''

Risk of HBV reactivation has been observed with other B-cell depleting antibodies. There have been no cases of HBV reactivation in patients treated with UPLIZNA, but patients with chronic HBV infection were excluded from clinical trials. Perform HBV screening in all patients before initiation of treatment with UPLIZNA. Do not administer UPLIZNA to patients with active hepatitis. For patients who are chronic carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment.

'''Progressive Multifocal Leukoencephalopathy (PML)'''

PML is an opportunistic viral infection of the brain caused by the JC virus that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Although no confirmed cases of PML were identified in UPLIZNA clinical trials, JC virus infection resulting in PML has been observed in patients treated with other B-cell depleting antibodies and other therapies that affect immune competence. In UPLIZNA clinical trials one subject died following the development of new brain lesions for which a definitive diagnosis could not be established, though the differential diagnosis included an atypical NMOSD relapse, PML, or acute disseminated encephalomyelitis. At the first sign or symptom suggestive of PML, withhold UPLIZNA and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.

'''Tuberculosis'''

Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating UPLIZNA. Consider anti-tuberculosis therapy prior to initiation of UPLIZNA in patients with a history of latent active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consult infectious disease experts regarding whether initiating anti-tuberculosis therapy is appropriate before starting treatment.

'''Vaccinations'''

Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of UPLIZNA. The safety of immunization with live or live-attenuated vaccines following UPLIZNA therapy has not been studied, and vaccination with live-attenuated or live vaccines is not recommended during treatment and until B-cell repletion.

'''Vaccination of Infants Born to Mothers Treated with UPLIZNA During Pregnancy'''

In infants of mothers exposed to UPLIZNA during pregnancy, do not administer live or live-attenuated vaccines before confirming recovery of B-cell counts in the infant. Depletion of B-cells in these exposed infants may increase the risks from live or live-attenuated vaccines. Non-live vaccines, as indicated, may be administered prior to recovery from B-cell and immunoglobulin level depletion, but consultation with a qualified specialist should be considered to assess whether a protective immune response was mounted.

'''Reduction in Immunoglobulins'''
There may be a progressive and prolonged hypogammaglobulinemia or decline in the levels of total and individual immunoglobulins such as immunoglobulins G and M (IgG and IgM) with continued UPLIZNA treatment [see Adverse Reactions (6.1)]. Monitor the levels of quantitative serum immunoglobulins during treatment with UPLIZNA, especially in patients with opportunistic or recurrent infections, and until B-cell repletion after discontinuation of therapy. Consider discontinuing UPLIZNA therapy if a patient with low immunoglobulin G or M develops a serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins.

'''Fetal Risk'''
Based on animal data, UPLIZNA can cause fetal harm due to B-cell lymphopenia and reduce antibody response in offspring exposed to UPLIZNA even after B-cell repletion. Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other B-cell depleting antibodies during pregnancy. Advise females of reproductive potential to use effective contraception while receiving UPLIZNA and for at least 6 months after the last dose
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

'''NMOSD'''

The safety of UPLIZNA was evaluated in Study 1, in which 161 patients were exposed to UPLIZNA at the recommended dosage regimen during the randomized, controlled treatment period; during which 52 patients received placebo. Subsequently, 198 patients were exposed to UPLIZNA during an open-label treatment period.

Two-hundred and eight patients in the randomized and open-label treatment periods had a total of 324 person-years of exposure to UPLIZNA, including 165 patients with exposure for at least 6 months and 128 with exposure for one year or more.

Table 3 lists adverse reactions that occurred in at least 5% of patients treated with UPLIZNA and at a greater incidence than in patients who received placebo in Study 1. The most common adverse reactions (incidence of at least 10% in patients treated with UPLIZNA and at a greater incidence than placebo) were urinary tract infection and arthralgia.

Across both the randomized and open-label treatment in Study 1, the most common adverse reactions (greater than 10%) were urinary tract infection (20%), nasopharyngitis (13%), infusion reaction (12%), arthralgia (11%), and headache (10%).

'''IgG4-RD'''

The safety of UPLIZNA was evaluated in Study 2, in which 68 patients were exposed to UPLIZNA at the recommended dosage regimen during the randomized, controlled treatment period; during which 67 patients received placebo.

Table 4 lists adverse reactions that occurred in at least 5% of patients treated with UPLIZNA and at a greater incidence than in patients who received placebo in Study 2. The most common adverse reactions (incidence of at least 10% in patients treated with UPLIZNA and at a greater incidence than placebo) were urinary tract infection and lymphopenia.
|drugInteractions='''Immunosuppressive or Immune-Modulating Therapies'''
Concomitant usage of UPLIZNA with immunosuppressant drugs, including systemic corticosteroids, may increase the risk of infection. Consider the risk of additive immune system effects when co-administering immunosuppressive therapies with UPLIZNA.
|useInLaborDelivery=There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to UPLIZNA during pregnancy or shortly before conception. Healthcare providers are encouraged to advise their patients to register by contacting the UPLIZNA Pregnancy Registry by calling the coordinating center at 1 (303) 724-4644 or www.upliznapregnancyregistry.com.
|useInNursing=There are no data on the presence of inebilizumab-cdon in human milk, the effects on a breastfed infant, or the effects on milk production. Human IgG is excreted in human milk, and the potential for absorption of UPLIZNA to lead to B-cell depletion in the breastfed infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for UPLIZNA and any potential adverse effects on the breastfed infant from UPLIZNA or from the underlying maternal condition.
|useInPed=Safety and effectiveness in pediatric patients have not been established.
|useInGeri='''NMOSD'''

Clinical studies of UPLIZNA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

'''IgG4-RD'''

Twenty-nine percent (32 out of 112) of patients 65 years of age or older, were treated with UPLIZNA. There were no overall age-related differences in safety or efficacy observed compared to younger patients.
|useInGender='''Contraception'''

Women of childbearing potential should use contraception while receiving UPLIZNA and for 6 months after the last infusion of UPLIZNA
|monitoring=Monitor the patient closely for infusion reactions during and for at least one hour after the completion of the infusion.
|mechAction=The precise mechanism by which inebilizumab-cdon exerts its therapeutic effects in NMOSD and IgG4-RD is unknown but is presumed to involve binding to CD19, a cell surface antigen presents on pre-B and mature B lymphocytes. Following cell surface binding to B lymphocytes, inebilizumab-cdon results in antibody-dependent cellular cytolysis.
|PD=Pharmacodynamics of UPLIZNA were assessed with an assay for CD20+ B-cells, since UPLIZNA can interfere with the CD19+ B-cell assay. Treatment with UPLIZNA reduces CD20+ B-cell counts in blood by 8 days after infusion.CD20+ B-cell counts were reduced below the lower limit of normal by 4 weeks in 100% of patients treated with UPLIZNA and remained below the lower limit of normal in 94% of patients for 28 weeks after initiation of treatment.

CD20+ B-cell counts were reduced below the lower limit of normal by week 2 in 100% of patients treated with UPLIZNA and remained below the lower limit of normal in 85% of patients for up to 52 weeks after initiation of treatment.
|PK=The pharmacokinetics of inebilizumab-cdon in NMOSD patients following intravenous administration of UPLIZNA was biphasic with a mean terminal half-life of 18 days. The mean maximum concentration was 108 µg/mL (300 mg, second dose on Day 15), and the cumulative AUC of the 26-week treatment period in which NMOSD patients received two intravenous administrations 2 week apart was 2980 µg∙d/mL.

The pharmacokinetics of inebilizumab-cdon in IgG4-RD patients following intravenous administration of UPLIZNA was biphasic with a mean terminal half-life of 18 days. The mean maximum concentration was 127 µg/mL (300 mg, second dose on Day 15), and the cumulative AUC of the 52-week treatment period in which IgG4-RD patients received two intravenous administrations 2 weeks apart, followed by a third dose at week 26 was 4290 µg×d/mL.

'''Distribution'''

Based on population pharmacokinetic analysis, the estimated typical central and peripheral volume of distribution of inebilizumab-cdon was 2.95 L and 2.57 L, respectively.

'''Metabolism'''

Inebilizumab-cdon is a humanized IgG1 monoclonal antibody that is degraded by proteolytic enzymes widely distributed in the body.

'''Elimination'''

The results of population pharmacokinetic analysis indicated that the estimated inebilizumab-cdon systemic clearance of the first-order elimination pathway was 0.19 L/day. At low exposure levels, inebilizumab-cdon was likely subject to the receptor (CD19)-mediated clearance, which decreased with time presumably because of the depletion of B-cells by UPLIZNA treatment.

'''Specific Populations'''

''Gender, Race, Geriatric Use''

A population pharmacokinetic analysis indicated that there was no significant effect of gender, race, and age on inebilizumab-cdon clearance.

'''Renal/Hepatic Impairment'''

No formal clinical studies have been conducted to investigate the effect of renal impairment or hepatic impairment on inebilizumab-cdon pharmacokinetic parameters.

'''Drug Interaction Studies'''

Cytochrome P450 enzymes and transporters are not involved in the clearance of inebilizumab-cdon; therefore, the potential risk of interactions between UPLIZNA and concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes and transporters is low.
|nonClinToxic='''Carcinogenesis'''

No studies have been conducted to assess the carcinogenic potential of inebilizumab-cdon.

'''Mutagenesis'''

No studies have been conducted to assess the genotoxic potential of inebilizumab-cdon.

'''Impairment of Fertility'''

Intravenous administration of inebilizumab-cdon (0, 3, or 30 mg/kg/week) to human CD19 transgenic male and female mice prior to and during mating and continuing in females through gestation day 15 resulted in reduced fertility at both doses tested. A no-effect dose for adverse effects on fertility was not identified.
|clinicalStudies='''Neuromyelitis Optica Spectrum Disorder (NMOSD)'''

The efficacy of UPLIZNA for the treatment of NMOSD was established in Study 1 (NCT02200770), a randomized (3:1), double-blind, placebo-controlled trial that enrolled 213 patients with NMOSD who were anti-AQP4 antibody positive and 17 who were anti-AQP4 antibody negative.

Patients met the following eligibility criteria:

A history of one or more relapses that required rescue therapy within the year prior to screening, or 2 or more relapses that required rescue therapy in 2 years prior to screening.
Expanded Disability Status Scale (EDSS) score of 7.5 or less. Patients with an EDSS score of 8.0 were eligible if they were deemed capable of participating.
Patients were excluded if previously treated with immunosuppressant therapies within an interval specified for each such therapy.
The use of immunosuppressants during the blinded phase of the trial was prohibited.

The use of oral or intravenous corticosteroids during the blinded phase of the trial was prohibited, with the exception of premedication for investigational treatment and treatment for a relapse.

Of the 213 enrolled anti-AQP4 antibody positive patients, a total of 161 were randomized to receive treatment with UPLIZNA, and 52 were randomized to receive placebo.

The baseline demographic and disease characteristics were balanced between the treatment groups. Females accounted for 94% of the study population. Fifty-two percent of patients were White, 21% Asian, and 9% Black or African American. The mean age was 43 years (range 18 to 74 years). The mean EDSS score was 4.0. The number of relapses in the two years prior to randomization was 2 or more in 83% of the patients.

UPLIZNA was administered according to the recommended dosage regimen.

All potential relapses were evaluated by a blinded, independent, adjudication committee, who determined whether the relapse met protocol-defined criteria. Patients who experienced an adjudicated relapse in the randomized-controlled period (RCP), or who completed the Day 197 visit without a relapse, exited the RCP.

The primary efficacy endpoint was the time to the onset of the first adjudicated relapse on or before Day 197.

The time to the first adjudicated relapse was significantly longer in patients treated with UPLIZNA compared to patients who received placebo (relative risk reduction 73%; hazard ratio: 0.272; p < 0.0001). In the anti-AQP4 antibody positive population there was a 77.3% relative reduction (hazard ratio: 0.227, p < 0.0001). There was no evidence of a benefit in patients who were anti-AQP4 antibody negative.

Compared to placebo-treated patients, patients treated with UPLIZNA who were anti-AQP4 antibody positive had reduced annualized rates of hospitalizations (0.11 for UPLIZNA versus 0.50 for placebo).

'''Immunoglobulin G4-Related Disease (IgG4-RD)'''
The efficacy of UPLIZNA for the treatment of IgG4-RD was established in Study 2 (NCT04540497), a randomized, double-blind, multicenter, 52-week placebo-controlled trial that enrolled 135 adult patients who met the following eligibility criteria:

*Newly diagnosed or recurrent IgG4-RD that required glucocorticoid (GC) treatment at screening.
*Confirmed history of organ involvement at any time in the course of disease.
The concomitant use of biologic and non-biologic immunosuppressive agents was prohibited during the blinded phase of the trial. Of the 135 enrolled IgG4-RD patients, 68 patients were randomized to receive UPLIZNA and 67 were randomized to receive placebo. The baseline demographic and disease characteristics were generally balanced between the treatment groups. Females accounted for 35% of the study population. Thirty-nine percent of patients were White, 47% Asian, and 1% Black or African American. The mean age was 58 years (range 24 to 80 years). The median disease duration was 0.9 years. Forty-six percent of patients were newly diagnosed with IgG4-RD and 54% had recurrent disease.

Patients were at a uniform 20 mg per day dose of glucocorticoids at the time of randomization and then began a prespecified taper of 5 mg dose every two weeks until discontinuation at the end of 8 weeks. The use of glucocorticoids during the trial was permitted for premedication for investigational treatment, treatment for a relapse and in certain situations other than an IgG4-RD flare. UPLIZNA was administered according to the recommended dosage regimen.

Disease flare was defined as new/worsening signs or symptoms that were positively adjudicated and warranted treatment by the investigator. All potential flares were assessed by the investigator and subsequently reviewed by a blinded, independent, adjudication committee, who determined whether the flare met one or more of the protocol-defined, organ-specific flare diagnostic criteria.

The primary efficacy endpoint was the time to First Treated and Adjudication Committee (AC)-determined IgG4-RD flare within the 52-week RCP. The time to the First Treated and AC determined IgG4-RD flare was significantly longer in the UPLIZNA group, compared with the placebo group (Figure 2). UPLIZNA reduced the risk of treated and AC-determined IgG4-RD flare by 87%, compared with placebo (hazard ratio: 0.13; p < 0.0001).

For all patients in the trial, the mean (SD) total GC use for IgG4-RD control per patient other than the planned GC taper was lower in the UPLIZNA-treated group compared with the placebo- treated group, with a mean (SD) of 118.25 (438.97) mg prednisone equivalent versus 1384.53 (1723.26) mg prednisone equivalent, respectively during the RCP. Forty-two (62.7%) placebo-treated patients and 7 (10.3%) UPLIZNA-treated patients received GC for IgG4-RD control other than the planned GC taper. The mean (SD) total GC use per patient for the 42 placebo-treated patients was 2202.76 (1709) mg prednisone equivalent and for the 7 UPLIZNA-treated patients was 1148.71 (878) mg prednisone equivalent.
|howSupplied=UPLIZNA (inebilizumab-cdon) injection is a clear to slightly opalescent, colorless to slightly yellow solution supplied as:

*One carton containing three 100 mg/10 mL single-dose vials – NDC 75987-150-03
|storage=*Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in original carton to protect from light.
*Do not freeze.
*Do not shake.
*Store vials upright.
|fdaPatientInfo=Advise the patient and/or caregiver to read the FDA-approved patient labeling.

'''Infusion Reactions'''

Inform patients about the signs and symptoms of infusion reactions, including anaphylaxis, and advise them to contact their healthcare provider immediately if they observe signs or symptoms of infusion reactions.

'''Infections'''

Advise patients to contact their healthcare provider for any signs of infection during treatment or after the last dose. Signs include fever, chills, constant cough, or dysuria.

Advise patients that UPLIZNA may cause reactivation of hepatitis B infection and that monitoring will be required if they are at risk .

Advise patients that PML has happened with drugs that are similar to UPLIZNA and may happen with UPLIZNA. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months. Instruct the patient of the importance of contacting their healthcare provider if they develop any symptoms suggestive of PML. Inform the patient that typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.

'''Vaccinations'''

Advise patients to complete any required vaccinations at least 4 weeks prior to initiation of UPLIZNA. Administration of live-attenuated or live vaccines is not recommended during UPLIZNA treatment and until B-cell recovery.

'''Pregnancy'''

Instruct patients that if they are pregnant or plan to become pregnant while taking UPLIZNA, they should inform their healthcare provider. Advise females of reproductive potential that they should use effective contraception during treatment and for 6 months after UPLIZNA therapy. Advise patients to register with the UPLIZNA pregnancy exposure registry.
|alcohol=Alcohol-Inebilizumab-cdon interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=UPLIZNA
}}

Lurbinectedin

2025-05-03T16:19:27Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=lurbinectedin |aOrAn=a |drugClass=inhibits transcription |indication=ZEPZELCA is indicated for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this in..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=lurbinectedin
|aOrAn=a
|drugClass=inhibits transcription
|indication=ZEPZELCA is indicated for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
|adverseReactions=The following clinically significant adverse reactions are described elsewhere in the labeling:

*Myelosuppression

*Hepatotoxicity

*Extravasation Resulting in Tissue Necrosis

*Rhabdomyolysis
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=ZEPZELCA is indicated for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

'''DOSAGE'''
The recommended dosage of ZEPZELCA is 3.2 mg/m2 by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity.

Initiate treatment with ZEPZELCA only if absolute neutrophil count (ANC) is at least 1,500 cells/mm3 and platelet count is at least 100,000/mm3.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Lurbinectedin in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Lurbinectedin in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Lurbinectedin in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Lurbinectedin in pediatric patients.
|contraindications=None
|warnings='''Myelosuppression'''
ZEPZELCA can cause myelosuppression.

In clinical studies of 554 patients with advanced solid tumors receiving ZEPZELCA, Grade 3 or 4 neutropenia occurred in 41% of patients, with a median time to onset of 15 days and a median duration of 7 days. Febrile neutropenia occurred in 7% of patients. Sepsis occurred in 2% of patients and was fatal in 1% (all cases occurred in patients with solid tumors other than SCLC). Grade 3 or 4 thrombocytopenia occurred in 10%, with a median time to onset of 10 days and a median duration of 7 days. Grade 3 or 4 anemia occurred in 17% of patients.

Administer ZEPZELCA only to patients with baseline neutrophil count of at least 1,500 cells/mm3 and platelet count of at least 100,000/mm3. Monitor blood counts including neutrophil count and platelet count prior to each administration. For neutrophil count less than 500 cells/mm3 or any value less than lower limit of normal, the use of G-CSF is recommended. Withhold, reduce the dose, or permanently discontinue ZEPZELCA based on severity.

'''Hepatotoxicity'''
ZEPZELCA can cause hepatotoxicity.

In clinical studies of 554 patients with advanced solid tumors receiving ZEPZELCA, Grade 3 elevations of ALT and AST were observed in 6% and 3% of patients, respectively, and Grade 4 elevations of ALT and AST were observed in 0.4% and 0.5% of patients, respectively. The median time to onset of Grade ≥ 3 elevation in transaminases was 8 days (range: 3 to 49), with a median duration of 7 days.

Monitor liver function tests prior to initiating ZEPZELCA and periodically during treatment as clinically indicated. Withhold, reduce the dose, or permanently discontinue ZEPZELCA based on severity.

'''Extravasation Resulting in Tissue Necrosis'''
Extravasation of ZEPZELCA resulting in skin and soft tissue injury, including necrosis requiring debridement, can occur. Consider use of a central venous catheter to reduce the risk of extravasation, particularly in patients with limited venous access. Monitor patients for signs and symptoms of extravasation during the ZEPZELCA infusion. If extravasation occurs, immediately discontinue the infusion, remove the infusion catheter, and monitor for signs and symptoms of tissue necrosis. The time to onset of necrosis after extravasation may vary.

Administer supportive care and consult with an appropriate medical specialist as needed for signs and symptoms of extravasation. Administer subsequent infusions at a site that was not affected by extravasation.

'''Rhabdomyolysis'''
Rhabdomyolysis has been reported in patients treated with ZEPZELCA. Monitor creatine phosphokinase (CPK) prior to initiating ZEPZELCA and periodically during treatment as clinically indicated. Withhold or reduce the dose based on severity.

'''Embryo-Fetal Toxicity'''
Based on animal data and its mechanism of action ZEPZELCA can cause fetal harm when administered to a pregnant woman. Intravenous administration of a single dose of lurbinectedin (approximately 0.2 times the 3.2 mg/m2 clinical dose) to pregnant animals during the period of organogenesis caused 100% embryolethality in rats. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with ZEPZELCA and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ZEPZELCA and for 4 months after the last dose.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to ZEPZELCA as a single agent at a dose of 3.2 mg/m2 intravenously every 21 days in 554 patients with advanced solid tumors. Among 554 patients who received ZEPZELCA, including 105 patients with small cell lung cancer (SCLC) in PM1183-B-005-14 (Study B-005), 24% were exposed for 6 months or longer and 5% were exposed for greater than one year.

'''Small Cell Lung Cancer (SCLC)'''

The safety of ZEPZELCA was evaluated in a cohort of 105 patients with previously treated SCLC in Study B-005. Patients received ZEPZELCA 3.2 mg/m2 intravenously every 21 days. All patients in this study received a pre-specified anti-emetic regimen consisting of a corticosteroid and serotonin antagonist. Patients could receive G-CSF for secondary prophylaxis (i.e., after patients had an initial decrease in WBC), but not primary prophylaxis. Among patients who received ZEPZELCA, 29% were exposed for 6 months or longer and 6% were exposed for greater than one year.

Serious adverse reactions occurred in 34% of patients who received ZEPZELCA. Serious adverse reactions in ≥ 3% of patients included pneumonia, febrile neutropenia, neutropenia, respiratory tract infection, anemia, dyspnea, and thrombocytopenia.

Permanent discontinuation due to an adverse reaction occurred in two patients (1.9%) who received ZEPZELCA. Adverse reactions resulting in permanent discontinuation in ≥ 1% of patients who received ZEPZELCA, which included peripheral neuropathy and myelosuppression.

Dosage interruptions due to an adverse reaction occurred in 30.5% of patients who received ZEPZELCA. Adverse reactions requiring dosage interruption in ≥ 3% of patients who received ZEPZELCA included neutropenia, and hypoalbuminemia.

Dose reductions due to an adverse reaction occurred in 25% of patients who received ZEPZELCA. Adverse reactions requiring dosage reductions in ≥ 3% of patients who received ZEPZELCA included neutropenia, febrile neutropenia and fatigue.

The most common adverse reactions, including laboratory abnormalities, (≥ 20%) were leukopenia, lymphopenia, fatigue, anemia, neutropenia, increased creatinine, increased alanine aminotransferase, increased glucose, thrombocytopenia, nausea, decreased appetite, musculoskeletal pain, decreased albumin, constipation, dyspnea, decreased sodium, increased aspartate aminotransferase, vomiting, cough, decreased magnesium and diarrhea.
|postmarketing=The following adverse reactions have been identified during post-approval use of ZEPZELCA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General disorders and administration site conditions: Extravasation including tissue necrosis requiring debridement.

'''Musculoskeletal and Connective Tissue Disorders:''' Rhabdomyolysis.

'''Metabolism and nutrition disorders:''' Tumor lysis syndrome.
|drugInteractions='''Strong and Moderate CYP3A Inhibitors'''

Coadministration of ZEPZELCA with a strong or a moderate CYP3A inhibitor increases lurbinectedin systemic exposure, which may increase the incidence and severity of adverse reactions to ZEPZELCA.

Avoid grapefruit and Seville oranges during ZEPZELCA treatment, as these contain strong or moderate inhibitors of CYP3A.

'''Strong CYP3A Inhibitors'''

Avoid coadministration of ZEPZELCA with strong CYP3A inhibitors. If coadministration cannot be avoided, reduce the dose of ZEPZELCA.

'''Moderate CYP3A Inhibitors'''

Avoid coadministration of ZEPZELCA with moderate CYP3A inhibitors. If coadministration cannot be avoided, consider dose reduction of ZEPZELCA if clinically indicated.

'''Strong CYP3A Inducers'''

Avoid coadministration of ZEPZELCA with strong CYP3A inducers. Coadministration of ZEPZELCA with a strong CYP3A inducer may decrease lurbinectedin systemic exposure, which may decrease the efficacy of ZEPZELCA
|useInLaborDelivery=Based on animal data and its mechanism of action, ZEPZELCA can cause fetal harm when administered to a pregnant woman. There are no available data to inform the risk of ZEPZELCA use in pregnant women. Intravenous administration of a single lurbinectedin dose (approximately 0.2 times the 3.2 mg/m2 clinical dose) to pregnant rats during the period of organogenesis caused embryolethality.

Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
|useInNursing=There are no data on the presence of lurbinectedin in human milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions from ZEPZELCA in breastfed children, advise women not to breastfeed during treatment with ZEPZELCA and for 2 weeks after the last dose.
|useInPed=The safety and effectiveness of ZEPZELCA in pediatric patients have not been established.
|useInGeri=Of the 105 patients with SCLC administered ZEPZELCA in clinical studies, 37 (35%) patients were 65 years of age and older, while 9 (9%) patients were 75 years of age and older. No overall difference in effectiveness was observed between patients aged 65 and older and younger patients.

There was a higher incidence of serious adverse reactions in patients ≥ 65 years of age than in patients < 65 years of age (49% vs. 26%, respectively). The serious adverse reactions most frequently reported in patients ≥ 65 years of age were related to myelosuppression and consisted of febrile neutropenia (11%), neutropenia (11%), thrombocytopenia (8%), and anemia (8%)
|useInGender=ZEPZELCA can cause embryolethality at doses lower than the human dose of 3.2 mg/m2.

'''Pregnancy Testing'''

Verify the pregnancy status of females of reproductive potential prior to initiating ZEPZELCA.

'''Contraception'''

''Females''

Advise female patients of reproductive potential to use effective contraception during treatment with ZEPZELCA and for 6 months after the last dose.

''Males''

Advise males with a female sexual partner of reproductive potential to use effective contraception during treatment with ZEPZELCA and for 4 months after the last dose.
|useInHepaticImpair=The effect of moderate or severe hepatic impairment (total bilirubin > 1.5 × ULN and any AST) on the pharmacokinetics of lurbinectedin has not been studied. No dose adjustment of ZEPZELCA is recommended for patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin 1 to 1.5 × ULN and any AST)
|administration=*Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter is observed, do not administer.

*ZEPZELCA can be administered with or without an in-line filter. If infusion lines containing in-line filters are utilized for administration of ZEPZELCA, polyethersulfone (PES) in-line filters with pore sizes of 0.22 micron are recommended.

*Do not use in-line nylon membrane filters when the reconstituted ZEPZELCA solution is diluted using 0.9% Sodium Chloride Injection, USP. Adsorption of ZEPZELCA to the Nylon membrane filters has been observed when 0.9% Sodium Chloride Injection, USP is used as the diluent.

*Compatibility with other intravenous administration materials and the diluted ZEPZELCA solution has been demonstrated in the following materials:

*Polyolefin containers (polyethylene, polypropylene and mixtures).

*Polyvinyl Chloride (PVC) (non-DEHP-containing), polyurethane and polynlefin infusion sets (polyethylene, polypropylene and polybutadiene).

*Implantable venous access systems with titanium and plastic resin ports and with polyurethane or silicone intravenous catheters.

*Do not co-administer ZEPZELCA and other intravenous drugs concurrently within the same intravenous line.
|monitoring=Monitor blood counts including neutrophil count and platelet count prior to each administration. For neutrophil count less than 500 cells/mm3 or any value less than lower limit of normal, the use of G-CSF is recommended. Withhold, reduce the dose, or permanently discontinue ZEPZELCA based on severity
|mechAction=Lurbinectedin is an alkylating drug that binds guanine residues in the minor groove of DNA, forming adducts and resulting in a bending of the DNA helix towards the major groove. Adduct formation triggers a cascade of events that can affect the subsequent activity of DNA binding proteins, including some transcription factors, and DNA repair pathways, resulting in perturbation of the cell cycle and eventual cell death.

Lurbinectedin inhibited human monocyte activity in vitro and reduced macrophage infiltration in implanted tumors in mice.
|PD=Lurbinectedin exposure-response relationships and the pharmacodynamic time-course for efficacy have not been fully characterized.

Increased incidence of Grade 4 neutropenia and Grade ≥ 3 thrombocytopenia were observed with increased lurbinectedin exposure.

'''Cardiac Electrophysiology'''

No large mean increase in QTc (i.e., > 20 ms) was detected at the recommended dose of 3.2 mg/m2.
|PK=Following the approved recommended dosage, geometric mean (%CV) of plasma Cmax and AUC0-inf, were 107 µg/L (79%) and 551 µg•h/L (94%), respectively. No accumulation of lurbinectedin in plasma is observed upon administrations every 3 weeks.

'''Distribution'''

The volume of distribution of lurbinectedin at steady state is 504 L (39%). Plasma protein binding is approximately 99%, to both albumin and α-1-acid glycoprotein.

'''Elimination'''

The terminal half-life of lurbinectedin is 51 hours. Total plasma clearance of lurbinectedin is 11 L/h (50%).

'''Metabolism'''

'''Lurbinectedin is metabolized by CYP3A in vitro.'''

''Excretion''

After a single dose of radiolabeled lurbinectedin, 89% of the radioactivity was recovered in feces (< 0.2% unchanged) and 6% in urine (1% unchanged).

'''Specific Populations'''

No clinically significant differences in the pharmacokinetics of lurbinectedin were identified based on age (18-85 years), sex, body weight (39-154 kg), mild to moderate renal impairment (CLcr 30 to 89 mL/min) or mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin between 1 to 1.5 × ULN and any AST). The effects of severe renal impairment (CLcr < 30 mL/min) and moderate or severe hepatic impairment (total bilirubin > 1.5 × ULN and any AST) on the pharmacokinetics of lurbinectedin have not been studied.

'''Drug Interactions Studies'''

''Clinical Studies''

Effects of CYP3A Inhibitors on Lurbinectedin: Coadministration of itraconazole (a strong CYP3A inhibitor) increased systemic exposure (AUC) of total lurbinectedin by 2.7-fold and unbound lurbinectedin by 2.4-fold.

Effects of CYP3A Inducers on Lurbinectedin: Coadministration of bosentan (a moderate CYP3A inducer) decreased systemic exposure (AUC) of total lurbinectedin by 20% and unbound lurbinectedin by 19%. These changes are not considered clinically relevant.

''In vitro Studies''

Cytochrome P450 (CYP) Enzymes: Lurbinectedin is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4.

Lurbinectedin is not an inducer of CYP1A2 or CYP3A4.

'''Transporter Systems:''' Lurbinectedin is a substrate of MDR1, but is not a substrate of OATB1P1, OATP1B3, OCT1, or MATE1. Lurbinectedin inhibits MDR1, OATP1B1, OATP1B3, and OCT1 but not BCRP, BSEP, MATE1, OAT1, OAT3, or OCT2.
|nonClinToxic=Carcinogenicity testing of lurbinectedin has not been performed. Lurbinectedin is genotoxic to mammalian cells in the presence and absence of metabolic activation. Lurbinectedin was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay.

Fertility studies with lurbinectedin were not performed. There were no findings in reproductive organs in general toxicology studies in rats, dogs, or monkeys; however, the highest doses and exposures in these studies were all at levels lower than those at the human dose of 3.2 mg/m2.
|clinicalStudies=PM1183-B-005-14 (Study B-005; NCT02454972) is a multicenter, open-label, multi-cohort trial evaluating ZEPZELCA as a single agent in patients with advanced or metastatic solid tumors. A cohort of patients with small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy received ZEPZELCA 3.2 mg/m2 by intravenous infusion every 21 days (one cycle). Patients received a median of 4 cycles of ZEPZELCA (range 1 to 24 cycles). The trial excluded patients with central nervous system (CNS) involvement, grade ≥ 3 dyspnea, daily intermittent oxygen requirement, hepatitis or cirrhosis, and immunocompromised patients. Tumor assessments were conducted every 6 weeks for the first 18 weeks and every 9 weeks thereafter. The major efficacy outcome measure was confirmed investigator-assessed overall response rate (ORR). Additional efficacy outcome measures included duration of response (DoR), and an Independent Review Committee (IRC) assessed ORR using Response Evaluation Criteria in Solid Tumors (RECIST v1.1).

A total of 105 patients with SCLC who progressed on or after platinum-based chemotherapy were enrolled. The median age was 60 years (range: 40 to 83) with 65% of patients < 65 years and 35% of patients ≥ 65 years, and 60% were male. The majority (75%) of the patients were White, 1% were Asian, 1% were Black and 23% were not reported. Baseline ECOG performance status was 0 or 1 in 92% of patients, and 92% were former/current smokers. All patients received at least one line of platinum-based chemotherapy (range 1-2 lines), and prior radiotherapy had been administered to 71% of patients. Eight patients (8%) had prior immunotherapy in addition to platinum-based chemotherapy. Sixty patients (57%) had platinum-sensitive SCLC, defined as recurrence or progression ≥ 90 days after the last dose of platinum-containing therapy (chemotherapy free interval [CTFI] ≥ 90 days). The remaining 45 patients had platinum-resistant SCLC, defined as recurrence or progression < 90 days after the last dose of platinum-containing therapy (CTFI < 90 days).
|howSupplied=ZEPZELCA (lurbinectedin) for injection is supplied as a sterile, preservative-free, white to off‑white lyophilized powder in a single-dose clear glass vial. Each carton (NDC 68727‑712-01) contains 4 mg in one single-dose vial.
|storage=Store refrigerated at 2° to 8°C (36° to 46°F).
ZEPZELCA is a hazardous drug. Follow applicable special handling and disposal procedures1.
|fdaPatientInfo='''Myelosuppression'''

Advise patients to immediately contact their healthcare provider for fever, other signs of infection, unusual bruising, bleeding, tiredness or pallor.

'''Hepatotoxicity'''

Advise patients to contact their healthcare provider immediately for signs and symptoms suggestive of hepatotoxicity.

'''Extravasation Resulting in Tissue Necrosis'''

Advise patients to contact their healthcare provider immediately for signs and symptoms of extravasation. The time to onset of necrosis after extravasation may vary.

'''Rhabdomyolysis'''

Advise patients to contact their healthcare provider immediately for signs and symptoms of rhabdomyolysis.

'''Embryo-Fetal Toxicity'''

*Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.

Advise females of reproductive potential to use effective contraception during treatment with ZEPZELCA and for 6 months after the last dose.

*Advise males with female partners of reproductive potential to use effective contraception during treatment with ZEPZELCA and for 4 months after the last dose.
'''Lactation'''

Advise women not to breastfeed during treatment with ZEPZELCA and for at least 2 weeks after the last dose.

'''Drug Interactions'''

Advise patients to inform their healthcare providers of all concomitant medications, herbal and dietary supplements. Advise patients to avoid grapefruit products and Seville oranges during treatment with ZEPZELCA
|alcohol=Alcohol-Lurbinectedin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=Zepzelca
}}

Triheptanoin

2025-05-03T15:12:58Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=triheptanoin |aOrAn=a |drugClass=source of heptanoate fatty acids |indicationType=treatment |indication=of adult and pediatric patients with molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAOD). |blackBoxWarningTitle='''TITLE''' |blackBoxWarningBody=''Condition Name:'' (Content) |fdaLIADAdu..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=triheptanoin
|aOrAn=a
|drugClass=source of heptanoate fatty acids
|indicationType=treatment
|indication=of adult and pediatric patients with molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAOD).
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=DOJOLVI is indicated as a source of calories and fatty acids for the treatment of adult and pediatric patients with molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAOD).

'''DOSAGE'''
The recommended target daily dosage of DOJOLVI is up to 35% of the patient's total prescribed DCI divided into at least four doses and administered by mixing thoroughly into semi-solid food/liquid or medical food/formula at mealtimes or with snacks.

In order to reach a target daily dosage, patients may require an increase in their total fat intake.

The neonatal population may require higher fat intake and therefore an increased amount of DOJOLVI. Consider current nutritional recommendations when dosing the neonatal population.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Triheptanoin in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Triheptanoin in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Triheptanoin in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Triheptanoin in pediatric patients.
|contraindications=None
|warnings='''Feeding Tube Dysfunction'''
Feeding tube performance and functionality can degrade over time depending on usage and environmental conditions. In clinical trials, feeding tube dysfunction was reported in patients receiving triheptanoin. The contribution of DOJOLVI cannot be ruled out. Do not administer DOJOLVI in feeding tubes manufactured of polyvinyl chloride (PVC). Regularly monitor the feeding tube to ensure proper functioning and integrity.

'''Intestinal Malabsorption in Patients with Pancreatic Insufficiency'''
Pancreatic enzymes hydrolyze triheptanoin and release heptanoate as medium-chain fatty acids in the small intestine. Low or absent pancreatic enzymes may result in reduced absorption of heptanoate subsequently leading to insufficient supplementation of medium-chain fatty acids. Avoid administration of DOJOLVI in patients with pancreatic insufficiency.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety population included 79 patients with LC-FAOD exposed to DOJOLVI in two studies: one open-label 78-week study of DOJOLVI in 29 patients (Study 1) followed by an open-label extension study (Study 2). Twenty-four patients from Study 1 continued into Study 2. Patients ranged from 4 months to 63 years of age and the population was 52% male. Of the 79 patients, 87% were White, 5% were Black or African-American, 4% were Asian, and 4% other. The daily dosage of DOJOLVI ranged between 12% and 41% DCI (which corresponds to 0.7 g/kg/day to 6.0 g/kg/day for pediatric patients and 0.5 g/kg/day to 1.3 g/kg/day for adult patients) for a mean duration of 23 months.

The most common adverse reactions to DOJOLVI reported in the pooled safety population of Study 1 and Study 2 were gastrointestinal (GI)-related, and included abdominal pain (abdominal discomfort, abdominal distension, abdominal pain, abdominal pain upper, GI pain) [60%], diarrhea [44%], vomiting [44%], and nausea [14%].

'''Gastrointestinal (GI) Adverse Reactions'''

In Study 1 and Study 2, median time to onset of a first occurrence of a GI adverse reaction was 7.3 weeks. GI adverse reactions led to dose reductions in 35% and 12% of patients in Study 1 and Study 2, respectively.

In Study 3, a 4-month double-blind randomized controlled study, commonly reported adverse reactions with triheptanoin were similar to those reported in Study 1 and Study 2.
|drugInteractions='''Pancreatic Lipase Inhibitors'''
Co-administration of triheptanoin with a pancreatic lipase inhibitor (e.g., orlistat) may reduce exposure to the triheptanoin metabolite, heptanoate, and reduce the clinical effect of triheptanoin. Avoid co-administration of DOJOLVI with pancreatic lipase inhibitors.
|useInLaborDelivery=There are no available data on triheptanoin use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies conducted in pregnant rats and rabbits administered triheptanoin during the period of organogenesis, the primary toxicological effect (reduced body weight gain) was considered to be specific to decreased food consumption related to taste aversion in animals, and therefore is not relevant to clinical use in the intended populations.

There is a pregnancy safety study for DOJOLVI. If a patient becomes pregnant while receiving DOJOLVI, healthcare providers should report DOJOLVI exposure by calling Ultragenyx Pharmaceutical Inc. at 1-888-756-8657.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
|useInNursing=There are no data on the presence of triheptanoin or its metabolites in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Medium-chain triglycerides and other fatty acids are normal components of breastmilk and the composition of breastmilk varies within feedings, over stages of lactation, and between mothers and populations due to maternal factors including genetics, environment, and diet. The developmental and health benefits of breastfeeding should be considered along with the clinical need for DOJOLVI and any potential adverse effect on the breastfed infant from DOJOLVI or from the underlying maternal condition.
|useInPed=The safety and effectiveness of DOJOLVI have been established in pediatric patients
|useInGeri=Clinical studies of DOJOLVI did not include patients 65 years of age and older to determine if they respond differently from younger adult patients.
|administration=Administer DOJOLVI by mixing thoroughly with semi-solid food/liquid (oral administration) or medical food/formula (feeding tube administration). Do not administer DOJOLVI alone to avoid gastrointestinal upset and feeding tube degradation.

Prepare or administer DOJOLVI using containers, oral syringes, or measuring cups made of compatible materials such as stainless steel, glass, high density polyethylene (HDPE), polypropylene, low density polyethylene, polyurethane, and silicone.

Do not prepare or administer DOJOLVI using containers, oral syringes, or measuring cups made of polystyrene or polyvinyl chloride (PVC) plastics.

Regularly monitor the containers, dosing components, or utensils that are in contact with DOJOLVI to ensure proper functioning and integrity.

'''Oral Preparation and Administration'''

*Use an oral syringe or measuring cup made of compatible materials as listed above to withdraw the prescribed volume of DOJOLVI from the bottle.
*DOJOLVI can be mixed with soft food or liquid such as:
*plain or artificially sweetened fat free yogurt
*fat free milk, formula, or cottage cheese
*whole grain hot cereal
*fat free low carbohydrate pudding, smoothies, applesauce, or baby food
*Add the prescribed amount of DOJOLVI to a clean bowl, cup, or container, made of the compatible materials as listed above, which contains an appropriate amount of semi-solid food or liquid that takes into consideration the age, size, and fluid needs of the patient to ensure administration of the full dose.
*Mix DOJOLVI thoroughly into the food or liquid.
*Any unused mixture may be stored for up to 24 hours in refrigerated conditions.
*If not used within 24 hours, discard the DOJOLVI mixture in the trash. Do not pour down the sink. Do not save for later.
'''Feeding Tube Preparation and Administration'''

DOJOLVI is administered as an oral or enteral bolus medication. Do not add DOJOLVI to the feeding bag, as the feeding equipment may degrade over time.

DOJOLVI can be administered via oral or enteral feeding tubes manufactured of silicone or polyurethane. Do not use feeding tubes manufactured of polyvinyl chloride (PVC). Feeding device performance and functionality can degrade over time depending on usage and environmental conditions. Regularly monitor the feeding tube to ensure proper functioning and integrity.

Use an oral syringe or measuring cup made of compatible materials as listed above to withdraw the prescribed volume of DOJOLVI from the bottle.
Add the prescribed amount of DOJOLVI to a clean bowl, cup, or container, made of compatible materials as listed above, which contains an amount of medical food or formula that takes into consideration the age, size, and fluid needs of the patient in order to ensure administration of the full dose.
Mix DOJOLVI thoroughly into the medical food or formula prior to administering via feeding tube, y-connector, or feeding tube extension set made of silicone or polyurethane.
Draw up the entire amount of the DOJOLVI mixture into a slip tip syringe.
Remove the residual air from the syringe and connect the syringe directly into the feeding tube port.
Push the syringe contents into the feeding tube port using steady pressure until empty.
Flush the feeding tubes with between 5 mL to 30 mL of water. Flush volume should be modified based on specific patient needs and in cases of fluid restriction.
Discard any unused DOJOLVI mixture in the trash. Do not pour down the sink. Do not save for later use.
|monitoring=*Monitor the patient's total caloric intake during dosage titration, especially in a patient with gastrointestinal adverse reactions, and adjust all components of the diet as needed.

*Regularly monitor the containers, dosing components, or utensils that are in contact with DOJOLVI to ensure proper functioning and integrity.
|mechAction=Triheptanoin is a medium-chain triglyceride consisting of three odd-chain 7-carbon length fatty acids (heptanoate) that provide a source of calories and fatty acids to bypass the long-chain FAOD enzyme deficiencies for energy production and replacement.
|PD=No formal pharmacodynamic studies have been conducted with DOJOLVI.
|PK=Following oral administration, triheptanoin is extensively hydrolyzed to heptanoate and glycerol by pancreatic lipases in the intestines. The exposure of triheptanoin in the human plasma is minimal. Pharmacokinetics of heptanoate exhibits high inter-patient variability. Heptanoate exposure increases greater than dose-proportional in the dose range between triheptanoin 0.3 and 0.4 g/kg.

'''Absorption'''

The pharmacokinetics of heptanoate in healthy adult subjects following an oral administration of DOJOLVI mixed with food are summarized.

'''Distribution'''

The plasma protein binding of heptanoate is approximately 80% and is independent of total concentration.

'''Elimination'''

After a single dose of either 0.3 g/kg or 0.4 g/kg triheptanoin to healthy subjects, the mean apparent clearance (CL/F) of heptanoate was 6.05 and 4.31 L/hr/kg, respectively. Half-life (t1/2) of heptanoate could not be determined due to multiple peak concentrations of heptanoate observed.

'''Metabolism'''

Heptanoate, formed by hydrolysis of triheptanoin, can be metabolized to beta-hydroxypentanoate (BHP) and beta-hydroxybutyrate (BHB) in the liver.

'''Excretion'''

After single or multiple repeat doses of triheptanoin to healthy subjects, triheptanoin and its metabolites were minimally excreted in urine.

'''Drug Interaction Studies'''

''In Vitro Studies''

Heptanoate is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Heptanoate and BHP are not CYP substrates nor UGT substrates. Heptanoate increases the unbound fraction of valproic acid by approximately 2-fold.
|nonClinToxic='''Carcinogenesis'''

Nonclinical animal studies evaluating long-term administration of triheptanoin have not been conducted to assess the carcinogenic potential of the drug. In a published chronic 9-month dietary study conducted in rats, daily administration of triheptanoin at dose levels up to 1.14 g/kg was associated with atrophy or hyperplasia of the intestinal villa. In a chronic 9-month dietary study conducted in juvenile minipigs, treatment with triheptanoin at dose levels up to 10 g/kg was well tolerated with no changes in histopathology suggestive of any carcinogenic potential.

Published studies with structurally similar triglycerides (i.e., MCTs) were also evaluated. In a 2-year dietary study of rats fed tricaprylin (C8 MCT) at dose levels up to 9.5 g/kg (approximately 1.2 times the anticipated maximum clinical dose), there were increased incidences of pancreatic and forestomach hyperplasia and adenomas but not carcinomas. Chronic administration of a diet containing approximately 17% MCT was not shown to promote effects on colon tumor incidence in an azomethane-induced colon tumorigenicity rat model.

'''Mutagenesis'''

Triheptanoin was not genotoxic in a battery of genotoxicity tests including the in vitro bacterial reverse mutation in S. typhimurium and E. coli, in vitro mammalian chromosomal aberration test in human peripheral blood lymphocytes and the in vivo mammalian erythrocyte micronucleus test in rat bone marrow.

'''Impairment of Fertility'''

Triheptanoin had no effect on fertility or any other parameters of mating performance in rats exposed to repeat dietary administration at dose levels equivalent to up to 50% daily caloric intake (16 g/kg) that resulted in systemic drug exposure (AUC) of heptanoate approximately equal to the maximum recommended human dose.
|clinicalStudies=The efficacy of triheptanoin as a source of calories and fatty acids was evaluated in Study 3 (NCT01379625), a 4-month double-blind randomized controlled study comparing triheptanoin (7-carbon chain fatty acid) with trioctanoin (8-carbon chain fatty acid). The study enrolled 32 adult and pediatric patients with a confirmed diagnosis of LC-FAOD and evidence of at least one significant episode of rhabdomyolysis and at least two of the following diagnostic criteria: disease specific elevation of acylcarnitines on a newborn blood spot or in plasma, low enzyme activity in cultured fibroblasts, or one or more known pathogenic mutations in CPT2, ACADVL, HADHA, or HADHB.

The dosage of study drug was titrated to a protocol-specified target of 20% DCI (actual mean daily dose achieved was 16% for triheptanoin and 14% for trioctanoin). The recommended target dosage of DOJOLVI is up to 35% of DCI. Patients ranged in age from 7 years to 64 years (median 24 years) and 12 were male. Of the 32 patients, 100% were White and 3% were Hispanic.

Baseline cardiovascular function in both groups was normal and within test/retest variability normally observed in repeated echocardiograms. After 4 months, patients in both groups had similar mean changes from baseline in left ventricular ejection fraction and wall mass on resting echocardiogram and similar maximal heart rates on treadmill ergometry.

Five patients experienced 7 events of rhabdomyolysis in the triheptanoin group and 4 patients experienced 7 events of rhabdomyolysis in the trioctanoin group.

No differences were observed between triheptanoin and trioctanoin groups in blood markers of metabolism including glucose, insulin, lactate, total serum, ketones, acylcarnitines, and serum-free fatty acid concentrations.
|howSupplied=500 mL bottle
|storage=Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature). Do not freeze.

DOJOLVI can be used for up to 9 months after opening but not beyond the expiration date on the bottle.

Do not dose or store using materials made of polystyrene or polyvinyl chloride (PVC) containers
|fdaPatientInfo=Advise the patient and/or caregiver to read the FDA-approved patient labeling.

'''Preparation and Administration'''

'''Instruct the patient or caregiver:'''

To read the Instructions for Use for appropriate preparation and administration instructions on oral versus feeding tube administration.
Before administration, to mix DOJOLVI thoroughly into semi-solid food/liquid (oral) or medical food/formula (feeding tube) at mealtimes or with snacks.
To not prepare or administer DOJOLVI using containers, oral syringes, or measuring cups made of polystyrene or polyvinyl chloride (PVC) plastics.
That if a dose is missed, to take the next dose as soon as possible with subsequent doses taken at 3 to 4-hour intervals. Skip the missed dose if it will not be possible to take all doses in a day.
'''Storage'''

Instruct the patient or caregiver to store DOJOLVI at room temperature in the bottle in which it was dispensed.

'''Feeding Tube Dysfunction'''

Advise the patient or caregiver to regularly monitor the feeding tube for proper functioning and integrity and report to the healthcare provider if any issues are identified [see Warnings and Precautions (5.1)].

'''Intestinal Malabsorption in Patients with Pancreatic Insufficiency'''

Inform the patient or caregiver that pancreatic insufficiency may reduce the clinical effect of DOJOLVI. Any known pancreatic insufficiency should be reported to the healthcare provider.

'''Pregnancy'''

Advise a patient who is exposed to DOJOLVI during pregnancy that there is a pregnancy safety study that monitors pregnancy outcomes. Encourage the patient to report the pregnancy to Ultragenyx Pharmaceutical Inc. at 1-888-756-8657
|alcohol=Alcohol-Triheptanoin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=Dojolvi
}}

Remimazolam

2025-05-03T14:53:13Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=remimazolam |aOrAn=a |drugClass=activate of GABAa receptors |indication=BYFAVO® is indicated for the induction and maintenance of procedural sedation in adults undergoing procedures lasting 30 minutes or less. |hasBlackBoxWarning=Yes |adverseReactions=*Neonatal Sedation and Withdrawal Syndrome |blackBoxWarningTitle='''PERSONNEL AND EQUIPMENT FOR MONITO..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=remimazolam
|aOrAn=a
|drugClass=activate of GABAa receptors
|indication=BYFAVO® is indicated for the induction and maintenance of procedural sedation in adults undergoing procedures lasting 30 minutes or less.
|hasBlackBoxWarning=Yes
|adverseReactions=*Neonatal Sedation and Withdrawal Syndrome
|blackBoxWarningTitle='''PERSONNEL AND EQUIPMENT FOR MONITORING AND RESUSCITATION AND RISKS FROM CONCOMITANT USE WITH OPIOID ANALGESICS'''
|blackBoxWarningBody=''Personnel and Equipment for Monitoring and Resuscitation:'' (*Only personnel trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer BYFAVO.
*Administering personnel must be trained in the detection and management of airway obstruction, hypoventilation, and apnea, including the maintenance of a patent airway, supportive ventilation, and cardiovascular resuscitation.
*BYFAVO has been associated with hypoxia, bradycardia, and hypotension. Continuously monitor vital signs during sedation and during the recovery period.
*Resuscitative drugs, and age- and size-appropriate equipment for bag/valve/mask assisted ventilation must be immediately available during administration of BYFAVO.
''Risks From Concomitant Use With Opioid Analgesics and Other Sedative-Hypnotics:'' (Concomitant use of benzodiazepines, including BYFAVO, and opioid analgesics may result in profound sedation, respiratory depression, coma, and death. The sedative effect of intravenous BYFAVO can be accentuated by concomitantly administered CNS depressant medications, including other benzodiazepines and propofol. Continuously monitor patients for respiratory depression and depth of sedation)
|fdaLIADAdult=BYFAVO® is indicated for the induction and maintenance of procedural sedation in adults undergoing procedures lasting 30 minutes or less.

'''DOSAGE'''
BYFAVO can depress respiration. Continuously monitor patients for early signs of hypoventilation, airway obstruction, and apnea using capnography, pulse oximetry, and clinical assessment.

Only personnel trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer BYFAVO.

Administering personnel must be trained in the detection and management of airway obstruction, hypoventilation, and apnea, including the maintenance of a patent airway, supportive ventilation, and cardiovascular resuscitation.

Supplemental oxygen, resuscitative drugs, and age- and size-appropriate equipment for bag/valve/mask assisted ventilation must be immediately available during administration of BYFAVO. A benzodiazepine reversal agent should be immediately available.

Continuously monitor vital signs during sedation and through the recovery period.

Peak sedation occurs approximately 3 to 3.5 minutes after an initial 5 mg intravenous injection of BYFAVO given over a 1-minute period.

Titrate subsequent doses of BYFAVO on the basis of clinical judgment and assessment of the depth of sedation. If maintenance of procedural sedation is inadequate, consider alternative medications
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Remimazolam in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Remimazolam in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Remimazolam in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Remimazolam in pediatric patients.
|contraindications=BYFAVO is contraindicated in patients with a history of severe hypersensitivity reaction to dextran 40 or products containing dextran 40
|warnings='''Personnel and Equipment for Monitoring and Resuscitation'''
Clinically notable hypoxia, bradycardia, and hypotension were observed in Phase 3 studies of BYFAVO. Continuously monitor vital signs during sedation and through the recovery period.

Only personnel trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer BYFAVO.

Administering personnel must be trained in the detection and management of airway obstruction, hypoventilation, and apnea, including the maintenance of a patent airway, supportive ventilation, and cardiovascular resuscitation.

Resuscitative drugs, and age- and size-appropriate equipment for bag/valve/mask assisted ventilation must be immediately available during administration of BYFAVO.

Consider the potential for worsened cardiorespiratory depression prior to using BYFAVO concomitantly with other drugs that have the same potential (e.g., opioid analgesics or other sedative-hypnotics)

Administer supplemental oxygen to sedated patients through the recovery period.

A benzodiazepine reversal agent (flumazenil) should be immediately available during administration of BYFAVO.

'''Risks from Concomitant Use with Opioid Analgesics and Other Sedative-Hypnotics'''
Concomitant use of benzodiazepines, including BYFAVO, and opioid analgesics may result in profound sedation, respiratory depression, coma, and death.

The sedative effect of intravenous BYFAVO can be accentuated by concomitantly administered CNS depressant medications, including other benzodiazepines and propofol.

Titrate the dose of BYFAVO when administered with opioid analgesics and sedative-hypnotics to the desired clinical response.

Continuously monitor sedated patients for hypotension, airway obstruction, hypoventilation, apnea, and oxygen desaturation. These cardiorespiratory effects may be more likely to occur in patients with obstructive sleep apnea, the elderly, and ASA III or IV patients.

'''Hypersensitivity Reactions'''
BYFAVO contains dextran 40, which can cause hypersensitivity reactions, including rash, urticaria, pruritus, and anaphylaxis. BYFAVO is contraindicated in patients with a history of severe hypersensitivity reaction to dextran 40 or products containing dextran 40.

'''Neonatal Sedation and Withdrawal Syndrome'''
Receiving benzodiazepines late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate. Monitor neonates exposed to benzodiazepines, including BYFAVO, during pregnancy or labor for signs of sedation and monitor neonates exposed to benzodiazepines during pregnancy for signs of withdrawal and manage these neonates accordingly.

'''Pediatric Neurotoxicity'''
Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours.

The clinical significance of these findings is not clear. However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans.

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of BYFAVO was evaluated in three prospective, randomized, double-blind, multicenter, parallel group clinical studies in 630 patients undergoing colonoscopy (two studies) or bronchoscopy (one study). Colonoscopy Study 1 and the bronchoscopy study evaluated American Society of Anesthesiologists (ASA) physical status I to III patients, and Colonoscopy Study 2 evaluated ASA III and IV patients.

All three studies evaluated the safety of BYFAVO compared to placebo with midazolam rescue and an open-label midazolam treatment arm. Patients were administered a total dose ranging from 5 to 30 mg of BYFAVO. In these studies, the most common adverse reactions (incidence greater than 10%) following BYFAVO administration were hypotension, hypertension, diastolic hypertension, systolic hypertension, hypoxia, and diastolic hypotension. There were two patients who experienced an adverse reaction that led to discontinuation of study drug. One patient in the BYFAVO arm in the bronchoscopy study discontinued treatment due to bradycardia, hypertension, hypotension, hypoxia, and respiratory rate increase. One patient in the open-label midazolam arm in Colonoscopy Study 2 discontinued due to respiratory acidosis. No deaths were reported during the studies.
|drugInteractions='''Opioid Analgesics and Other Sedative-Hypnotics'''
The sedative effect of intravenous BYFAVO can be accentuated by concomitantly administered CNS depressant medications, including opioid analgesics, other benzodiazepines, and propofol. Continuously monitor vital signs during sedation and through the recovery period. Titrate the dose of BYFAVO when administered with opioid analgesics and sedative-hypnotics to the desired clinical response
|useInLaborDelivery=Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal. Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects.

In animal studies, reduced fetal weights but no evidence of malformations or embryofetal lethality were noted in a study in which pregnant rabbits were treated intravenously with 4 times the maximum recommended human dose (MRHD) of 30 mg during organogenesis. Adequate rodent reproductive and developmental toxicology studies have not been completed to fully evaluate the effects of BYFAVO.

Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours. There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
|useInNursing=There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk. There are no data on the effects of remimazolam in human milk, the effects on the breastfed infant or the effects on milk production. Remimazolam is present in animal milk. When a drug is present in animal milk, it is likely that it will be present in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BYFAVO and any potential adverse effects on the breastfed child from BYFAVO or from the underlying maternal condition.
|useInPed=Safety and effectiveness in pediatric patients have not been established. No studies are available in any pediatric population and extrapolation of adult effectiveness data to the pediatric population is not possible.

Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as BYFAVO, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss; however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical dataSafety and effectiveness in pediatric patients have not been established. No studies are available in any pediatric population and extrapolation of adult effectiveness data to the pediatric population is not possible.

Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as BYFAVO, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss; however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data
|useInGeri=Of the total number of subjects treated with BYFAVO in clinical studies for procedural sedation, there were 649 subjects <65 years of age, 221 subjects >65 years of age, 171 subjects between 65-74 years of age, and 50 subjects >75 years of age.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. Some data suggest a potential of greater sensitivity (a faster onset of loss of consciousness and a longer duration of sedation) of some older individuals.

Administer supplemental doses of BYFAVO slowly to achieve the level of sedation required for the procedure, and monitor all patients for cardiorespiratory complications.
|useInHepaticImpair=In patients with severe hepatic impairment, the dose of BYFAVO should be carefully titrated to effect. Depending on the overall status of the patient, lower frequency of supplemental doses may be needed to achieve the level of sedation required for the procedure. All patients should be monitored for sedation-related cardiorespiratory complications
|administration=*BYFAVO has been shown to be compatible with the following intravenous fluids:
*0.9% Sodium Chloride Injection, USP
*5% Dextrose Injection, USP
*20% Dextrose Injection, USP
*5% Dextrose and 0.45% Sodium Chloride Injection, USP.
*BYFAVO has also been shown to be compatible with Ringer's Solution, a solution containing Sodium Chloride, Potassium Chloride and Calcium Chloride Dihydrate.
*BYFAVO has been shown to be incompatible with the following intravenous fluids:
*Lactated Ringer's Solution, a solution containing Sodium Chloride, Sodium Lactate, Potassium Chloride, and Calcium Chloride Dihydrate. Lactated Ringer's Solution is also known as Ringer's Lactate Solution, Compound Sodium Lactate Solution, and Hartmann's Solution.
Acetated Ringer's Solution, a solution containing Sodium Chloride, Sodium Acetate, Potassium Chloride, and Calcium Chloride Dihydrate.
BYFAVO compatibility with other agents has not been adequately evaluated.
*Do not mix BYFAVO with other drugs or fluids prior to administration.
|monitoring=Clinically notable hypoxia, bradycardia, and hypotension were observed in Phase 3 studies of BYFAVO. Continuously monitor vital signs during sedation and through the recovery period.

Only personnel trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer BYFAVO.

Administering personnel must be trained in the detection and management of airway obstruction, hypoventilation, and apnea, including the maintenance of a patent airway, supportive ventilation, and cardiovascular resuscitation.

Resuscitative drugs, and age- and size-appropriate equipment for bag/valve/mask assisted ventilation must be immediately available during administration of BYFAVO
|overdose=Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal. Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage.
|mechAction=BYFAVO is a benzodiazepine. BYFAVO binds to brain benzodiazepine sites (gamma amino butyric acid type A [GABAA] receptors), while its carboxylic acid metabolite (CNS7054) has a 300 times lower affinity for the receptor. BYFAVO, like other benzodiazepines, did not show clear selectivity between subtypes of the GABAA receptor.
|PD=Dose finding studies determined the IV dosing recommendation of the initial 5 mg bolus, followed by 2.5 mg top-up doses. Median time to peak sedation, defined as the lowest Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score after the initial dose, in the Phase 3 trials was 3 to 3.5 minutes and median time to fully alert, defined as time to the first of three consecutive MOAA/S scores of five, following the last dose of BYFAVO was 11 to 14 minutes.

'''Cardiac Electrophysiology'''

In a thorough QT study, 57 healthy volunteers were given an IV push of 10 mg or 20 mg BYFAVO, intravenous midazolam (2.5 mg or 7.5 mg) or placebo, or a single tablet of moxifloxacin 400 mg given orally. The largest mean placebo-adjusted change-from-baseline QTc (upper bound of 2-sided 90% confidence interval) was 6.7 (9.5) ms, 10.7 (13.4) ms, 4.5 (7.3) ms, and 8.1 (10.8) ms, respectively, after treatment with 10 mg or 20 mg BYFAVO, or 2.5 mg or 7.5 mg midazolam.

BYFAVO treatment is associated with increases in heart rate. The largest mean placebo-adjusted change-from-baseline HR (upper bound of 2-sided 90% confidence interval) was 12.3 (14.2) bpm and 15.2 (17.1) bpm, respectively, after treatment with 10 mg and 20 mg BYFAVO.
|PK=*BYFAVO has a terminal elimination half-life from plasma of 37 to 53 minutes.
*Mean distribution half-life (t1/2α) is between 0.5 and 2 minutes.
*Half-life (t1/2) is prolonged with increasing severity of hepatic impairment leading to a need for careful dose titration in patients with severe hepatic impairment.
*Clearance (54 to 75 L/h) is not related to body weight.
*In healthy subjects at least 80% and in colonoscopy patients 50% to 60% of dose is excreted in urine as inactive metabolite.
'''Absorption'''

BYFAVO is administered intravenously. BYFAVO overall maximum plasma concentration (Cmax) after IV administration of 0.01 to 0.5 mg/kg was 189 to 6,960 ng/mL, and overall area under the concentration versus time curve from time 0 to infinity (AUC0-∞) was 12.1 to 452 ng∙h/mL; BYFAVO cumulative dose versus BYFAVO total exposure (AUC0-∞) suggested a close to dose-proportional relationship. Metabolite Cmax was achieved approximately 20-30 minutes post dose. Metabolite AUC0-∞ was 231 to 7,090 ng∙h/mL.

'''Distribution'''

BYFAVO volume of distribution (Vz) was 0.76 to 0.98 L/kg. Plasma protein binding of BYFAVO was >91%, primarily to human serum albumin.

'''Elimination'''

BYFAVO has a terminal elimination half-life from plasma of 37 to 53 minutes and mean distribution half-life (t1/2α) is between 0.5 and 2 minutes.

'''Metabolism'''

The main route of metabolism of BYFAVO is via conversion to primary inactive metabolite CNS7054, which is then subject to hydroxylation and glucuronidation. Conversion to CNS7054 is mediated by tissue carboxylesterases (primarily type 1A), with no meaningful contribution by cytochrome P450 enzymes. The t1/2 of the metabolite was 2.4 to 3.8 hours.

'''Excretion'''

In colonoscopy patients, approximately 0.003% BYFAVO is excreted unchanged in urine, and 50% to 60% is excreted in urine as the metabolite CNS7054.

'''Specific Populations'''

''Pediatric Patients''

There were no pediatric patients who received BYFAVO.

''Patients with Renal Impairment''

The pharmacokinetics of BYFAVO were not altered in patients with mild to end stage renal disease not requiring dialysis. In a renal impairment study, BYFAVO PK parameters (e.g., AUC and Cmax) were not statistically different in subjects with varying degrees of renal function (from normal to severely impaired). Increased exposure to inactive metabolite CNS7054 was observed with increasing degree of renal impairment.

''Patients with Hepatic Impairment''

A Phase 1 open-label, single-dose trial evaluated the PK and safety of BYFAVO given as an IV bolus of 0.1 mg/kg over 1 minute in subjects with hepatic impairment (8 moderately hepatically impaired subjects and 3 severely hepatically impaired subjects) and 9 matched healthy subjects.

The Cmax values of total BYFAVO were 10% to 20% lower in subjects with hepatic impairment than in healthy subjects. Larger Vz (33% increase in moderately impaired and 41% increase in severely impaired) and Vss (50% increase in moderately impaired and 115% increase in severely impaired), and prolonged t1/2 (60 minutes in moderately impaired and 105 minutes in severely impaired as compared to 42 minutes in healthy subjects), of BYFAVO were observed with increasing severity of hepatic impairment. Sedation lasted longer and recovery took longer for subjects with hepatic impairment compared to healthy subjects. The average duration of loss of consciousness and recovery time was 3.2 minutes and 12.1 minutes, respectively for subjects in the moderately hepatically impaired group. These times were 2.0 minutes and 16.7 minutes, respectively, for the subjects in the severely hepatically impaired group. Healthy control subjects had a loss of consciousness of 1.6 minutes and a recovery time of 8.0 minutes.

In patients with severe hepatic impairment, the dose of BYFAVO should be carefully titrated to effect. Depending on the overall status of the patient, less frequency of supplemental doses may be needed to achieve the level of sedation required for the procedure. All patients should be monitored for sedation-related cardiorespiratory complications.

''Other Specific Populations''

Age, sex, race, and weight had no clinically relevant effect on BYFAVO pharmacokinetics.

''Drug Interactions''

BYFAVO and the metabolite CNS7054 caused no relevant inhibition of cytochrome P450 isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4. There were no inducing effects on CYP1A2, 2B6, and 3A4. BYFAVO was not a relevant substrate of a panel of human drug transporters (OATP1B1, OATP1B3, BCRP).

No relevant inhibition of human drug transporters (OAT3, OCT2, OATP1B1, OATP1B3, OAT1, BCRP) was seen with BYFAVO or CNS7054. Remifentanil did not influence the hydrolysis of BYFAVO by human liver S9 fractions, reducing the possibility of an interaction by competition for liver carboxylesterases.

These results together show a very low potential of BYFAVO for pharmacokinetic drug interactions.
|nonClinToxic='''Carcinogenesis, Mutagenesis, Impairment of Fertility'''
''Carcinogenesis''

Long-term animal studies have not been performed to evaluate the carcinogenic potential of remimazolam.

''Mutagenesis''

Remimazolam was not mutagenic or clastogenic when evaluated in an in vitro bacterial reverse mutation assay (Ames test), an in vivo rat micronucleus assay, mouse lymphoma cells, in vivo rat bone marrow micronucleus assay, or comet assay.

''Impairment of Fertility''

In a study that did not test exposures comparable to the MRHD of 30 mg/day, there were no adverse effects on male or female fertility when male rats were treated for 28 days prior to mating and female rats were treated for 14 days prior to mating with up to 30 mg/kg remimazolam via intravenous bolus (approximately 0.03 times the MRHD based on AUC).

There was no impact on female fertility when female rabbits were administered remimazolam by intravenous infusion (up to 4 hours/day) up to 20 mg/kg/day (approximately 17 times the MRHD of 30 mg/day based on AUC) from 14 days prior to mating.

No adverse effects on histology of the testes and epididymides or evaluation of spermatid count, sperm motility, and sperm morphology were reported in a repeat-dose toxicity study in which male minipigs were administered remimazolam by intravenous infusion (6 hours) up to 120 mg/kg/day (approximately 400 times the MRHD based on AUC) for 28 days followed by a 14-day recovery period.

'''Animal Toxicology and/or Pharmacology'''
Published studies in animals demonstrate that the use of anesthetic agents during the period of rapid brain growth or synaptogenesis results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester through the first several months of life but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of an anesthetic regimen that produced a light surgical plane of anesthesia did not increase neuronal cell loss; however, treatment regimens of 5 hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with subtle but prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in neonates and young children who require procedures against the potential risks suggested by the nonclinical data
|clinicalStudies=The safety and efficacy of BYFAVO compared to a saline placebo with midazolam rescue treatment group and an open-label midazolam treatment group was evaluated in three randomized, double-blind, multicenter Phase 3 studies conducted in 969 adult patients receiving procedural sedation.

'''Colonoscopy Study 1 (NCT 02290873)'''
This Phase 3 study was conducted in 461 ASA I to III patients undergoing colonoscopy. BYFAVO 5 mg (2 mL) IV was administered as an initial bolus, followed by 2.5 mg (1 mL) top-up doses versus placebo 2 mL administered as an initial bolus, followed by 1 mL top-up doses. Midazolam rescue was dosed per investigator discretion in both treatment groups. Fentanyl was administered as an analgesic pre-treatment at an initial dose of 50 to 75 mcg IV (or a reduced dose for ASA III patients) immediately prior to administration of the initial dose of study medication. Top-up doses of fentanyl 25 mcg every 5 to 10 minutes were allowed until analgesia was adequate or a maximum dose of 200 mcg had been administered. Supplemental oxygen was administered prior to the start of the procedure and continued at a rate of 1 to 5 L/minute until the patient was fully alert after procedure completion. Colonoscopy started when adequate sedation was achieved, defined as an MOAA/S score ≤3. The primary efficacy endpoint for BYFAVO versus placebo was success of the colonoscopy procedure, defined as a composite of the following:

*Completion of the colonoscopy procedure, AND
*No requirement for a rescue sedative medication, AND
*No requirement for more than 5 doses of study medication within any 15-minute window.

There were 63 patients (13.8%) who were aged 65 years or older, 218 patients (47.6%) who were male, 339 (74.0%) who were white, 80 (17.5%) who were Black or African American, 31 (6.8%) who were Asian, and 73 (15.9%) who were Hispanic or Latino. There were 143 patients in ASA I, 285 in ASA II, and 30 in ASA III. As shown in Table 6, the colonoscopy sedation success rate was statistically significantly higher in the BYFAVO group than in the placebo group.

'''Bronchoscopy Study (NCT 02296892)'''
This Phase 3 study was conducted in 431 ASA I to III patients undergoing bronchoscopy. BYFAVO 5 mg (2 mL) IV was administered as an initial bolus, followed by 2.5 mg (1 mL) top-up doses versus placebo 2 mL administered as an initial bolus, followed by 1 mL top-up doses. Midazolam rescue was dosed per investigator discretion in both treatment groups. Fentanyl was administered as an analgesic pre-treatment at an initial dose of 25 to 50 mcg IV immediately prior to administration of the initial dose of study medication. Top-up doses of fentanyl 25 mcg every 5 to 10 minutes were allowed until analgesia was adequate. A maximum dose of fentanyl 200 mcg was recommended. Supplemental oxygen was administered prior to the start of the procedure and continued at a rate of 1 to 15 L/minute until the patient was fully alert after procedure completion. Bronchoscopy started when adequate sedation was achieved, defined as an MOAA/S score ≤3. The primary efficacy endpoint for BYFAVO versus placebo was successful sedation for the bronchoscopy procedure, defined as a composite of the following:

*Completion of the bronchoscopy procedure, AND
*No requirement for a rescue sedative medication, AND
*No requirement for more than 5 doses of study medication within any 15-minute window.
There were 209 patients (48.5%) who were 65 years or older, 198 patients (45.9%) who were male, 358 (83.1%) who were white, 62 (14.4%) who were Black or African American, 5 (1.2%) who were Asian, and 8 (1.9%) who were Hispanic or Latino. There were 15 patients in ASA I, 254 in ASA II, and 162 in ASA III. As shown in Table 10, the bronchoscopy sedation success rate was statistically significantly higher for the BYFAVO group than for the placebo group.

'''Colonoscopy Study 2 (NCT 02532647)'''
This Phase 3 study was conducted in 77 ASA III and IV patients undergoing colonoscopy. BYFAVO 2.5 mg (1 mL) to 5 mg (2 mL) IV was administered as an initial bolus, followed by 1.25 mg (0.5 mL) to 2.5 mg (1 mL) top-up doses versus placebo 1 to 2 mL administered with midazolam rescue, dosed per investigator discretion. Fentanyl was administered as an analgesic pre-treatment at an initial maximum dose of 50 mcg (with dose reduction for debilitated patients), immediately prior to administration of the initial dose of study medication. Top-up doses of fentanyl 25 mcg every 5 to 10 minutes were allowed until analgesia was adequate or a maximum dose of 200 mcg had been administered. Supplemental oxygen was administered prior to the start of the procedure and continued at a rate of up to 4 L/minute until the patient was fully alert after procedure completion. Colonoscopy started when adequate sedation was achieved, defined as an MOAA/S score ≤3.

The primary objective of the study was to assess the safety of multiple doses of BYFAVO compared to placebo and midazolam. Procedure success was a secondary objective and was defined as follows:

*Completion of the colonoscopy procedure, AND
*No requirement for a rescue sedative medication, AND
*No requirement for more than 5 doses of study medication within any 15-minute window.
The total patient population, including all randomized patients who received any amount of study medication, comprised 31 patients in the remimazolam group, 16 patients in the placebo group, and 30 patients in the midazolam group. There were two patients, one each in the remimazolam and midazolam treatment groups, who were randomized, but did not receive a dose of study medication.

There were 31 patients (40.2%) who were aged 65 years or older, 43 patients (55.8%) who were male, 57 (74.0%) who were white, 19 (24.7%) who were Black or African American, 1 (1.30%) who was Asian, and none who were Hispanic or Latino. There were 40 patients in ASA III and 37 patients in ASA IV.

Patients in the remimazolam group received a mean (± SD) of 9.0 (± 3.7) mg of remimazolam and a mean (± SD) of 2.5 (± 10.2) mg of midazolam compared to 7.2 (± 2.5) mg in the placebo group. The mean total dose of fentanyl was lower in the remimazolam group (mean ± SD: 59.7 ± 15.4 mcg) than in the placebo group (mean ± SD: 67.2 ± 21.8 mcg).

In the remimazolam group, 90.3% of patients did not receive any rescue sedative medication, compared to 0.0% in the placebo group.

There were no serious adverse reactions and no discontinuations due to adverse reactions observed in the remimazolam group. The incidence of hypotension (SMQ) was 61.3% in the remimazolam group and 75% in the placebo group.

No inferential statistical tests were performed in this trial. Patients who received BYFAVO for sedation during scheduled colonoscopy responded at a numerically greater rate than patients who received placebo (randomized analysis population – remimazolam: 27/32 [84.4%]; placebo: 0/16 [0%]).
|howSupplied=BYFAVO (remimazolam) for injection, for intravenous use is supplied as follows:

NDC 71390-011-11: Carton of 10 × 12 mL vials. Each 12 mL glass vial of BYFAVO (NDC 71390-011-00) provides a sterile lyophilized white to off-white powder intended for single-patient use only and contains 20 mg remimazolam (equivalent to 27.2 mg remimazolam besylate) ready for reconstitution.
|storage=Store at controlled room temperature 20°C to 25°C (68°F to 77°F) excursions between 15° and 30°C (59° and 86°F) are allowed.

Reconstituted BYFAVO can be stored in the vial for up to 8 hours under controlled room temperature at 20°C to 25°C (68°F to 77°F).

Protect vials from light once they are removed from packaging.

Discard unused portion.
|fdaPatientInfo='''Alcohol and Current Medications'''

Advise patients to notify their healthcare provider about alcohol or medication use. Alcohol and other CNS depressants, such as opioid analgesics and benzodiazepines, can have an additive effect when administered with BYFAVO.

'''Pregnancy'''

Advise pregnant females that receiving BYFAVO late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns. Instruct patients to inform their healthcare provider if they are pregnant during treatment with BYFAVO.

'''Effect of Anesthetic and Sedation Drugs on Early Brain Development'''

Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains. Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs .

'''Lactation'''

Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients receiving BYFAVO to monitor infants for excessive sedation, poor feeding and poor weight gain, and to seek medical attention if they notice these signs. A lactating woman may consider pumping and discarding breast milk for 5 hours after receiving BYFAVO during procedural sedation to minimize drug exposure to the breastfed infant.
|alcohol=Alcohol-Remimazolam interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=Byfavo
}}

Fostemsavir

2025-05-03T13:38:39Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=fostemsavir |aOrAn=a |drugClass=first-in-class HIV attachment inhibitor that works by attaching directly to HIV gp120 |indicationType=treatment |indication=of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety con..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=fostemsavir
|aOrAn=a
|drugClass=first-in-class HIV attachment inhibitor that works by attaching directly to HIV gp120
|indicationType=treatment
|indication=of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations
|adverseReactions=The following adverse reactions are discussed in greater detail in other sections of the labeling:

*Immune reconstitution syndrome.

*QTc prolongation.

*Elevations in hepatic transaminases in patients with hepatitis B or C virus co-infection
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=RUKOBIA, in combination with other antiretroviral(s), is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations

'''DOSAGE'''
The recommended dosage of RUKOBIA is one 600-mg tablet taken orally twice daily with or without food.Swallow tablets whole. Do not chew, crush, or split tablets.

Each RUKOBIA extended-release tablet contains 600 mg of fostemsavir (equivalent to 725 mg of fostemsavir tromethamine). The tablets are beige, oval, film-coated, biconvex tablets, debossed with “SV 1V7” on one side.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Fostemsavir in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Fostemsavir in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Fostemsavir in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Fostemsavir in pediatric patients.
|contraindications=RUKOBIA is contraindicated in patients:

*with previous hypersensitivity to fostemsavir or any of the components of RUKOBIA.

*coadministered strong cytochrome P450 (CYP)3A inducers, as significant decreases in temsavir (the active moiety of fostemsavir) plasma concentrations may occur which may result in loss of virologic response. These drugs include, but are not limited to:

*Androgen receptor inhibitor: Enzalutamide

*Anticonvulsants: Carbamazepine, phenytoin

*Antimycobacterial: Rifampin

*Antineoplastic: Mitotane

*Herbal product: St John’s wort (Hypericum perforatum)
|warnings='''Immune Reconstitution Syndrome'''
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including RUKOBIA. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.

'''QTc Prolongation with Higher than Recommended Dosages'''
RUKOBIA at 2,400 mg twice daily, 4 times the recommended daily dose, has been shown to significantly prolong the QTc interval of the electrocardiogram. RUKOBIA should be used with caution in patients with a history of QTc interval prolongation, when coadministered with a drug with a known risk of Torsade de Pointes, or in patients with relevant pre-existing cardiac disease. Elderly patients may be more susceptible to drug-induced QT interval prolongation.

'''Elevations in Hepatic Transaminases in Patients with Hepatitis B or C Virus Co-Infection'''
Monitoring of liver chemistries is recommended in patients with hepatitis B (HBV) and/or C (HCV) virus co-infection. Elevations in hepatic transaminases were observed in a greater proportion of subjects with HBV and/or HCV co-infection compared with those with HIV mono-infection. Some of these elevations in transaminases were consistent with hepatitis B reactivation, particularly in the setting where anti-hepatitis therapy was withdrawn. Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) when starting RUKOBIA in patients co-infected with hepatitis B.

'''Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions'''

The concomitant use of RUKOBIA and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to:

*Loss of therapeutic effect of RUKOBIA and possible development of resistance due to reduced exposure of temsavir.

*Possible prolongation of QTc interval from increased exposure to temsavir.

Consider the potential for drug interactions prior to and during therapy with RUKOBIA, review concomitant medications during therapy with RUKOBIA, and monitor for the adverse reactions associated with the concomitant drugs.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 620 subjects with HIV-1 infection received at least one dose of RUKOBIA as part of a controlled clinical trial.

The primary safety assessment of RUKOBIA is based on 96 weeks of data from a Phase 3 partially randomized, international, multicenter, double-blind, placebo-controlled trial (BRIGHTE) conducted in 371 heavily treatment-experienced adult subjects [see Clinical Studies (14)]. In the randomized cohort, 203 subjects received at least one dose of blinded RUKOBIA 600 mg twice daily and 69 subjects received placebo in addition to their current failing regimen for 8 days of functional monotherapy. Beyond Day 8, all randomized subjects except one received open-label RUKOBIA 600 mg twice daily plus an optimized background therapy (OBT). In the nonrandomized cohort, 99 subjects received open-label RUKOBIA 600 mg twice daily plus OBT from Day 1 onward.

A total of 370 subjects (271 randomized and 99 nonrandomized) received at least 1 dose of RUKOBIA 600 mg twice daily in the BRIGHTE trial. Overall, most (81%) of the adverse reactions reported with RUKOBIA were mild or moderate in severity. The proportion of subjects who discontinued treatment with RUKOBIA due to an adverse event was 7% at Week 96 (randomized: 5% and nonrandomized: 12%). The most common adverse events leading to discontinuation were related to infections (3% of subjects receiving RUKOBIA). Serious drug reactions occurred in 3% of subjects and included 3 cases of severe immune reconstitution inflammatory syndrome.

Data from the randomized cohort form the basis of the safety assessment of RUKOBIA because the presence of significant comorbid illness in the nonrandomized cohort (associated with advanced HIV infection) may confound the assessment of causality.

Adverse reactions in the nonrandomized cohort were similar to those observed in the randomized cohort. The most common adverse reactions reported in nonrandomized subjects were fatigue (7%), nausea (6%), and diarrhea (6%).

'''Less Common Adverse Reactions'''

The following adverse reactions occurred in <2% of subjects receiving RUKOBIA in the randomized cohort of the BRIGHTE trial. These events have been included based on the assessment of potential causal relationship and were also reported in the nonrandomized cohort.

'''Cardiac Disorders''': Electrocardiogram QT prolonged. All reports were asymptomatic.

'''Musculoskeletal Disorders''': Myalgia.

'''Nervous System Disorders''': Dizziness, dysgeusia, neuropathy peripheral (includes pooled terms: neuropathy peripheral and peripheral sensory neuropathy).

'''Skin and Subcutaneous Tissue Disorders''': Pruritus.

'''Laboratory Abnormalities'''

Selected laboratory abnormalities (Grades 3 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in ≥2% of subjects in the randomized cohort of the BRIGHTE trial.

The incidence of selected laboratory abnormalities (Grades 3 to 4) in the nonrandomized cohort were overall consistent with those of the randomized cohort, with the exception of direct bilirubin (14% versus 7%), bilirubin (6% versus 3%), lipase (10% versus 5%), triglycerides (10% versus 5%), neutrophils (7% versus 4%), and leukocytes (6% versus 1%), respectively.

'''Changes in Serum Creatinine''': Clinically relevant increases in serum creatinine have primarily occurred in patients with identifiable risk factors for reduced renal function, including pre-existing medical history of renal disease and/or concomitant medications known to cause increases in creatinine. A causal association between RUKOBIA and elevation in serum creatinine has not been established.

'''Changes in Direct Bilirubin''': Increases in direct (conjugated) bilirubin have been observed following treatment with RUKOBIA (Table 2). Cases of clinical significance were uncommon and were confounded by the presence of intercurrent serious comorbid events (e.g., sepsis, cholangiocarcinoma, or other complications of viral hepatitis co-infection). In the remaining cases, elevations in direct bilirubin (without clinical jaundice) were typically transient, occurred without increases in liver transaminases, and resolved on continued RUKOBIA.

'''Changes in ALT and AST in Subjects with Hepatitis B and/or Hepatitis C Virus Co-Infection''': A total of 29 subjects with Hepatitis B and/or Hepatitis C co-infection were enrolled in the BRIGHTE trial (randomized and nonrandomized cohorts combined). Grade 3 and 4 elevations in ALT and AST occurred in 14% of these subjects compared with 3% (ALT) and 2% (AST) of subjects without viral hepatitis co-infection. Some of these elevations in transaminases were consistent with hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn
|drugInteractions='''Potential for RUKOBIA to Affect Other Drugs'''
Temsavir may increase plasma concentrations of grazoprevir or voxilaprevir to a clinically relevant extent due to organic anion transporting polypeptide (OATP)1B1/3 inhibition.

When RUKOBIA was coadministered with oral contraceptives, temsavir increased concentrations of ethinyl estradiol.

'''Potential for Other Drugs to Affect RUKOBIA'''
Coadministration of RUKOBIA with rifampin, a strong CYP3A4 inducer, significantly decreases temsavir plasma concentrations. The use of RUKOBIA with drugs that are strong inducers of CYP3A4 can significantly decrease temsavir plasma concentrations which may lead to loss of virologic response.

'''Established and Other Potentially Significant Drug Interactions'''
Information regarding potential drug interactions with RUKOBIA is provided. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy .

'''Drugs that Prolong QT Interval'''
Coadministration of RUKOBIA with a drug with a known risk of Torsade de Pointes may increase the risk of Torsade de Pointes. Use RUKOBIA with caution when coadministered with drugs with a known risk of Torsade de Pointes.

'''Drugs without Clinically Significant Interactions with RUKOBIA
Based on drug interaction study results, the following drugs can be coadministered with RUKOBIA without a dose adjustment:''' atazanavir/ritonavir, buprenorphine/naloxone, cobicistat, darunavir/cobicistat, darunavir/ritonavir with and without etravirine, etravirine, famotidine, maraviroc, methadone, norethindrone, raltegravir, ritonavir, rifabutin with and without ritonavir, tenofovir disoproxil fumarate.
|useInLaborDelivery=There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to RUKOBIA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
|useInNursing=It is not known whether RUKOBIA is present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, fostemsavir-related drug was present in rat milk (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk.

Potential risks of breastfeeding include: (1) HIV-1 transmission (in HIV-1–negative infants), (2) developing viral resistance (in HIV-1–positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults.
|useInPed=The safety and effectiveness of RUKOBIA have not been established in pediatric patients.
|useInGeri=Clinical trials of RUKOBIA did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in administration of RUKOBIA in elderly patients reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients may be more susceptible to drug-induced QT interval prolongation.
|useInRenalImpair=No dosage adjustment is required for patients with renal impairment or those on hemodialysis
|useInHepaticImpair=No dosage adjustment is required in patients with mild to severe hepatic impairment (Child-Pugh Score A, B, or C)
|administration=The recommended dosage of RUKOBIA is one 600-mg tablet taken orally twice daily with or without food. Swallow tablets whole. Do not chew, crush, or split tablets.
|monitoring=Monitoring of liver chemistries is recommended in patients with hepatitis B (HBV) and/or C (HCV) virus co-infection. Elevations in hepatic transaminases were observed in a greater proportion of subjects with HBV and/or HCV co-infection compared with those with HIV mono-infection. Some of these elevations in transaminases were consistent with hepatitis B reactivation, particularly in the setting where anti-hepatitis therapy was withdrawn. Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) when starting RUKOBIA in patients co-infected with hepatitis B.
There is no known specific treatment for overdose with RUKOBIA. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required, including monitoring of vital signs and ECG (QT interval), as well as observation of the clinical status of the patient. As fostemsavir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.
|IVCompat=Dosing in absolute bioavailability study: single-dose administration of fostemsavir extended-release tablet 600 mg followed by single IV infusion of [13C] temsavir 100 mcg.
|overdose=There is no known specific treatment for overdose with RUKOBIA. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required, including monitoring of vital signs and ECG (QT interval), as well as observation of the clinical status of the patient. As fostemsavir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.
|mechAction=RUKOBIA is an HIV-1 antiretroviral agent
|PD='''Cardiac Electrophysiology'''

At therapeutic doses, RUKOBIA does not prolong the QT interval to any clinically relevant extent. At 4 times the recommended dose, the mean (upper 90% confidence interval) QTcF increase was 11.2 milliseconds (13.3 milliseconds). The observed increase in QTcF was temsavir concentration-dependent.

'''Exposure-Response Relationship'''

In the Phase 3 trial evaluating the recommended dosing regimen of RUKOBIA (600 mg twice daily) in subjects with multidrug resistant HIV-1 infection on their failing regimen, no relationship was observed between plasma temsavir Ctrough and change in plasma HIV-1 RNA from Day 1 to Day 8.
|PK=Fostemsavir is a prodrug of temsavir, its active moiety. Fostemsavir was generally not detectable in plasma following oral administration. However, temsavir was readily absorbed. Following oral administration, increases in plasma temsavir exposure (Cmax and AUCtau) appeared dose proportional or slightly greater than dose proportional, over the range of 600 mg to 1,800 mg of RUKOBIA. The pharmacokinetics of temsavir following administration of RUKOBIA are similar between healthy and HIV-1–infected subjects.

'''Absorption, Distribution, Metabolism, and Excretion'''

The pharmacokinetic properties of temsavir following administration of RUKOBIA are provided. The multiple-dose pharmacokinetic parameters are provided
|nonClinToxic='''Carcinogenesis'''

In a 2-year carcinogenicity study conducted in rats and a 26-week carcinogenicity study conducted in transgenic mice, fostemsavir produced no statistically significant increases in tumors over controls. The maximum daily exposures in rats were approximately 5 times (males) and 16 times (females) greater than those in humans at the MRHD.

'''Mutagenesis'''

Fostemsavir was not genotoxic in the bacterial reverse mutation assay (Ames test in Salmonella and E. coli), a chromosome aberration test in human lymphocytes, and rat bone marrow micronucleus test.

'''Impairment of Fertility'''

Oral administration of fostemsavir had no adverse effects on male or female fertility in rats at exposures approximately 10 times (males) and 186 times (females) of those in humans at the MRHD. At higher exposures (>80 times those in humans at the MRHD) in male rats, decreases in prostate gland/seminal vesicle weights, sperm density/motility, and increased abnormal sperm were observed
|clinicalStudies=The efficacy of RUKOBIA in heavily treatment-experienced adult subjects with HIV-1 infection is based on 96-week data from a Phase 3, partially-randomized, international, double-blind, placebo-controlled trial .

The BRIGHTE trial was conducted in 371 heavily treatment-experienced subjects with multi-class HIV-1 resistance. All subjects were required to have a viral load ≥400 copies/mL and ≤2 classes of antiretroviral medications remaining at baseline due to resistance, intolerability, contraindication, or other safety concerns. Subjects were enrolled in either a randomized or nonrandomized cohort defined as follows:

*Within the randomized cohort (n = 272), subjects had 1, but no more than 2, fully active and available antiretroviral agent(s) at screening which could be combined as part of an efficacious background regimen. Randomized subjects received either blinded RUKOBIA 600 mg twice daily (n = 203) or placebo (n = 69) in addition to their current failing regimen for 8 days of functional monotherapy. Beyond Day 8, randomized subjects received open-label RUKOBIA 600 mg twice daily plus an investigator-selected OBT. This cohort provides primary evidence of efficacy of RUKOBIA.

*Within the nonrandomized cohort (n = 99), subjects had no fully active and approved antiretroviral agent(s) available at screening. Nonrandomized subjects were treated with open-label RUKOBIA 600 mg twice daily plus OBT from Day 1 onward. The use of an investigational drug(s) as a component of the OBT was permitted in the nonrandomized cohort.
Overall, the majority of subjects were male (78%), White (70%), and the median age was 49 years (range: 17 to 73 years). At baseline, the median HIV-1 RNA was 4.6 log10 copies/mL and the median CD4+ cell count was 80 cells/mm3 (100 and 41 cells/mm3 for randomized and nonrandomized subjects, respectively). Seventy-five percent (75%) of all treated subjects had a CD4+ cell count <200 cells/mm3 at baseline (with 30% <20 cells/mm3). Overall, 86% had a history of Acquired Immune Deficiency Syndrome (AIDS) and 8% had a history of hepatitis B and/or C virus co-infection at baseline. Seventy one percent (71%) of subjects had been treated for HIV for >15 years; 85% had been exposed to ≥5 different HIV treatment regimens upon entry into the trial.

*Fifty-two percent (52%) of subjects in the randomized cohort had 1 fully active agent within their initial failing background regimen, 42% had 2, and 6% had no fully active agent. Within the nonrandomized cohort, 81% of subjects had no fully active agent(s) in their original regimen and 19% had 1 fully active agent, including 15% (n = 15) who received ibalizumab, which was an investigational agent at the time of the BRIGHTE trial start-up.

'''Randomized Cohort'''

The primary efficacy endpoint was the adjusted mean decline in HIV-1 RNA from Day 1 to Day 8 with RUKOBIA versus placebo in the randomized cohort. The results of the primary endpoint analysis demonstrated superiority of RUKOBIA compared with placebo.

At Day 8, 65% (131/203) and 46% (93/203) of subjects who received RUKOBIA had a reduction in viral load from baseline >0.5 log10 copies/mL and >1 log10 copies/mL, respectively, compared with 19% (13/69) and 10% (7/69) of subjects, respectively, in the placebo group.

By subgroup analysis, randomized subjects who received RUKOBIA with baseline HIV-1 RNA >1,000 copies/mL achieved a mean decline in viral load of 0.86 log10 copies/mL at Day 8 compared with 0.20 log10 copies/mL in subjects treated with blinded placebo. Subjects with baseline HIV-1 RNA ≤1,000 copies/mL achieved a mean decline in viral load of 0.22 log10 copies/mL at Day 8 compared with a mean increase of 0.10 log10 copies/mL in subjects treated with blinded placebo.

Virologic outcomes by ITT-E Snapshot Analysis at Weeks 24 and 96 in the BRIGHTE trial are shown in Table 12 and Table 13 for the randomized cohort. There was considerable variability in the number of antiretrovirals (fully active and otherwise) included in OBT regimens. The majority of subjects (84%) received dolutegravir as a component of OBT, of which approximately half (51% overall) also received darunavir with ritonavir or cobicistat. Virologic outcomes by ITT-E Snapshot Analysis at Week 48 were consistent with those observed at Week 24.

In the randomized cohort, HIV-1 RNA <200 copies/mL was achieved in 68% and 64% of subjects at Weeks 24 and 96, respectively (ITT-E, Snapshot algorithm). Mean changes in CD4+ cell count from baseline increased over time: 90 cells/mm3 at Week 24 and 205 cells/mm3 at Week 96. Based on a sub-analysis in the randomized cohort, subjects with the lowest baseline CD4+ cell counts (<20 cells/mm3) had a similar increase in CD4+ cell count over time compared with subjects with higher baseline CD4+ cell count (>200 to <500 cells/mm3).

'''Nonrandomized Cohort'''

In the nonrandomized cohort, HIV-1 RNA <40 copies/mL was achieved in 37% of subjects at Weeks 24 and 96. At these timepoints, the proportion of subjects with HIV-1 RNA <200 copies/mL was 42% and 39%, respectively (ITT-E, Snapshot algorithm). Mean changes in CD4+ cell count from baseline increased over time: 41 cells/mm3 at Week 24 and 119 cells/mm3 at Week 96.
|howSupplied=RUKOBIA extended-release tablets, 600 mg, are beige, oval, film-coated, biconvex tablets debossed with “SV 1V7” on one side.

Bottle of 60 tablets with child-resistant closure. NDC 49702-250-18.
|storage=Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F)
|fdaPatientInfo=Advise the patient to read the FDA-approved patient labeling .

'''Hypersensitivity Reactions'''

Inform patients that if they have had a hypersensitivity reaction to RUKOBIA or any of its components, they should not take RUKOBIA.

'''Immune Reconstitution Syndrome'''

Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection, as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when RUKOBIA is started.

'''QTc Interval Prolongation'''

Advise patients that RUKOBIA may produce changes in their electrocardiogram (i.e., QT prolongation). Instruct patients to consult their healthcare provider if they experience symptoms such as dizziness, lightheadedness, abnormal heart rhythm, or loss of consciousness.

'''Patients with Hepatitis B or C Virus Co-Infection'''

Advise patients that it is recommended to have laboratory testing and to take medications for HBV or HCV as prescribed.

'''Drug Interactions'''

RUKOBIA may interact with other drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John’s wort

'''Pregnancy Registry'''

Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to RUKOBIA during pregnancy.

'''Lactation'''

Inform individuals with HIV-1 infection that the potential risks of breastfeeding include: (1) HIV-1 transmission (in HIV-1–negative infants), (2) developing viral resistance (in HIV-1–positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults.

'''Potential Odor of Tablets'''

RUKOBIA tablets may have a slight vinegar-like odor.

'''Missed Dosage'''

Advise patients to avoid missing doses as it can result in development of resistance. Instruct patients that if they miss a dose of RUKOBIA, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose.

Trademark is owned by or licensed to the ViiV Healthcare group of companies.
|alcohol=Alcohol-Fostemsavir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=RUKOBIA
}}

Decitabine and cedazuridine

2025-05-03T13:10:32Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=decitabine and cedazuridine |drugClass=inhibits cytidine deaminase |indicationType=treatment |indication=INQOVI is indicated for treatment of adult patients with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, ref..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=decitabine and cedazuridine
|drugClass=inhibits cytidine deaminase
|indicationType=treatment
|indication=INQOVI is indicated for treatment of adult patients with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.
|adverseReactions=Myelosuppression
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=INQOVI is indicated for treatment of adult patients with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.

'''DOSAGE'''
The recommended dosage of INQOVI is 1 tablet (containing 35 mg decitabine and 100 mg cedazuridine) orally once daily on Days 1 through 5 of each 28-day cycle for a minimum of 4 cycles until disease progression or unacceptable toxicity. A complete or partial response may take longer than 4 cycles.

Instruct patients of the following:

*Take INQOVI at the same time each day.
*Swallow tablets whole. Do not cut, crush, or chew tablets.
*Do not consume food 2 hours before and 2 hours after each dose.
*Take one tablet a day for 5 days in each cycle. If the patient misses a dose within 12 hours of the time it is usually taken, instruct patients to take the missed dose as soon as possible and then to resume the normal daily dosing schedule. Extend the dosing period by one day for every missed dose to complete 5 daily doses for each cycle.
*Do not take an additional dose if vomiting occurs after INQOVI administration but continue with the next schedule dose.

INQOVI is a hazardous drug. Follow applicable special handling and disposal procedures
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Decitabine and cedazuridine in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Decitabine and cedazuridine in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Decitabine and cedazuridine in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Decitabine and cedazuridine in pediatric patients.
|contraindications=None
|warnings='''Myelosuppression'''
Fatal and serious myelosuppression can occur with INQOVI. Based on laboratory values, new or worsening thrombocytopenia occurred in 82% of patients, with Grade 3 or 4 occurring in 76%. Neutropenia occurred in 73% of patients, with Grade 3 or 4 occurring in 71%. Anemia occurred in 71% of patients, with Grade 3 or 4 occurring in 55%. Febrile neutropenia occurred in 33% of patients, with Grade 3 or 4 occurring in 32%. Myelosuppression (thrombocytopenia, neutropenia, anemia, and febrile neutropenia) is the most frequent cause of INQOVI dose reduction or interruption, occurring in 36% of patients. Permanent discontinuation due to myelosuppression (febrile neutropenia) occurred in 1% of patients. Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and may not necessarily indicate progression of underlying MDS.

Fatal and serious infectious complications can occur with INQOVI. Pneumonia occurred in 21% of patients, with Grade 3 or 4 occurring in 15%. Sepsis occurred in 14% of patients, with Grade 3 or 4 occurring in 11%. Fatal pneumonia occurred in 1% of patients, fatal sepsis in 1%, and fatal septic shock in 1%.

Obtain complete blood cell counts prior to initiation of INQOVI, prior to each cycle, and as clinically indicated to monitor response and toxicity. Administer growth factors and anti-infective therapies for treatment or prophylaxis as appropriate. Delay the next cycle and resume at the same or reduced dose as recommended.

'''Embryo-Fetal Toxicity'''
Based on findings from human data, animal studies, and its mechanism of action, INQOVI can cause fetal harm when administered to a pregnant woman. In nonclinical studies with decitabine in mice and rats, decitabine was teratogenic, fetotoxic, and embryotoxic at doses less than the recommended human dose.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with INQOVI and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with INQOVI and for 3 months after the last dose
|clinicalTrials=*Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice.

'''Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia'''

The safety of INQOVI was evaluated in a pooled safety population that includes patients enrolled in Study ASTX727-01-B and Study ASTX727-02.

Patients were randomized to receive INQOVI (35 mg decitabine and 100 mg cedazuridine) orally once daily on Days 1 through 5 in Cycle 1 and decitabine 20 mg/m2 intravenously on Days 1 through 5 in Cycle 2, or the reverse sequence, and then INQOVI (35 mg decitabine and 100 mg cedazuridine) orally once daily on Days 1 through 5 of each 28-day cycle in Cycles 3 and beyond. Patients were allowed to have one prior cycle of decitabine or azacitidine and there was no limit for body weight or surface area. Among the patients who received INQOVI, 61% of patients were exposed for 6 months or longer and 24% were exposed to INQOVI for greater than 1 year.

Serious adverse reactions occurred in 68% of patients who received INQOVI. Serious adverse reactions in > 5% of patients included febrile neutropenia (30%), pneumonia (14%), and sepsis (13%). Fatal adverse reactions occurred in 6% of patients. These included sepsis (1%), septic shock (1%), pneumonia (1%), respiratory failure (1%), and one case each of cerebral hemorrhage and sudden death.

Permanent discontinuation due to an adverse reaction occurred in 5% of patients who received INQOVI. The most frequent adverse reactions resulting in permanent discontinuation were febrile neutropenia (1%) and pneumonia (1%).

Dose interruptions due to an adverse reaction occurred in 41% of patients who received INQOVI. Adverse reactions requiring dosage interruptions in > 5% of patients who received INQOVI included neutropenia (18%), febrile neutropenia (8%), thrombocytopenia (6%), and anemia (5%).

Dose reductions due to an adverse reaction occurred in 19% of patients who received INQOVI. Adverse reactions requiring dosage reductions in > 2% of patients who received INQOVI included neutropenia (12%), anemia (3%), and thrombocytopenia (3%).

The most common adverse reactions (≥ 20%) were fatigue, constipation, hemorrhage, myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, edema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia, and transaminase increased. The most common Grade 3 or 4 laboratory abnormalities (≥ 50%) were leukocytes decreased, platelet count decreased, neutrophil count decreased, and hemoglobin decreased.

Clinically relevant adverse reactions in < 10% of patients who received INQOVI included:

*Acute febrile neutrophilic dermatosis (Sweet’s syndrome) (1%)
*Tumor lysis syndrome (0.5%)
|postmarketing=The following adverse reactions have been identified during postapproval use of intravenous decitabine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

*Blood and Lymphatic System Disorders: Differentiation syndrome

*Respiratory, Thoracic and Mediastinal Disorders: Interstitial lung disease

*Cardiac Disorders: Cardiomyopathy
|drugInteractions='''Effects of INQOVI on Other Drugs'''
Drugs Metabolized by Cytidine Deaminase

Cedazuridine is an inhibitor of the cytidine deaminase (CDA) enzyme. Coadministration of INQOVI with drugs that are metabolized by CDA may result in increased systemic exposure with potential for increased toxicity of these drugs. Avoid coadministration of INQOVI with drugs that are metabolized by CDA.
|useInLaborDelivery=Based on findings from human data, animal studies, and its mechanism of action, INQOVI can cause fetal harm when administered to a pregnant woman. A single published case report of intravenous decitabine use throughout the first trimester during pregnancy describes adverse developmental outcomes, including major birth defects (structural abnormalities). In animal reproduction studies, intravenous administration of decitabine to pregnant mice and rats during organogenesis at doses approximately 7% of the recommended human dose on a body surface area (mg/m2) basis caused adverse developmental outcomes, including increased embryo-fetal mortality, alterations to growth, and structural abnormalities (see Data). Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
|useInNursing=There are no data on the presence of cedazuridine, decitabine, or their metabolites in human milk or on their effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with INQOVI and for 2 weeks after the last dose.
|useInPed=The safety and effectiveness of INQOVI have not been established in pediatric patients.
|useInGeri=Of the 208 patients in clinical studies who received INQOVI, 75% were age 65 years and older, while 36% were age 75 years and older. No overall differences in safety or effectiveness were observed between patients age 65 years and older, 75 years and older, and younger patients.
|useInGender=INQOVI can cause fetal harm when administered to a pregnant woman.
'''Pregnancy Testing'''

Verify the pregnancy status in females of reproductive potential prior to initiating INQOVI.

'''Contraception'''

''Females''

Advise females of reproductive potential to use effective contraception during treatment with INQOVI and for 6 months after the last dose.

''Males''

Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with INQOVI and for 3 months after the last dose.

'''Infertility'''

Based on findings of decitabine and cedazuridine in animals, INQOVI may impair male fertility [see Nonclinical Toxicology (13.1)]. The reversibility of the effect on fertility is unknown.
|useInRenalImpair=No dosage modification of INQOVI is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] of 30 to 89 mL/min based on Cockcroft-Gault). Due to the potential for increased adverse reactions, monitor patients with moderate renal impairment (CLcr 30 to 59 mL/min) frequently for adverse reactions. INQOVI has not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min) or end-stage renal disease (ESRD: CLcr <15 mL/min)
|administration=Do NOT substitute INQOVI for an intravenous decitabine product within a cycle.

Consider administering antiemetics prior to each dose to minimize nausea and vomiting
|monitoring='''Hematologic Adverse Reactions'''

Obtain complete blood cell counts prior to initiating INQOVI and before each cycle. Delay the next cycle if absolute neutrophil count (ANC) is less than 1,000/μL and platelets are less than 50,000/μL in the absence of active disease. Monitor complete blood cell counts until ANC is 1,000/μL or greater and platelets are 50,000/μL or greater.

*If hematologic recovery occurs (ANC at least 1,000/μL and platelets at least 50,000/μL) within 2 weeks of achieving remission, continue INQOVI at the same dose.
*If hematologic recovery does not occur (ANC at least 1,000/μL and platelets at least 50,000/μL) within 2 weeks of achieving remission,
*Delay INQOVI for up to 2 additional weeks AND
*Resume at a reduced dose by administering INQOVI on Days 1 through 4. Consider further dose reductions in the order listed in Table 1 if myelosuppression persists after a dose reduction. Maintain or increase dose in subsequent cycles as clinically indicated.

*Manage persistent severe neutropenia and febrile neutropenia with supportive treatment

'''Non-Hematologic Adverse Reactions'''
Delay the next cycle for the following non-hematologic adverse reactions and resume at the same or reduced dose upon resolution:

*Serum creatinine 2 mg/dL or greater
*Serum bilirubin 2 times upper limit of normal (ULN) or greater
*Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 2 times ULN or greater
*Active or uncontrolled infection
|mechAction=Decitabine is a nucleoside metabolic inhibitor that is believed to exert its effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation and/or apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. Decitabine-induced hypomethylation in cancer cells may restore normal function to genes that are critical for the control of cellular differentiation and proliferation. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and decitabine incorporated into DNA. Non-proliferating cells are relatively insensitive to decitabine.

Cytidine deaminase (CDA) is an enzyme that catalyzes the degradation of cytidine, including the cytidine analog decitabine. High levels of CDA in the gastrointestinal tract and liver degrade decitabine and limit its oral bioavailability. Cedazuridine is a CDA inhibitor. Administration of cedazuridine with decitabine increases systemic exposure of decitabine.
|PD=Decitabine induced hypomethylation both in vitro and in vivo. In patients administered the recommended dosage of INQOVI, the maximum change from baseline in the long interspersed nucleotide elements-1 (LINE-1) demethylation was observed at Day 8, with less than complete recovery of LINE-1 methylation to baseline at the end of the treatment cycle.

Based on the exposure-response analyses, a relationship between an increase in 5-day cumulative daily decitabine exposure and a greater likelihood of some adverse reactions (e.g., any grade neutropenias, thrombocytopenia) was observed in clinical studies.
|PK=The pharmacokinetics of decitabine and cedazuridine following administration of INQOVI at the recommended dosage in patients with MDS and CMML.

The geometric mean ratio (GMR) of decitabine area under the curve (AUC) following the first dose of INQOVI compared to that of intravenous decitabine on Day 1 was 60% (90% confidence intervals (CI): 55, 65) in patients with MDS and CMML. The GMR of decitabine AUC following 5 consecutive once daily doses of INQOVI compared to that of intravenous decitabine on Day 5 was 106% (90% CI: 98, 114) and the GMR of the 5-day cumulative decitabine AUC following 5 consecutive once daily doses of INQOVI compared to that of intravenous decitabine was 99% (90% CI: 93, 106).

An approximately dose-proportional increase in peak concentrations (Cmax) and AUC over the dosing interval was observed for decitabine following administration of oral decitabine at 20 mg to 40 mg once daily (0.6 to 1.1 times the recommended dose) in combination with 100 mg oral cedazuridine, and for cedazuridine following administration of oral cedazuridine at 40 to 100 mg once daily (0.4 to 1.0 times the recommended dose) in combination with 20 mg oral decitabine.
|clinicalStudies='''Study ASTX727-01-B'''

INQOVI was evaluated in Study ASTX727-01-B, an open-label, randomized, 2-cycle, 2-sequence crossover study (NCT02103478) that included 80 adult patients with MDS (International Prognostic Scoring System [IPSS] Intermediate-1, Intermediate-2, or high-risk) or CMML. Patients were randomized 1:1 to receive INQOVI (35 mg decitabine and 100 mg cedazuridine) orally in Cycle 1 and decitabine 20 mg/m2 intravenously in Cycle 2 or the reverse sequence. Both INQOVI and intravenous decitabine were administered once daily on Days 1 through 5 of the 28-day cycle. Starting with Cycle 3, all patients received INQOVI orally once daily on Days 1 through 5 of each 28-day cycle until disease progression or unacceptable toxicity. Randomization was stratified by IPSS risk level. Twelve (15%) of the 80 patients went on to stem cell transplantation following INQOVI treatment.

Efficacy was established on the basis of complete response (CR) and the rate of conversion from transfusion dependence to transfusion independence. Efficacy results are shown. The median follow-up time was 24.0 months (range: 12.0 to 28.8 months) and median treatment duration was 6.6 months (range < 0.1 to 27.9).

Among the 41 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 20 (49%) became independent of RBC and platelet transfusions during any consecutive 56-day post-baseline period. Of the 39 patients who were independent of both RBC and platelet transfusions at baseline, 25 (64%) remained transfusion-independent during any consecutive 56-day post-baseline period.

'''Study ASTX727-02'''

INQOVI was evaluated in ASTX727-02, an open-label, randomized, 2-cycle, 2-sequence crossover study (NCT03306264) that included 133 adult patients with MDS or CMML, including all French-American-British (FAB) classification criteria and IPSS Intermediate-1, Intermediate-2, or high-risk prognostic scores. Patients were randomized 1:1 to receive INQOVI (35 mg decitabine and 100 mg cedazuridine) orally in Cycle 1 and decitabine 20 mg/m2 intravenously in Cycle 2 or the reverse sequence. Both INQOVI and intravenous decitabine were administered once daily on Days 1 through 5 of the 28-day cycle. Starting with Cycle 3, all patients received INQOVI orally once daily on Days 1 through 5 of each 28-day cycle until disease progression or unacceptable toxicity. No stratification was performed. Twenty-seven (20%) of the 133 patients went on to stem cell transplantation following INQOVI treatment.

The primary outcome measure was comparison of the 5-day cumulative decitabine AUC between INQOVI and intravenous decitabine. Efficacy was established on the basis of complete response (CR) and the rate of conversion from transfusion dependence to transfusion independence. Efficacy results are shown. The median follow-up time was 12.6 months (range: 9.3 to 20.5) and median treatment duration was 8.2 months (range 0.2 to 19.7).

Among the 57 patients who were dependent on RBC and/or platelet transfusions at baseline, 30 (53%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 76 patients who were independent of both RBC and platelet transfusions at baseline, 48 (63%) remained transfusion-independent during any 56-day post-baseline period.
|howSupplied=INQOVI tablets are biconvex, oval-shaped, film-coated, red, and debossed with “H35” on one side.

The tablets are packaged in blisters and supplied as follows:

*NDC: 64842-0727-9; 5 tablets in one blister card in a child-resistant carton
|storage=Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense medication in the original packaging.
|fdaPatientInfo=Advise the patient to read the FDA-approved patient labeling.

'''Myelosuppression'''

Advise patients of the risk of myelosuppression and to report any symptoms of fever, infection, anemia, or bleeding to their healthcare provider as soon as possible. Advise patients for the need for laboratory monitoring.

'''Embryo-Fetal Toxicity'''

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.

Advise females of reproductive potential to use effective contraception during treatment with INQOVI and for 6 months after the last dose.

Advise males with female partners of reproductive potential to use effective contraception during treatment with INQOVI and for 3 months after the last dose.

'''Lactation'''

Advise women not to breastfeed during treatment with INQOVI and for 2 weeks after the last dose.

'''Administration'''

Advise patients to take INQOVI at approximately the same time each day on an empty stomach. Instruct patients to avoid eating for at least 2 hours before and 2 hours after taking INQOVI. Advise patients on what to do when a dose is missed or vomited.
|alcohol=Alcohol-Decitabine and cedazuridine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=INQOVI
}}

Abametapir

2025-05-03T12:44:57Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=abametapir |aOrAn=a |drugClass=metalloproteinase inhibitor |indicationType=treatment |indication=of head lice infestation in patients 6 months of age and older. XEGLYZE should be used in the context of an overall lice management program: *Wash (with hot water) or dry-clean all recently worn clothing, hats, used bedding and towels *Wash personal care items such as combs, br..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=abametapir
|aOrAn=a
|drugClass=metalloproteinase inhibitor
|indicationType=treatment
|indication=of head lice infestation in patients 6 months of age and older.

XEGLYZE should be used in the context of an overall lice management program:

*Wash (with hot water) or dry-clean all recently worn clothing, hats, used bedding and towels

*Wash personal care items such as combs, brushes, and hair clips in hot water

Use a fine-tooth comb or special nit comb to remove dead lice and nits
|adverseReactions=*Erythema
*Rash
*Skin burning sensation
*Contact dermatitis
*Vomiting
*Eye irritation
*Hair color changes
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=XEGLYZE is indicated for the topical treatment of head lice infestation in patients 6 months of age and older.

XEGLYZE should be used in the context of an overall lice management program:

*Wash (with hot water) or dry-clean all recently worn clothing, hats, used bedding and towels

*Wash personal care items such as combs, brushes, and hair clips in hot water

Use a fine-tooth comb or special nit comb to remove dead lice and nits

'''DOSAGE'''
For topical use only. XEGLYZE is not for oral, ophthalmic, or intravaginal use. Treatment with XEGLYZE involves a single application.

Shake well before use. Apply XEGLYZE to dry hair in an amount (up to the full content of one bottle) sufficient to thoroughly coat the hair and scalp. Massage XEGLYZE into the scalp and throughout the hair. Avoid contact with eyes. Leave on the hair and scalp for 10 minutes and then rinse off with warm water. Wash hands after application. Hair may be shampooed any time after the treatment.

Discard any unused product. Do not flush contents down sink or toilet.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Abametapir in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Abametapir in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Abametapir in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Abametapir in pediatric patients.
|contraindications=None
|warnings='''Risk of Neonatal Benzyl Alcohol Toxicity'''
XEGLYZE contains benzyl alcohol. Systemic exposure to benzyl alcohol has been associated with serious and fatal adverse reactions including “gasping syndrome” in neonates and low birth weight infants. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth weight infants may be more likely to develop toxicity.

The safety and effectiveness of XEGLYZE have not been established in pediatric patients below the age of 6 months. Use is not recommended in pediatric patients under 6 months of age because of the potential for increased systemic absorption.

'''Risk of Benzyl Alcohol Toxicity from Accidental Ingestion'''
In order to prevent accidental ingestion in pediatric patients, XEGLYZE should only be administered under direct supervision of an adult.

Ingestion of benzyl alcohol in large quantities may result in gastrointestinal (nausea, vomiting, diarrhea) and central nervous system (headache, ataxia, convulsions, coma) adverse reactions. Serious adverse reactions may include respiratory depression and death. If accidentally swallowed, advise the patient or the caregiver to call their Poison Control Center at 1-800-222-1222.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug, and may not reflect the rates observed in practice.

The data described below reflect exposure to a single 10-minute treatment of XEGLYZE in 349 subjects (6 months of age and older) with head lice infestation in randomized, double-blind, vehicle-controlled trials (Trials 1 and 2). Of these subjects, 21 were 6 months to 4 years of age, 166 subjects were 4 to 12 years of age, 57 subjects were 12 to 18 years of age, and 105 subjects were 18 years of age or older.

Table 1 provides adverse reactions that occurred in at least 1% of subjects in the XEGLYZE group and at a greater frequency than in the vehicle group.

During the trials, subjects were monitored for new onset of scalp erythema/edema, scalp pruritus, and eye irritation. The number and percentage of subjects who developed these local adverse reactions after treatment are presented.

* For the calculation of the percentages, the denominators are the number of subjects who did not have the monitored local adverse reaction at baseline.
|drugInteractions=In vitro studies suggest there is a potential for inhibition of cytochrome P450 (CYP) 3A4, 2B6 and 1A2 enzymes following a single application of XEGLYZE. Use of XEGLYZE with drugs that are substrates of these enzymes may lead to increased systemic concentrations of the interacting drugs. Avoid administration of drugs that are substrates of CYP3A4, CYP2B6, or CYP1A2 within 2 weeks after application of XEGLYZE. If this is not feasible, avoid use of XEGLYZE.
|useInLaborDelivery=There are no available data on XEGLYZE use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In embryofetal development studies conducted with oral administration of abametapir during organogenesis, no evidence of fetal harm or malformations, independent of maternal toxicity were observed in pregnant rats and rabbits at doses that produced exposures up to 50 times and equivalent to the maximum recommended human dose (MRHD) in rats and rabbits, respectively. The highest dose evaluated in rabbits was limited due to maternal toxicity associated with the vehicle used in the study (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

No data are available regarding the presence of abametapir in human milk or the effects of abametapir on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XEGLYZE and any potential adverse effects on the breastfed child from XEGLYZE or from the underlying maternal condition.
|useInPed=The safety and effectiveness of XEGLYZE have been established in pediatric patients 6 months of age and older.

The safety and effectiveness of XEGLYZE have not been established in pediatric patients below the age of 6 months. XEGLYZE is not recommended in pediatric patients under 6 months of age because of the potential for increased systemic absorption due to a high ratio of skin surface to body mass and the potential for an immature skin barrier.

XEGLYZE contains benzyl alcohol. Benzyl alcohol has been associated with serious adverse reactions and death in neonates and low birth-weight infants. The “gasping syndrome” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with intravenously administered benzyl alcohol dosages >99 mg/kg/day in neonates and low birthweight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.

The minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birthweight infants, as well as patients receiving high dosages, may be more likely to develop toxicity.

Because of the risk of accidental ingestion, XEGLYZE should be administered to pediatric patients only under direct adult supervision
|useInGeri=Clinical studies of XEGLYZE did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger subjects.
|administration=For topical use only. XEGLYZE is not for oral, ophthalmic, or intravaginal use. Treatment with XEGLYZE involves a single application.

Shake well before use. Apply XEGLYZE to dry hair in an amount (up to the full content of one bottle) sufficient to thoroughly coat the hair and scalp. Massage XEGLYZE into the scalp and throughout the hair. Avoid contact with eyes. Leave on the hair and scalp for 10 minutes and then rinse off with warm water. Wash hands after application. Hair may be shampooed any time after the treatment.

Discard any unused product. Do not flush contents down sink or toilet.
|overdose=If accidentally swallowed, advise patients to seek medical advice immediately and to call their local Poison Control Center at 1-800-222-1222.
|mechAction=Abametapir (5,5’-dimethyl 2,2’-bipyridinyl) is a metalloproteinase inhibitor. Metalloproteinases have a role in physiological processes critical to egg development and survival of lice.
|PK='''Absorption'''

The pharmacokinetics of XEGLYZE were evaluated in 3 trials, Trials A, B, and C. Each trial enrolled lice infested subjects who received a single 10-minute application of XEGLYZE. Pharmacokinetic samplings were carried out to 72 hours post-dose in adults and 8 hours post-dose in pediatric subjects in all trials.

Trial A evaluated pharmacokinetics in 6 adult and 12 pediatric subjects 3 to 12 years of age. The mean (%CV) abametapir plasma maximum concentration (Cmax) and area under the concentration time curve from 0 to 8 hours post-dose (AUC0-8h) in the adult group were 41 (66%) ng/mL and 121 (50%) ng*h/mL, respectively. The mean (%CV) Cmax and AUC0-8h in the pediatric group were 73 (57%) ng/mL and 264 (62%) ng*h/mL, respectively. The mean (%CV) terminal half-life in adults was 21 (11%) hours.

Trials B and C evaluated pharmacokinetics in 50 pediatric subjects 6 months to 17 years old. The pharmacokinetic results for plasma abametapir are shown in Table 3. Even though the values varied between the 2 trials, abametapir exposure increased as the age of the subject decreased. Abametapir absorption was rapid with a median Tmax of 0.57 to 1.54 hours.

Serum concentration of benzyl alcohol, an excipient in the formulation of XEGLYZE, was assessed in Trials B and C. Benzyl alcohol in serum was measurable (limit of quantitation = 0.5 µg/mL) in 7 subjects out of 39 evaluable subjects. The Cmax of benzyl alcohol in these 7 subjects ranged from 0.52 to 3.57 µg/mL.

'''Distribution'''

Abametapir and its primary human metabolite, abametapir carboxyl, are highly bound to proteins in plasma. Abametapir is 91.3 – 92.3% bound to plasma proteins, and abametapir carboxyl is 96.0% – 97.5% bound to plasma proteins.

'''Elimination'''

''Metabolism''

Abametapir is extensively metabolized, primarily by the cytochrome P450 enzyme CYP1A2 to a mono-hydroxylated metabolite (abametapir hydroxyl) and further to a mono-carboxylated metabolite (abametapir carboxyl). Abametapir carboxyl is cleared slowly from the systemic circulation resulting in plasma concentration higher than that of abametapir. Based on data in adults in Trial A above, where sampling was carried out to 72 hours, the ratios of Cmax and AUC0-72h between abametapir carboxyl and abametapir were about 30 and 250, respectively. The elimination half-life of abametapir carboxyl has not been well characterized but is estimated to be approximately (mean ± SD) 71 ± 40 hours or longer in adults.

'''Excretion'''

Excretion of abametapir and its human metabolites was not examined in patients.

''Drug Interaction Studies''

In vitro studies suggest that there is a potential for inhibition of cytochrome P450 3A4, 2B6, and 1A2 enzymes following application of XEGLYZE due to high and prolonged systemic exposure of the metabolite abametapir carboxyl
|nonClinToxic=Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of XEGLYZE or abametapir.

Abametapir was not mutagenic or clastogenic based on the results of two in vitro genotoxicity tests (Ames test and human lymphocyte chromosomal aberration assay) and one in vivo genotoxicity test (rat micronucleus assay).

No effects on fertility have been observed in rats following repeated oral doses of up to 75 mg/kg/dayabametapir (50 times the MRHD based on Cmax comparisons).
|clinicalStudies=Two identical multi-center, randomized, double-blind, vehicle-controlled trials (Trials 1 and 2) were conducted in 704 subjects 6 months of age and older with head lice infestation. All subjects received a single application of either XEGLYZE or vehicle control. For the evaluation of efficacy, the youngest subject from each household was considered to be the index subject of the household (N=216). Other enrolled infested household members received the same treatment as the youngest subject and were evaluated for all efficacy and safety parameters. Index subjects ranged from 6 months to 49 years of age (mean 7 years), and approximately 85% of the index subjects were female, and 95% of the index subjects were Caucasian.

Efficacy was assessed as the proportion of index subjects who were treated with a single 10-minute application and were free of live lice at all follow-up visits on Days 1, 7, and 14. Subjects with live lice at any time up to the final evaluation were considered treatment failures. Table 4 presents the proportion of subjects who were free of live lice at all visits Day 1 through Day 14.
|howSupplied=XEGLYZE is a white to off-white oil in water emulsion containing 0.74% [weight by weight] abametapir and supplied in a polyvinyl chloride (PVC) safety-coated single-use round amber glass bottle affixed with a polypropylene child resistant cap (NDC # 43598-921-11) featuring a tri-foil inner liner. The container is filled to a nominal 200 g (approximately 7 oz. or 210 mL) of the lotion.
|storage=Store upright at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F and 86°F)

Do not refrigerate or freeze.
|fdaPatientInfo=Advise the patient or caregiver to read the FDA-approved patient labeling.

Inform the patient and caregiver of the following instructions:

*Do not ingest XEGLYZE.
*Keep out of reach of children. Use on children should be under the direct supervision of an adult because of the risk of benzyl alcohol toxicity.
*Avoid contact with eyes.
*Wash hands after application.
*Hair may be shampooed any time after the treatment.
*Treatment with XEGLYZE involves a single application. Do not re-treat.
*Discard any unused portion. Do not flush contents down sink or toilet.
|alcohol=Alcohol-Abametapir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=XEGLYZE
}}

Tafasitamab-cxix

2025-05-03T09:25:11Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=tafasitamab-cxix |aOrAn=a |drugClass=CD19-directed cytolytic monoclonal antibody |indication=MONJUVI, in combination with lenalidomide, is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplan..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=tafasitamab-cxix
|aOrAn=a
|drugClass=CD19-directed cytolytic monoclonal antibody
|indication=MONJUVI, in combination with lenalidomide, is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant (ASCT).

This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
|adverseReactions=The following clinically significant adverse reactions are described elsewhere in the labeling:

*Infusion-related reactions
*Myelosuppression
*Infections
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=MONJUVI, in combination with lenalidomide, is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant (ASCT).

This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

'''DOSAGE'''
The recommended dose of MONJUVI is 12 mg/kg based on actual body weight administered as an intravenous infusion according to the dosing schedule.

Administer MONJUVI in combination with lenalidomide 25 mg for a maximum of 12 cycles, then continue MONJUVI as monotherapy until disease progression or unacceptable toxicity. Refer to the lenalidomide prescribing information for lenalidomide dosage recommendations.

MONJUVI should be administered by a healthcare professional with immediate access to emergency equipment and appropriate medical support to manage infusion-related reactions (IRRs).
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Tafasitamab-cxix in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Tafasitamab-cxix in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Tafasitamab-cxix in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Tafasitamab-cxix in pediatric patients.
|contraindications=None
|warnings='''Infusion-Related Reactions'''
MONJUVI can cause infusion-related reactions [see Adverse Reactions (6. In L-MIND, infusion-related reactions occurred in 6% of the 81 patients. Eighty percent of infusion-related reactions occurred during cycle 1 or 2. Signs and symptoms included fever, chills, rash, flushing, dyspnea, and hypertension. These reactions were managed with temporary interruption of the infusion and/or with supportive medication.

Premedicate patients prior to starting MONJUVI infusion. Monitor patients frequently during infusion. Based on the severity of the infusion-related reaction, interrupt or discontinue MONJUVI. Institute appropriate medical management.

'''Myelosuppression'''
MONJUVI can cause serious or severe myelosuppression, including neutropenia, thrombocytopenia, and anemia. In L-MIND, Grade 3 neutropenia occurred in 25% of patients, thrombocytopenia in 12%, and anemia in 7%. Grade 4 neutropenia occurred in 25% and thrombocytopenia in 6%. Neutropenia led to treatment discontinuation in 3.7% of patients.

Monitor CBC prior to administration of each treatment cycle and throughout treatment. Monitor patients with neutropenia for signs of infection. Consider granulocyte colony-stimulating factor administration. Withhold MONJUVI based on the severity of the adverse reaction. Refer to the lenalidomide prescribing information for dosage modifications.

'''Infections'''
Fatal and serious infections, including opportunistic infections, occurred in patients during treatment with MONJUVI and following the last dose.

In L-MIND, 73% of the 81 patients developed an infection. The most frequent infections were respiratory tract infection (24%), urinary tract infection (17%), bronchitis (16%), nasopharyngitis (10%) and pneumonia (10%). Grade 3 or higher infection occurred in 30% of the 81 patients. The most frequent grade 3 or higher infection was pneumonia (7%). Infection-related deaths were reported in 2.5% of the 81 patients.

Monitor patients for signs and symptoms of infection and manage infections as appropriate.

'''Embryo-Fetal Toxicity'''
Based on its mechanism of action, MONJUVI may cause fetal B-cell depletion when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with MONJUVI and for at least 3 months after the last dose [see Use in Specific Populations.

MONJUVI is initially administered in combination with lenalidomide. The combination of MONJUVI with lenalidomide is contraindicated in pregnant women because lenalidomide can cause birth defects and death of the unborn child. Refer to the lenalidomide prescribing information on use during pregnancy.
|clinicalTrials=The following clinically significant adverse reactions are described elsewhere in the labeling:

*Infusion-related reactions
*Myelosuppression
*Infections

'''Clinical Trials Experience'''
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in other clinical trials of another drug and may not reflect the rates observed in practice.

Relapsed or Refractory Diffuse Large B-Cell Lymphoma

The safety of MONJUVI was evaluated in L-MIND. Patients (n=81) received MONJUVI 12 mg/kg intravenously in combination with lenalidomide for a maximum of 12 cycles, followed by MONJUVI as monotherapy until disease progression or unacceptable toxicity as follows:

*Cycle 1: Days 1, 4, 8, 15 and 22 of the 28-day cycle;
*Cycles 2 and 3: Days 1, 8, 15 and 22 of each 28-day cycle;
*Cycles 4 and beyond: Days 1 and 15 of each 28-day cycle.
Among patients who received MONJUVI, 57% were exposed for 6 months or longer, 42% were exposed for greater than one year, and 24% were exposed for greater than two years.

Serious adverse reactions occurred in 52% of patients who received MONJUVI. Serious adverse reactions in ≥6% of patients included infections (26%), including pneumonia (7%), and febrile neutropenia (6%). Fatal adverse reactions occurred in 5% of patients who received MONJUVI, including cerebrovascular accident (1.2%), respiratory failure (1.2%), progressive multifocal leukoencephalopathy (1.2%) and sudden death (1.2%).

Permanent discontinuation of MONJUVI or lenalidomide due to an adverse reaction occurred in 25% of patients and permanent discontinuation of MONJUVI due to an adverse reaction occurred in 15%. The most frequent adverse reactions which resulted in permanent discontinuation of MONJUVI were infections (5%), nervous system disorders (2.5%), respiratory, thoracic and mediastinal disorders (2.5%).

Dosage interruptions of MONJUVI or lenalidomide due to an adverse reaction occurred in 69% of patients and dosage interruption of MONJUVI due to an adverse reaction occurred in 65%. The most frequent adverse reactions which required a dosage interruption of MONJUVI were blood and lymphatic system disorders (41%), and infections (27%).

The most common adverse reactions (≥ 20%) were neutropenia, fatigue, anemia, diarrhea, thrombocytopenia, cough, pyrexia, peripheral edema, respiratory tract infection, and decreased appetite.

Clinically relevant adverse reactions in <10% of patients who received MONJUVI were:

*Blood and lymphatic system disorders: lymphopenia (6%)
General disorders and administration site conditions: infusion-related reaction (6%)
*Infections: sepsis (4.9%)
*Investigations: weight decreased (4.9%)
*Musculoskeletal and connective tissue disorders: arthralgia (9%), pain in extremity (9%), musculoskeletal pain (2.5%)
*Neoplasms benign, malignant and unspecified: basal cell carcinoma (1.2%)
*Nervous system disorders: headache (9%), paresthesia (7%), dysgeusia (6%)
*Respiratory, thoracic and mediastinal disorders: nasal congestion (4.9%), exacerbation of chronic obstructive pulmonary disease (1.2%)
Skin and subcutaneous tissue disorders: erythema (4.9%), alopecia (2.5%), hyperhidrosis (2.5%)
|useInLaborDelivery=Based on its mechanism of action, MONJUVI may cause fetal B-cell depletion when administered to a pregnant woman. There are no available data on MONJUVI use in pregnant women to evaluate for a drug-associated risk. Animal reproductive toxicity studies have not been conducted with tafasitamab-cxix.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

MONJUVI is administered in combination with lenalidomide for up to 12 cycles. Lenalidomide can cause embryo-fetal harm and is contraindicated for use in pregnancy. Refer to the lenalidomide prescribing information for additional information. Lenalidomide is only available through a REMS program.
|useInNursing=There are no data on the presence of tafasitamab-cxix in human milk or the effects on the breastfed child or milk production. Maternal immunoglobulin G is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to MONJUVI are unknown. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with MONJUVI and for at least 3 months after the last dose. Refer to lenalidomide prescribing information for additional information.
|useInPed=The safety and effectiveness of MONJUVI in pediatric patients have not been established.
|useInGeri=Among 81 patients who received MONJUVI and lenalidomide in L-MIND, 72% were 65 years and older, while 38% were 75 years and older. Clinical studies of MONJUVI did not include sufficient numbers of patients aged 65 and older to determine whether effectiveness differs compared to that of younger subjects. Patients 65 years and older had more serious adverse reactions (57%) than younger patients (39%).
|useInGender=MONJUVI can cause fetal B-cell depletion when administered to a pregnant woman.

'''Pregnancy Testing'''

Refer to the prescribing information for lenalidomide for pregnancy testing requirements prior to initiating the combination of MONJUVI with lenalidomide.

'''Contraception'''

''Females''

Advise females of reproductive potential to use effective contraception during treatment with MONJUVI and for at least 3 months after the last dose. Additionally, refer to the lenalidomide prescribing information for additional recommendations for contraception.

''Males''

Refer to the lenalidomide prescribing information for recommendations.
|administration=*Administer MONJUVI as an intravenous infusion.
*For the first infusion, use an infusion rate of 70 mL/h for the first 30 minutes, then, increase the rate so that the infusion is administered within 1.5 to 2.5 hours.
*Administer all subsequent infusions within 1.5 to 2 hours.
*Infuse the entire contents of the bag containing MONJUVI.
*Do not co-administer other drugs through the same infusion line.
*No incompatibilities have been observed between MONJUVI with infusion containers made of polypropylene (PP), polyvinylchloride (PVC), polyethylene (PE), polyethylenterephthalate (PET), or glass and infusion sets made of polyurethane (PUR) or PVC.
|mechAction=Tafasitamab-cxix is an Fc-modified monoclonal antibody that binds to CD19 antigen expressed on the surface of pre-B and mature B lymphocytes and on several B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL).

Upon binding to CD19, tafasitamab-cxix mediates B-cell lysis through apoptosis and immune effector mechanisms, including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).

In studies conducted in vitro in DLBCL tumor cells, tafasitamab-cxix in combination with lenalidomide resulted in increased ADCC activity compared to tafasitamab-cxix or lenalidomide alone.
|PD=Tafasitamab-cxix reduced peripheral blood B cell counts by 97% after eight days of treatment in patients with relapsed or refractory DLBCL. Nadir, with a reduction of 100%, was reached within 16 weeks of treatment.
|PK=Mean trough concentrations (± standard deviation) were 179 (± 53) μg/mL following administration of MONJUVI at 12 mg/kg on Days 1, 8, 15, and 22 in Cycle 1-3 (plus an additional dose on Cycle 1 Day 4), and 153 (± 68) μg/mL following administration of MONJUVI at 12 mg/kg on Days 1 and 15 from Cycle 4 onwards. Overall maximum tafasitamab-cxix serum concentrations were 483 (±109) μg/mL.

'''Distribution'''

The total volume of distribution for tafasitamab-cxix was 9.3 L (95% CI: 8.6, 10 L).

'''Elimination'''

The clearance of tafasitamab-cxix was 0.41 L/day (CV: 32%) and terminal elimination half-life was 17 days (95% CI: 15, 18 days).

'''Specific Populations'''

Bodyweight (40 to 163 kg) has a significant effect on the pharmacokinetics of tafasitamab-cxix, with higher clearance and volume of distribution expected with higher body weight. No clinically meaningful differences in the pharmacokinetics of tafasitamab-cxix were observed based on age (16 to 90 years), sex, mild to moderate renal impairment (CLcr 30-89 mL/min estimated by the Cockcroft-Gault equation), and mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 times ULN and any AST). The effect of severe renal impairment to end-stage renal disease (CLcr < 30 mL/min), moderate to severe hepatic impairment (total bilirubin > 1.5 times ULN and any AST), and race/ethnicity on tafasitamab-cxix pharmacokinetics is unknown.

'''Drug Interaction Studies'''

No clinically meaningful differences in tafasitamab-cxix pharmacokinetics were observed when used concomitantly with lenalidomide.
|nonClinToxic=Carcinogenicity and genotoxicity studies have not been conducted with tafasitamab-cxix.

Fertility studies have not been conducted with tafasitamab-cxix.

In the 13-week repeat-dose general toxicity study in cynomolgus monkeys, no adverse effects on male and female reproductive organs were observed up to the highest dose tested, 100 mg/kg/week (approximately 9 times the human exposure based on AUC at the clinical dose of 12 mg/kg/week).
|clinicalStudies=The efficacy of MONJUVI in combination with lenalidomide followed by MONJUVI as monotherapy was evaluated in L-MIND, an open-label, multicenter, single arm trial (NCT02399085). Eligible patients had relapsed or refractory DLBCL after 1 to 3 prior systemic therapies, including a CD20-directed cytolytic antibody, and were not candidates for high dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT). Patients received MONJUVI 12 mg/kg intravenously in combination with lenalidomide (25 mg orally on Days 1 to 21 of each 28-day cycle) for a maximum of 12 cycles, followed by MONJUVI as monotherapy until disease progression or unacceptable toxicity as follows:

*Cycle 1: Days 1, 4, 8, 15 and 22 of the 28-day cycle;
*Cycles 2 and 3: Days 1, 8, 15 and 22 of each 28-day cycle;
*Cycles 4 and beyond: Days 1 and 15 of each 28-day cycle.

Of the 71 patients with DLBCL confirmed by central laboratory who received the combination therapy, the median age was 71 years (range: 41 to 86 years); 55% were males, and 100% had received a prior CD20-containing therapy. Race was collected in 92% of patients; of these, 95% were White, and 3% were Asian. The median number of prior therapies was two; 49% had one prior line of treatment, and 51% had 2 to 4 prior lines. Thirty-two patients (45%) were refractory to their last prior therapy and 30 (42%) were refractory to rituximab. Nine patients (13%) had received prior ASCT. The primary reasons patients were not candidates for ASCT included age (47%), refractoriness to salvage chemotherapy (27%), comorbidities (13%) and refusal of high dose chemotherapy/ASCT (13%).

Efficacy was established based on best overall response rate, defined as the proportion of complete and partial responders, and duration of response, as assessed by an Independent Review Committee using the International Working Group Response Criteria (Cheson, 2007).
|howSupplied=MONJUVI (tafasitamab-cxix) for injection is a sterile, preservative-free, white to slightly yellowish lyophilized powder for reconstitution supplied as a 200 mg single-dose vial.

Each 200 mg vial is individually packaged in a carton (NDC 73535–208–01).
|storage=Store refrigerated at 36°F to 46°F (2°C to 8°C) in the original carton to protect from light. Do not shake. Do not freeze.
|fdaPatientInfo=Advise the patient to read the FDA-approved patient labeling

'''Infusion-Related Reactions'''

Advise patients to contact their healthcare provider if they experience signs and symptoms of infusion-related reactions.

'''Myelosuppression'''

Inform patients about the risk of myelosuppression. Advise patients to immediately contact their healthcare provider for a fever of 100.4°F (38°C) or greater or signs or symptoms of bruising or bleeding. Advise patients of the need for periodic monitoring of blood counts .

'''Infections'''

Inform patients about the risk of infections. Advise patients to immediately contact their healthcare provider for a fever of 100.4°F (38°C) or greater or signs or symptoms of infection.

'''Embryo-Fetal Toxicity'''

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.
Advise females of reproductive potential to use effective contraception during treatment with MONJUVI and for at least 3 months after the last dose.
Advise patients that lenalidomide has the potential to cause fetal harm and has specific requirements regarding contraception, pregnancy testing, blood and sperm donation, and transmission in sperm. Lenalidomide is only available through a REMS program.

'''Lactation'''

Advise women not to breastfeed during treatment with MONJUVI and for at least 3 months after the last dose.
|alcohol=Alcohol-Tafasitamab-cxix interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=MONJUVI
}}

Risdiplam

2025-05-01T08:32:19Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=risdiplam |aOrAn=a |drugClass=enhancer of SMN2 gene transcription |indicationType=treatment |indication=spinal muscular atrophy (SMA) in pediatric and adult patients. |adverseReactions=Fever Diarrhea Rash Mouth and Aphtous Ulcers Arthralgia UTI |blackBoxWarningTitle='''TITLE''' |blackBoxWarningBody=''Condition N..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=risdiplam
|aOrAn=a
|drugClass=enhancer of SMN2 gene transcription
|indicationType=treatment
|indication=spinal muscular atrophy (SMA) in pediatric and adult patients.
|adverseReactions=Fever
Diarrhea
Rash
Mouth and Aphtous Ulcers
Arthralgia
UTI
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=*EVRYSDI is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients.
'''DOSAGE''':
*Less than 2 months of age: 0.15 mg/kg
*2 months to less than 2 years of age: 0.2 mg/kg
*2 years of age and older weighing less than 20 kg: 0.25 mg/kg
*2 years of age and older weighing 20 kg or more: 5 mg
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Risdiplam in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Risdiplam in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Risdiplam in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Risdiplam in pediatric patients.
|contraindications=None
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials including patients with infantile-onset SMA, later-onset SMA, and pre-symptomatic SMA, a total of 491 patients (51% female, 74% Caucasian) were exposed to EVRYSDI for up to a median duration of 48.1 months (range: 0.6 to 63.4 months), with 231 patients receiving treatment for more than 24 months. At the time of first EVRYSDI dose, 90 (18%) patients were 18 years and older, 119 (24%) were 12 years to less than 18 years, 189 (39%) were 2 years to less than 12 years, 67 (14%) 2 months to less than 2 years, and 26 (5%) were less than 2 months.

'''Clinical Trial in Later-Onset SMA'''
The safety of EVRYSDI for later-onset SMA is based on data from a randomized, double-blinded, placebo-controlled study (Study 2 Part 2) in patients with SMA Type 2 or 3 (n = 180). The patient population in Study 2 Part 2 ranged in age from 2 to 25 years at the time of the first dose.
The most common adverse reactions (reported in at least 10% of patients treated with EVRYSDI and at an incidence greater than on placebo) in Study 2 Part 2 were fever, diarrhea, and rash.

'''Clinical Trial in Infantile-Onset SMA'''
The safety of EVRYSDI therapy for infantile-onset SMA is based on data from an open-label study in 62 patients. The patient population ranged in age from 2 to 7 months at the time of the first EVRYSDI dose (weight range: 4.1 to 10.6 kg).

The most frequent adverse reactions reported in infantile-onset SMA patients treated with EVRYSDI in Study 1 were similar to those observed in later-onset SMA patients in Study 2. Additionally, the following adverse reactions reported in ≥ 10% of patients were: upper respiratory tract infection (including nasopharyngitis, rhinitis), lower respiratory tract infection (including pneumonia, bronchitis), constipation, vomiting, and cough.

'''Clinical Trial in Pre-Symptomatic SMA'''
The safety of EVRYSDI therapy for pre-symptomatic SMA is based on data from an open-label, single-arm study in 26 patients. The patient population ranged in age from 16 to 41 days at the time of the first dose (weight range: 3.1 to 5.7 kg). The safety profile of EVRYSDI in pre-symptomatic patients in Study 3 is consistent with the safety profile for symptomatic SMA patients treated with EVRYSDI in clinical trials.
|drugInteractions='''Effect of EVRYSDI on Substrates of Multidrug and Toxin Extrusion (MATE) Protein Transporters'''
Based on in vitro data, EVRYSDI may increase plasma concentrations of drugs eliminated via MATE1 or MATE2-K [see Clinical Pharmacology (12.3)], such as metformin. Avoid coadministration of EVRYSDI with MATE substrates. If coadministration cannot be avoided, monitor for drug-related toxicities and consider dosage reduction of the coadministered drug (based on the labeling of that drug) if needed.
|useInLaborDelivery=There is a pregnancy exposure registry that monitors pregnancy and fetal/neonatal/infant outcomes in women exposed to EVRYSDI during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-833-760-1098 or visiting https://www.evrysdipregnancyregistry.com.
|useInNursing=There are no data on the presence of risdiplam in human milk, the effects on the breastfed infant, or the effects on milk production. Risdiplam was excreted in the milk of lactating rats orally administered risdiplam.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for EVRYSDI and any potential adverse effects on the breastfed infant from EVRYSDI or from the underlying maternal condition.
|useInPed=The safety and effectiveness of EVRYSDI in pediatric patients (neonates and older) have been established. Use of EVRYSDI for SMA is supported by evidence from adequate and well-controlled studies of EVRYSDI in patients 2 months of age and older with SMA. Use of EVRYSDI for SMA in patients 2 months of age and younger is supported by pharmacokinetic and safety data from pediatric patients 16 days and older, and pharmacokinetic modeling and simulation to identify the dosing regimen
|useInGeri=Clinical studies of EVRYSDI did not include patients aged 65 years and older to determine whether they respond differently from younger adult patients.
|useInGender=Studies of risdiplam in juvenile and adult rats and in monkeys demonstrated adverse effects on the reproductive organs, including germ cells, in males at clinically relevant plasma exposures.

'''Pregnancy Testing'''

Pregnancy testing is recommended for females of reproductive potential prior to initiating EVRYSDI.

'''Contraception'''

EVRYSDI may cause embryofetal harm when administered to a pregnant woman .

'''Female Patients'''

Advise female patients of reproductive potential to use effective contraception during treatment with EVRYSDI and for at least 1 month after her last dose.

'''Infertility'''

'''Male Patients'''

Male fertility may be compromised by treatment with EVRYSDI.

Counsel male patients of reproductive potential receiving EVRYSDI about the potential effects on fertility. Male patients may consider sperm preservation prior to treatment.
|administration=It is recommended that a healthcare provider discuss with the patient or caregiver how to prepare the prescribed daily dose prior to administration of the first dose.

EVRYSDI is taken orally once daily with or without food at approximately the same time each day.

'''EVRYSDI for Oral Solution'''

In infants who are breastfed, EVRYSDI for oral solution can be administered before or after breastfeeding. EVRYSDI cannot be mixed with formula or milk.

Instruct patients or caregivers to administer the dose using the reusable oral syringe provided.

EVRYSDI for oral solution must be taken immediately after it is drawn up into the oral syringe. If EVRYSDI is not taken within 5 minutes, EVRYSDI should be discarded from the oral syringe, and a new dose should be prepared.

Instruct patients to drink water after taking EVRYSDI for oral solution to ensure the drug has been completely swallowed.

If the patient is unable to swallow and has a nasogastric or gastrostomy tube, EVRYSDI for oral solution can be administered via the tube. The tube should be flushed with water after delivering EVRYSDI for oral solution
|monitoring=If coadministration cannot be avoided, monitor for drug-related toxicities and consider dosage reduction of the coadministered drug (based on the labeling of that drug) if needed.
|mechAction=Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier designed to treat patients with spinal muscular atrophy (SMA) caused by mutations in chromosome 5q that lead to SMN protein deficiency. Using in vitro assays and studies in transgenic animal models of SMA, risdiplam was shown to increase exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and production of full-length SMN protein in the brain.

In vitro and in vivo data indicate that risdiplam may cause alternative splicing of additional genes, including FOXM1 and MADD. FOXM1 and MADD are thought to be involved in cell cycle regulation and apoptosis, respectively, and have been identified as possible contributors to adverse effects seen in animals.
|PD=In clinical trials for infantile-onset SMA and later-onset SMA patients, EVRYSDI led to an increase in SMN protein with a greater than 2-fold median change from baseline within 4 weeks of treatment initiation across all SMA types studied. The increase was sustained throughout the treatment period (of at least 24 months).

'''Cardiac Electrophysiology'''

At the maximum recommended dose, clinically significant QTc interval prolongation was not observed.
|PK=Pharmacokinetics of EVRYSDI have been characterized in healthy adult subjects and in patients with SMA.

After administration of EVRYSDI as an oral solution, pharmacokinetics of risdiplam were approximately linear between 0.6 and 18 mg in a single-ascending-dose study in healthy adult subjects, and between 0.02 and 0.25 mg/kg once daily in a multiple-ascending-dose study in patients with SMA. Following once-daily oral administration of risdiplam in healthy subjects, approximately 3-fold accumulation of peak plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC0-24h) was observed. Risdiplam exposures reach steady state 7 to 14 days after once daily administration. EVRYSDI tablet (swallowed whole or dispersed in water) demonstrated comparable bioavailability to EVRYSDI for oral solution in adult healthy volunteers under fasted and fed states.

'''Absorption'''

Following oral administration of risdiplam in fasted state, the median time to reach maximum plasma concentration (Tmax) was 3.26 to 4 hours. The Tmax was delayed by up to1 hour in fed state compared to that under fasted state.

'''Effect of Food'''

Food (high-fat, high calorie breakfast) had no relevant effect on the exposure of risdiplam. In the clinical efficacy studies (Study 1 and Study 2), risdiplam was administered with a morning meal or after breastfeeding.

'''Distribution'''

The apparent volume of distribution at steady state is 190.4 L for a 31.3 kg patient.

Risdiplam is predominantly bound to serum albumin, without any binding to alpha-1 acid glycoprotein, with a free fraction of 11%.

'''Elimination'''

The apparent clearance (CL/F) of risdiplam is 2.45 L/h for a 31.3 kg patient.

The terminal elimination half-life of risdiplam was approximately 50 hours in healthy adults.

'''Metabolism'''

Risdiplam is primarily metabolized by flavin monooxygenase 1 and 3 (FMO1 and FMO3) and also by CYPs 1A1, 2J2, 3A4, and 3A7.

Parent drug was the major component found in plasma, accounting for 83% of drug-related material in circulation. The pharmacologically-inactive metabolite M1 was identified as the major circulating metabolite.

'''Excretion'''

Following a dose of 18 mg, approximately 53% of the dose (14% unchanged risdiplam) was excreted in the feces and 28% in urine (8% unchanged risdiplam).

'''Specific Populations'''

There were no clinically significant differences in the pharmacokinetics of EVRYSDI based on race or gender. Renal impairment is not expected to alter the exposures to risdiplam.

The impact of geriatric age on the pharmacokinetics of EVRYSDI has not been studied.

'''Hepatic Impairment'''

The pharmacokinetics and safety of risdiplam have been studied in subjects with mild or moderate hepatic impairment (as defined by Child-Pugh class A and B, respectively, n = 8 each) compared to subjects with normal hepatic function (n = 10). Following the administration of 5 mg EVRYSDI, the AUCinf and Cmax of risdiplam were approximately 20% and 5% lower, respectively, in subjects with mild hepatic impairment and were approximately 8% and 20% higher, respectively, in subjects with moderate hepatic impairment, versus matched healthy control subjects. The magnitude of these changes is not considered to be clinically meaningful. The pharmacokinetics and safety in patients with severe hepatic impairment (Child-Pugh class C) have not been studied.

'''Pediatric Patients'''

Body weight and age were found to have significant effect on the pharmacokinetics of risdiplam. The estimated exposure (mean AUC0-24h) in pre-symptomatic infants at the age of 1 to 2 months was 2090 ng.h/mL at the recommended dose of 0.15 mg/kg once daily. The estimated exposure for infantile-onset SMA patients (age 2 to 7 months at enrollment) at the recommended dose of 0.2 mg/kg once daily was 1930 ng.h/mL. The estimated exposure for later-onset SMA patients (2 to 25 years old at enrollment) at the recommended dose was 2070 ng.h/mL (0.25 mg/kg once daily for patients with a body weight < 20 kg and 5 mg once daily for patients with a body weight ≥ 20 kg).

No data on risdiplam pharmacokinetics are available in patients less than 16 days of age [see Use in Specific Populations (8.4)].

'''Drug Interaction Studies'''

Effect of Other Drugs on EVRYSDI

Coadministration of 200 mg itraconazole (a strong CYP3A inhibitor) twice daily with a single 6 mg oral dose of risdiplam did not have a clinically relevant effect on the pharmacokinetics of risdiplam (11% increase in AUC and 9% decrease in Cmax).

Risdiplam is a weak substrate of human MDR-1 and breast cancer resistant protein (BCRP) transporters in vitro. Human MDR-1 or BCRP inhibitors are not expected to result in a clinically significant increase of risdiplam concentrations.

'''Effect of EVRYSDI on Other Drugs'''

Risdiplam and its major circulating metabolite M1 did not induce CYP1A2, 2B6, 2C8, 2C9, 2C19, or 3A4 in vitro. Risdiplam and M1 did not inhibit (reversible or time-dependent inhibition) any of the CYP enzymes tested (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6), with the exception of CYP3A in vitro.

EVRYSDI is a weak inhibitor of CYP3A. In healthy adult subjects, administration of EVRYSDI once daily for 2 weeks slightly increased the exposure of midazolam, a sensitive CYP3A substrate (AUC 11%; Cmax 16%); this increase is not considered clinically relevant. Based on physiologically-based pharmacokinetic (PBPK) modeling, a similar increase is expected in children and infants as young as 2 months of age.

In vitro studies have shown that risdiplam and its major metabolite are not significant inhibitors of human MDR1, organic anion-transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter 1 and 3 (OAT 1 and 3) transporters, and human organic cation transporter 2 (OCT2), at clinically relevant concentrations. Risdiplam and its metabolite are, however, in vitro inhibitors of the multidrug and toxin extrusion (MATE) 1 and MATE2-K transporters.
|nonClinToxic='''Carcinogenesis'''

Risdiplam was not carcinogenic in Tg.rasH2 mice when administered at oral doses of up to 9 mg/kg/day for 26 weeks.

In a 2-year carcinogenicity study in rats, oral administration of risdiplam (0, 0.3, 1, or 3 mg/kg/day) resulted in increased incidences of preputial gland squamous cell carcinomas in males and combined thyroid follicular cell adenomas and carcinomas in females at the highest dose tested. The higher dose not associated with an increase in tumors (1 mg/kg/day) was associated with plasma drug exposures (AUC) similar to that in humans at the maximum recommended human dose (MRHD) of 5 mg/day.

'''Mutagenesis'''

Risdiplam was negative in an in vitro Ames assay. In an in vivo combined bone marrow micronucleus and comet assay in rat, risdiplam was clastogenic, as evidenced by an increase in micronuclei in bone marrow, but was negative in the comet assay. A pronounced increase in bone marrow micronuclei was also observed in toxicity studies in adult and juvenile rats.

'''Impairment of Fertility'''

Oral administration of risdiplam to rats for 4 (0, 1, 3, or 9 mg/kg/day) or 26 (0, 1, 3, or 7.5 mg/kg/day) weeks resulted in histopathological effects in the testis (degenerated spermatocytes, degeneration/atrophy of the seminiferous tubules) and epididymis (degeneration/necrosis of ductular epithelium) at the mid and/or high doses. At the high dose in the 26-week study, the testicular lesions persisted to the end of the recovery period, which corresponds, in rat, to approximately one spermatogenic cycle. The no-effect dose for adverse reproductive system effects in adult male rats (1 mg/kg/day) was associated with plasma drug exposures (AUC) similar to that in humans at the maximum recommended human dose (MRHD) of 5 mg/day.

Adverse effects of risdiplam on the testis could not be fully evaluated in the monkey because the majority of monkeys tested were sexually immature. However, oral administration of risdiplam (0, 2, 4, or 6 mg/kg/day) for 2 weeks resulted in histopathological changes in the testis (increases in multinucleate cells, germ cell degeneration) at the highest dose. At the no-effect dose for testicular toxicity in monkeys, plasma exposures were approximately 3 times that in humans at the MRHD.

Oral administration of risdiplam to postweaning juvenile rats resulted in male reproductive toxicity (degeneration/necrosis of the testis seminiferous epithelium with associated oligo/aspermia in the epididymis and abnormal sperm parameters). The no-effect dose for adverse reproductive effects in postweaning male juvenile rats was associated with plasma exposures approximately 4 times that in humans at the MRHD
|clinicalStudies=The efficacy of EVRYSDI for the treatment of patients with infantile-onset, later-onset, and pre-symptomatic SMA was evaluated in three clinical studies, Study 1 (NCT02913482) and Study 2 (NCT02908685), and Study 3 (NCT03779334), respectively.

The overall findings of these studies support the effectiveness of EVRYSDI in SMA pediatric and adult patients and appear to support the early initiation of treatment with EVRYSDI.

'''Infantile-Onset SMA'''
Study 1 was an open-label, 2-part study to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of EVRYSDI for oral solution in patients with Type 1 SMA (symptom onset between 28 days and 3 months of age). All patients had genetic confirmation of homozygous deletion or compound heterozygosity predictive of loss of function of the SMN1 gene, and two SMN2 gene copies.

Part 1 of Study 1 was designed as a dose-finding study. Part 2 of Study 1 assessed the safety and efficacy of EVRYSDI at 0.20 mg/kg, the recommended dose determined in Part 1. Patients from Part 1 did not take part in Part 2.

A total of 62 patients with symptomatic Type 1 SMA were enrolled in FIREFISH Part 1 (n = 21) and Part 2 (n = 41), of which 58 patients received the recommended dosage [see Dosage and Administration (2.1)]. The median age of onset of clinical signs and symptoms was 1.5 months (range: 0.9 to 3.0 months). The median age at enrollment was 5.6 months (range: 2.2 to 6.9 months), and the median time between onset of symptoms and the first dose was 3.7 months (range 1.0 to 6.0 months). Of these patients, 60% were female, 57% were Caucasian, and 29% were Asian. The demographics and baseline disease characteristics were comparable between Part 1 and Part 2 of the study.

Effectiveness was established based on the ability to sit without support for at least 5 seconds (as measured by Item 22 of the Bayley Scales of Infant and Toddler Development – Third Edition (BSID-III) gross motor scale) and on the basis of survival without permanent ventilation. Permanent ventilation was defined as requiring a tracheostomy or more than 21 consecutive days of either non-invasive ventilation (≥ 16 hours per day) or intubation, in the absence of an acute reversible event.

The primary endpoint was the proportion of patients with the ability to sit without support for at least 5 seconds (BSID-III gross motor scale, Item 22) after 12 months of treatment in Part 2; 29% of patients (n = 12/41) achieved this milestone.

'''Later Onset SMA'''
Study 2 was a 2-part, multicenter trial to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of EVRYSDI for oral solution in patients diagnosed with SMA Type 2 or Type 3. Part 1 of Study 2 was dose-finding and exploratory in 51 patients (14% ambulatory). Part 2 was randomized, double-blind, placebo-controlled, and is described below.

The primary endpoint in Study 2 Part 2 was the change from baseline to Month 12 in the Motor Function Measure 32 (MFM32) score. A key secondary endpoint was the proportion of patients with a 3-point or greater change from baseline to Month 12 in the MFM32 total score. The MFM32 measures motor function abilities that relate to daily functions. The total MFM32 score is expressed as a percentage (range: 0 to 100) of the maximum possible score, with higher scores indicating greater motor function. Another key secondary endpoint was the Revised Upper Limb Module (RULM). The RULM is a tool used to assess motor performance of the upper limb in SMA patients. It tests proximal and distal motor functions of the arm. The total score ranges from 0 (all the items cannot be performed) to 37 (all the activities are achieved fully without any compensatory maneuvers). Study 2 Part 2 enrolled 180 non-ambulatory patients with Type 2 (71%) or Type 3 (29%) SMA. Patients were randomized 2:1 to receive EVRYSDI at the recommended dosage or placebo. Randomization was stratified by age group (2 to 5, 6 to 11, 12 to 17, or 18 to 25 years of age). The median age of patients at the start of treatment was 9.0 years (range: 2 to 25), and the median time between onset of initial SMA symptoms and first treatment was 102.6 months (range: 1 to 275). Of the 180 patients included in the trial, 51% were female, 67% were Caucasian, and 19% were Asian. At baseline, 67% of patients had scoliosis (32% of them with severe scoliosis). Patients had a mean baseline MFM32 score of 46.1, and RULM score of 20.1. Overall baseline demographic characteristics were reasonably balanced between the treatment groups (EVRYSDI and placebo), with the exception of scoliosis (63% in the EVRYSDI arm vs. 73% in the placebo group).

The primary analysis on the change from baseline in MFM32 total score at Month 12 showed a clinically meaningful and statistically significant difference between patients treated with EVRYSDI and placebo.

'''Pre-Symptomatic SMA'''
Study 3 was an open-label, single-arm, multicenter clinical study to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of EVRYSDI in infants up to 6 weeks of age (at first dose) who have been genetically diagnosed with SMA but do not yet present with symptoms.

The efficacy in pre-symptomatic SMA patients was evaluated at Month 12 in 26 patients treated with EVRYSDI in Study 3: 8 patients had 2 copies of the SMN2 gene, 13 patients had 3 copies, and 5 patients had 4 or more copies. The median age of these patients at first dose was 25 days (range: 16 to 41), 62% were female, and 85% were Caucasian. The primary efficacy population (N = 5) included patients with 2 SMN2 copies and a baseline CMAP amplitude ≥1.5 mV.

The primary efficacy endpoint was the proportion of patients with the ability to sit without support for at least 5 seconds (BSID-III gross motor scale, Item 22) at Month 12. This milestone was achieved by 80% (4/5) of patients in the primary efficacy population. This milestone was also achieved by 87.5% (7/8) of all patients with 2 copies of SMN2 and 96.2% (25/26) of patients in the full treated population.

At Month 12, 80.8% (21/26) of patients in the full treated population achieved sitting without support for 30 seconds (BSID-III, Item 26). Of the 26 patients treated with EVRYSDI, 25 patients had motor milestones measured by the HINE-2 at Month 12. Of these, 24 (96%) achieved sitting (23 patients could pivot/rotate and 1 achieved stable sit); 21 (84%) could stand (13 patients could stand unaided and 8 could stand with support); and 12 (48%) could walk independently. Seven patients were not tested for walking at Month 12. All 26 patients were alive at 12 months without permanent ventilation.
|howSupplied=Each amber glass bottle of EVRYSDI for oral solution is packaged with a bottle adapter, two 1 mL reusable oral syringes, two 6 mL reusable oral syringes, and one 12 mL reusable oral syringe. EVRYSDI for oral solution is a light yellow, pale yellow, yellow, greyish yellow, greenish yellow, or light green powder. Each bottle contains 60 mg of risdiplam (NDC 50242-175-07).

'''EVRYSDI Tablets'''
Pale yellow film-coated tablet, round and curved, with EVR debossed on one side; available in HDPE bottles of 30 tablets with a child-resistant cap (NDC 50242-202-01).
|storage=Store the dry powder at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Keep in the original carton.

Keep the constituted oral solution of EVRYSDI in the original amber bottle to protect from light. Store in a refrigerator at 2°C to 8°C (36°F to 46°F)

'''EVRYSDI Tablets'''
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep the bottle tightly closed in order to protect from moisture.
|fdaPatientInfo=Advise the patient to read the FDA-approved patient labeling.

'''Pregnancy and Fetal Risk'''

Inform pregnant women and women of reproductive potential that, based on animal studies, EVRYSDI may cause fetal harm.

Discuss with women of childbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant.

Advise women of childbearing potential to use effective contraception during treatment with EVRYSDI and for at least 1 month after stopping EVRYSDI.

Advise a female patient to immediately inform the prescriber if she is pregnant or planning to become pregnant.

'''Pregnancy Registry'''

Encourage patients to enroll in the EVRYSDI Pregnancy Registry if they become pregnant while taking EVRYSDI.

'''Potential Effects on Male Fertility'''

Advise male patients that their fertility may be compromised while on treatment with EVRYSDI.

'''Instructions for Preparation of Oral Solution'''

Advise patients/caregivers to ensure that EVRYSDI oral solution is in liquid form when received from the pharmacy.

Instruct patients/caregivers to take EVRYSDI oral solution with or without food or before or after breastfeeding at approximately the same time each day. However, instruct caregivers not to mix EVRYSDI with formula or milk.

Instruct patients/caregivers to take EVRYSDI oral solution immediately after it is drawn up into the reusable oral syringe.

'''Instructions for EVRYSDI Tablets'''

Advise patients/caregivers to swallow EVRYSDI tablets whole with water. Do not chew, cut, or crush the tablets.

Alternatively, the tablet can be dispersed in one teaspoon (5 mL) of room temperature non-chlorinated drinking water (e.g., filtered water) and taken immediately. EVRYSDI tablets must not be dispersed in any liquid other than non-chlorinated drinking water. Instruct the patient/caregivers that the dispersion must be administered within 10 minutes of adding non-chlorinated drinking water, or it must be discarded.

Advise patients/caregivers that the EVRYSDI tablet dispersion is for oral administration only. If administration through a nasogastric/gastrostomy tube is required, EVRYSDI for oral solution should be used.

Advise patients/caregivers to wash their hands before and after preparing or taking EVRYSDI tablets.

Advise patients/caregivers to avoid getting the dispersed tablet on their skin or in their eyes. Advise patients/caregivers to wash the area with soap and water if the dispersed tablet gets on the skin. Advise patients/caregivers to rinse their eyes with water if the dispersed tablet gets in the eyes.

Advise patients/caregivers to use a dry paper towel to dry the area if the dispersion is spilled and then clean with soap and water. Advise patients/caregivers to throw the paper towel away in the trash and wash their hands with soap and water.
|alcohol=Alcohol-Risdiplam interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=EVRYSDI
}}

Oliceridine

2025-04-30T19:10:48Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=oliceridine |aOrAn=an |drugClass=μ opioid agonist |indication=OLINVYK is indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. |hasBlackBoxWarning=Yes |adverseReactions=The following adverse reactions are described, or described in greater detail, in other sections: *Addi..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=oliceridine
|aOrAn=an
|drugClass=μ opioid agonist
|indication=OLINVYK is indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate.
|hasBlackBoxWarning=Yes
|adverseReactions=The following adverse reactions are described, or described in greater detail, in other sections:

*Addiction, Abuse, and Misuse
*Life-threatening Respiratory Depression
*Interactions with Benzodiazepines or Other CNS Depressants.
*Neonatal Opioid Withdrawal Syndrome.
*Opioid-Induced Hyperalgesia and Allodynia.
*Adrenal Insufficiency.
*Severe Hypotension.
*Gastrointestinal Adverse Reactions.
*Seizures.
*Withdrawal.
|blackBoxWarningTitle='''SERIOUS AND LIFE-THREATENING RISKS FROM USE OF OLINVYK'''
|blackBoxWarningBody=''Addiction, Abuse, and Misuse:'' (Because the use of OLINVYK exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions)
'' Life-Threatening Respiratory Depression:'' (Serious, life-threatening, or fatal respiratory depression may occur with use of OLINVYK, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of OLINVYK are essential)
''Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants:'' (Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of OLINVYK and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate)
''Neonatal Opioid Withdrawal Syndrome:'' (If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery)
|fdaLIADAdult=OLINVYK is indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate.
'''DOSAGE'''
For intravenous administration only.

OLINVYK should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks.

Individual single doses greater than 3 mg have not been evaluated.

The cumulative daily dose should not exceed 27 mg.

OLINVYK 30 mg/30 mL (1mg/mL) vial is intended for patient-controlled analgesia (PCA) use only. Draw OLINVYK directly from the vial into the PCA syringe or IV bag without diluting.

Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of OLINVYK for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks.

Use of OLINVYK beyond 48 hours has not been studied in controlled clinical trials.

There is variability in opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse.

Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with OLINVYK. Consider this risk when selecting an initial dose and when making dose adjustments.

Inspect OLINVYK for particulate matter and discoloration prior to administration. The solution is a clear, colorless, preservative free solution for intravenous use. If visibly opaque particles, discoloration, or other foreign particles are observed, do not use.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Oliceridine in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Oliceridine in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Oliceridine in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Oliceridine in pediatric patients.
|contraindications=OLINVYK is contraindicated in patients with:

*Significant respiratory depression
*Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
*Known or suspected gastrointestinal obstruction, including paralytic ileus
*Known hypersensitivity to oliceridine (e.g., anaphylaxis)
|warnings='''Addiction, Abuse, and Misuse’’’
OLINVYK contains oliceridine, a Schedule II controlled substance. As an opioid, OLINVYK exposes users to the risks of addiction, abuse, and misuse
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed OLINVYK. Addiction can occur at recommended dosages and if the drug is misused or abused
Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing OLINVYK, and monitor all patients receiving OLINVYK for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as OLINVYK, but use in such patients necessitates intensive counseling about the risks and proper use of OLINVYK along with intensive monitoring for signs of addiction, abuse, and misuse.
Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing OLINVYK. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.
'''Life-Threatening Respiratory Depression'''
Serious, life-threatening respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of opioids, the risk is greatest during initiation of therapy or following a dose increase. Monitor patients closely for respiratory depression, especially when initiating therapy with OLINVYK and following dosage increases.
To reduce the risk of respiratory depression, proper dosing of OLINVYK is essential. Overestimating the OLINVYK dosage when converting patients from another opioid product can result in fatal overdose with the first dose.
Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper.
'''Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants'''
Profound sedation, respiratory depression, coma, and death may result from the concomitant use of OLINVYK with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, or alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics.
If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Monitor patients closely for signs and symptoms of respiratory depression and sedation.
'''Neonatal Opioid Withdrawal Syndrome'''
Use of OLINVYK for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that management by neonatology experts will be available at delivery.
Potential for QT prolongation with Daily Doses exceeding 27 mg
The effect of oliceridine on cardiac physiology was studied in single and multiple-dose thorough QT studies. The multiple-dose study was conducted with a maximum daily cumulative dose of 27 mg. In both studies, there was mild QTc interval prolongation. In the multiple-dose study, the maximum mean ΔΔQTcI was 11.7 ms (two-sided 90% UCI 14.7 ms) at 9 hours. The effect on QT prolongation at total cumulative daily doses >27 mg has not been studied in a thorough QT study. Total cumulative daily doses exceeding 27 mg per day may increase the risk for QTc interval prolongation. Therefore, the cumulative total daily dose of OLINVYK should not exceed 27 mg.
'''Risk of Use in Patients with Decreased Cytochrome P450 2D6 Function or Concomitant Use or Discontinuation with Cytochrome P450 3A4 Inhibitors and Inducers'''
Risk of Increased Oliceridine Plasma Concentrations
Increased plasma concentrations of oliceridine, which may result in prolonged opioid adverse reactions and exacerbated respiratory depression, may occur when OLINVYK is used under the following conditions:
*In patients with decreased Cytochrome P450 (CYP) 2D6 function (poor metabolizers of CYP2D6 or normal metabolizers taking moderate or strong CYP2D6 inhibitors.
*In patients taking a moderate or strong CYP3A4 inhibitor
*In patients with decreased CYP2D6 function who are also receiving a moderate or strong CYP3A4 inhibitor
*Discontinuation of a CYP3A4 inducer
These patients may require less frequent dosing of OLINVYK. Closely monitor these patients for respiratory depression and sedation at frequent intervals and base subsequent doses of OLINVYK on the patient’s severity of pain and response to treatment.
Risk of Lower than Expected Oliceridine Plasma Concentrations
Lower than expected concentrations of oliceridine, which may lead to decreased efficacy, may occur under the following conditions:
*Concomitant use of OLINVYK with CYP3A4 inducers
*Discontinuation of a moderate or strong CYP3A4 or CYP2D6 inhibitor
Closely monitor these patients at frequent intervals and consider supplemental doses of OLINVYK.
'''Opioid-Induced Hyperalgesia and Allodynia'''
Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.
Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety).
'''Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients'''
The use of OLINVYK in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.
Patients with Chronic Pulmonary Disease: OLINVYK-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of OLINVYK.
Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.
Monitor such patients closely, particularly when initiating and titrating OLINVYK and when OLINVYK is given concomitantly with other drugs that depress respiration. Alternatively, consider the use of non-opioid analgesics in these patients.
'''Adrenal Insufficiency'''
Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.
'''Severe Hypotension'''
OLINVYK may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics. Monitor these patients for signs of hypotension after initiating or titrating the dosage of OLINVYK. In patients with circulatory shock, OLINVYK may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of OLINVYK in patients with circulatory shock.
'''Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness'''
In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), OLINVYK may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with OLINVYK.
Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of OLINVYK in patients with impaired consciousness or coma.
'''Risks of Use in Patients with Gastrointestinal Conditions'''
OLINVYK is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.
OLINVYK may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.
'''Increased Risk of Seizures in Patients with Seizure Disorders'''
OLINVYK may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during OLINVYK therapy.
'''Withdrawal'''
Do not abruptly discontinue OLINVYK in a patient physically dependent on opioids. When discontinuing OLINVYK in a physically-dependent patient, gradually taper the dosage. Rapid tapering of oliceridine in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain.
Additionally, avoid the use of mixed agonist/antagonist (e.g, pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including OLINVYK. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms.
'''Risks of Driving and Operating Machinery'''
OLINVYK may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of OLINVYK and know how they will react to the medication.
'''Patient-Controlled Analgesia (PCA)'''
Although self-administration of opioids by PCA may allow each patient to individually titrate to an acceptable level of analgesia, PCA administration has resulted in adverse outcomes and episodes of respiratory depression. Health care providers and family members monitoring patients receiving PCA analgesia should be instructed in the need for appropriate monitoring for excessive sedation, respiratory depression, or other adverse effects of opioid medications.
|clinicalTrials=in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

A total of 1535 patients were treated with OLINVYK in controlled and open-label trials in patients with moderate to severe acute pain. Of these, 1181 patients received a total daily dose ≤27 mg and 354 patients received a total daily dose >27 mg during the first 24-hour treatment period. Among patients who received a daily dose of >27 mg, 198 patients received a daily dose between 27 mg and 40 mg, and 142 patients received a daily dose >40 mg.

The most common adverse drug reactions (≥10%) in controlled efficacy trials (Study 1 and Study 2) were nausea, vomiting, dizziness, headache, constipation, pruritus and hypoxia. Adverse reactions leading to discontinuation of OLINVYK were hypotension, hypoxia, nausea, hypoventilation, oxygen saturation decreased, alanine aminotransferase increased, aspartate aminotransferase increased, electrocardiogram QT prolongation, and urticaria. In two randomized, double-blind, placebo- and morphine-controlled studies, when stratified by 27 mg daily dosing limit, discontinuation of OLINVYK due to adverse reactions occurred in 4% of patients who received a daily dose ≤ 27 mg, and less than 1% of patients who received a daily dose >27 mg. In these same studies, discontinuation due to adverse reactions occurred in 5% of morphine-treated patients, and no placebo-treated patients. In an open-label safety study, discontinuation of OLINVYK due to adverse drug reactions occurred in 3% of patients who received a daily dose ≤ 27 mg, and 1% of patients who received a daily dose >27 mg.

In two randomized, double-blind, placebo- and morphine-controlled studies in patients with moderate to severe acute pain following either orthopedic surgery-bunionectomy (Study 1), or plastic surgery-abdominoplasty (Study 2), patients received one of three OLINVYK dosing regimens, a morphine- control regimen, or a volume‑matched placebo-control regimen. All dosing regimens were administered via patient-controlled analgesia (PCA), allowing patients to individually titrate the dose available to an acceptable level of analgesia. Patients were treated for up to 48 hours in the bunionectomy study (Study 1), and for up to 24 hours in the abdominoplasty study(Study 2). The loading dose for all OLINVYK treatment regimens was 1.5 mg; demand doses were 0.1, 0.35, or 0.5 mg, according to assigned treatment group; supplemental doses of 0.75 mg were permitted, beginning 1 hour after the loading dose, and hourly thereafter, as needed. The loading dose for the morphine treatment regimen was 4 mg; the demand dose was 1 mg; and supplemental doses of 2 mg were permitted, beginning 1 hour after the loading dose, and hourly thereafter, as needed. A lockout interval of 6 minutes was used for all PCA regimens.

In Study 1, a total of 136 patients received OLINVYK ≤27 mg/day, and 98 patients received OLINVYK >27 mg/day during the first 24 hours. In Study 2, a total of 180 patients received OLINVYK ≤27 mg/day, and 56 patients received OLINVYK >27 mg/day during the first 24 hours.

Table 1 and Table 2 list adverse drug reactions that were reported in ≥5% of OLINVYK-treated patients in each study, and that occurred at a frequency greater than placebo in at least one of the studies. Table 2 and Table 3 lists adverse drug reactions that were reported in ≥5% of OLINVYK-treated patients for pooled Studies 1 and 2 stratified by total daily dose (≤27 mg/day or >27 mg/day).

These data are not an adequate basis for comparison of rates between the OLINVYK treatment group and the morphine treatment group. The OLINVYK and morphine dosing regimens studied are not considered equipotent.
|postmarketing='''Serotonin syndrome:''' Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

'''Adrenal insufficiency:''' Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

'''Anaphylaxis:''' Anaphylaxis has been reported with ingredients contained in OLINVYK.

'''Androgen deficiency:''' Cases of androgen deficiency have occurred with use of opioids for an extended period of time.

'''Hyperalgesia and Allodynia:''' Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration.

'''Hypoglycemia:''' Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).
|drugInteractions=*Clinically Significant Drug Interactions with OLINVYK
Moderate to Strong Inhibitors of CYP2D6
*Moderate to Strong Inhibitors of CYP3A4
*Strong and Moderate CYP3A4 Inhibitors and CYP2D6 Inhibitors
*Inducers of CYP3A4
*Benzodiazepines and Other Central Nervous System (CNS) Depressants
*Serotonergic Drugs
*Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
*Muscle Relaxants
*Diuretics
*Anticholinergic Drugs
|useInLaborDelivery=Use of opioid analgesics for an extended period of time during pregnancy may result in neonatal opioid withdrawal syndrome. There are no available data on OLINVYK use in pregnant women to evaluate for a drug-associated risk of major birth defects and miscarriage or adverse maternal outcomes. There are adverse outcomes reported within detal exposure to opioid analgesics.

In animal reproductive studies, oliceridine reduced live litter size at birth and increased postnatal pup mortality between birth and Postnatal Day 4 when administered intravenously to rats from organogenesis through weaning at doses producing clinically relevant plasma exposure. Oliceridine had no effect on embryo-fetal development in rats and rabbits when administered intravenously during organogenesis at doses producing plasma exposures 7 and 8 times the estimated plasma exposure at the maximum recommended human dose (MRHD) on an AUC basis, respectively.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
|useInNursing=It is not known whether oliceridine is present in human milk. The effects of oliceridine on a breastfeeding infant and on milk production have not been evaluated.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for OLINVYK and any potential adverse effects on the breastfed infant from OLINVYK or from the underlying maternal condition.
|useInPed=The safety and effectiveness of OLINVYK in pediatric patients has not been established.
|useInGeri=Controlled clinical studies of OLINVYK did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Elderly patients (aged 65 years or older) may have increased sensitivity to OLINVYK. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of OLINVYK slowly in geriatric patients and monitor for signs of central nervous system and respiratory depression
|useInGender='''Human Data'''

Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

'''Animal Data'''

Oliceridine administered intravenously for 14 days prior to cohabitation and administered through GD15 caused prolonged estrous cycle lengths and decreased the number of implantations and viable embryos in female rats at doses producing plasma exposures ≥ 3 times the MRHD on an AUC basis.
|useInRenalImpair=In patients with end-stage renal disease, there was no clinically significant change in oliceridine clearance. Therefore, dosage adjustment of OLINVYK in patients with renal impairment is not required
|useInHepaticImpair=In patients with mild or moderate hepatic impairment, no adjustment of the initial dose is needed; however, these patients may require less frequent dosing. When using OLINVYK in patients with severe hepatic impairment, consider reducing the initial dose, and administer subsequent doses only after a careful review of the patient’s severity of pain and overall clinical status
|othersTitle=Poor Metabolizers of CYP2D6 Substrates
|useInOthers=In patients who are known or suspected to be poor CYP2D6 metabolizers, based on genotype or previous history/experience with other CYP2D6 substrates, less frequent dosing of OLINVYK may be required. These patients should be closely monitored, and subsequent doses should be based on the patient’s severity of pain and response to treatment.
|administration=OLINVYK can be administered by a healthcare provider with an initial dose of 1.5 mg. For PCA, the initial dose can be followed by access to patient demand doses with a 6-minute lock-out. The recommended demand dose is 0.35 mg. A demand dose of 0.5 mg may be considered for some patients if the potential benefit outweighs the risks. Supplemental doses of 0.75 mg OLINVYK can be administered by healthcare providers, beginning 1 hour after the initial dose, and hourly thereafter as needed.
|monitoring=Although self-administration of opioids by PCA may allow each patient to individually titrate to an acceptable level of analgesia, PCA administration has resulted in adverse outcomes and episodes of respiratory depression. Health care providers and family members monitoring patients receiving PCA analgesia should be instructed in the need for appropriate monitoring for excessive sedation, respiratory depression, or other adverse effects of opioid medications.
|IVCompat=OLINVYK 30 mg/30 mL (1mg/mL) vial is intended for patient-controlled analgesia (PCA) use only. Draw OLINVYK directly from the vial into the PCA syringe or IV bag without diluting. For intravenous administration only.
|overdose=Acute overdose with OLINVYK can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations

'''Treatment of Overdose'''
In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures.

The opioid antagonist, naloxone, is a specific antidote for respiratory depression resulting from opioid overdose. While naloxone reversal of OLINVYK’s effects has not been established in humans, some pharmacological effects (analgesia) of oliceridine have been shown to be reversed by naloxone in animals. For clinically significant respiratory or circulatory depression secondary to oliceridine overdose, administer an opioid antagonist.

Because the duration of opioid reversal is expected to be less than the duration of oliceridine in OLINVYK injection, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information.

In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.
|mechAction=Oliceridine is a full opioid agonist and is relatively selective for the mu-opioid receptor. The principal therapeutic action of oliceridine is analgesia. Like all full opioid agonists, there is no ceiling effect to analgesia for oliceridine. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory, and CNS depression.

The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.
|PD=In nonclinical models, the antinociceptive effect of oliceridine can be antagonized by the opioid antagonist naloxone.

'''Effects on the Central Nervous System'''

Opioids produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.

Opioids causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.

'''Effects on the Gastrointestinal Tract and Other Smooth Muscle'''

Opioids causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.

'''Effects on the Cardiovascular System'''

Opioids produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

'''Effects on the Endocrine System'''

Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date.

'''Effects on the Immune System'''

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

'''Concentration-Analgesia Relationships'''

In a fixed-dose bunionectomy trial (N=192), the onset of action of OLINVYK (as measured by the two-stopwatch method) was almost immediate (median 1-3 minutes) upon administration of the first dose. Perceptible pain relief was achieved in the majority of patients within 5 minutes after the first dose of OLINVYK.

The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of oliceridine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration.

'''Concentration-Adverse Experience Relationships'''

There is a general relationship between increasing oliceridine doses and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions.

'''Cardiac Electrophysiology'''

The effect of oliceridine on the QTc interval was evaluated in 2 dedicated Thorough QT/QTc studies. A single-dose, randomized, positive- (moxifloxacin) and placebo-controlled 4 period crossover study evaluated the ECG effects of oliceridine at a therapeutic (3 mg IV infusion) and a supratherapeutic (6 mg IV infusion) dose in 62 healthy volunteers. Dose-dependent QTc prolongation (3 mg: 7 ms [upper 90% CI: 9 ms]; 6 mg: 12 ms [14 ms]), which occurred after peak oliceridine plasma concentration, was observed in this study.

A multi-dose, randomized, positive- (moxifloxacin) and placebo-controlled 3-way crossover study in 65 healthy volunteers evaluated intermittent dosing over 24 hours to the maximum daily cumulative dose of 27 mg. The maximum mean ΔΔQTcI was 11.7 ms (two-sided 90% UCI 14.7 ms) at 9 hours. Thereafter, the QTc effect did not progressively increase with repeat dosing, and despite continued dosing began to diminish after 12 hours.

The underlying mechanism and clinical significance of the transient QT changes seen in the single-dose and multiple-dose studies in healthy volunteers are unknown. These findings should be carefully considered when OLINVYK is administered in clinical settings where prolongation of the QT interval has been observed either due to the use of concomitant medications known to prolong the QT interval or to underlying medical conditions associated with QT interval prolongation.
|PK='''Distribution'''

The mean steady-state volume of distribution of oliceridine ranges between 90-120 L indicating extensive tissue distribution. The plasma protein binding of oliceridine is 77%. In vitro data indicate that oliceridine is not an inhibitor of any of the major transporters, including breast cancer resistance protein (BCRP) and MDR1, at clinically relevant concentrations.

'''Elimination'''

'''Metabolism'''

In vitro studies suggest that oliceridine is metabolized primarily by CYP3A4 and CYP2D6 P450 hepatic enzymes, with minor contributions from CYP2C9 and CYP2C19 into inactive metabolites.

The mean clearance of oliceridine decreases slightly with increasing dose, resulting in greater-than-proportional exposure, particularly at doses greater than 2 mg. The percent of unchanged oliceridine excreted in the urine is low (0.97-6.75% of dose), reflecting its low renal clearance. The pharmacokinetics of oliceridine were not changed substantially (except for peak concentrations) when administered over different infusion times.

'''Excretion'''

Metabolic clearance is the major route of elimination of oliceridine, primarily by oxidation with subsequent glucuronidation. Additional biotransformation pathways included N−dealkylation, glucuronidation, and dehydrogenation. The majority of the metabolites (approximately 70%) are eliminated in the urine, with the remainder eliminated in the feces. Only a small amount of unchanged drug (0.97-6.75% of a dose) is found in the urine. The half-life of these metabolites (~44 hours) is much longer than that of unchanged oliceridine (1.3-3 hours). In vitro binding studies have demonstrated that none of these metabolites has any appreciable activity at the mu-opioid receptor.

'''Specific Populations'''

'''Renal Impairment'''

In a study comparing subjects with end stage renal disease (N=8) to healthy age and sex−matched healthy subjects (N=8), no significant difference in oliceridine clearance was observed. OLINVYK doses do not need to be adjusted in patients with renal impairment.

'''Hepatic Impairment'''

In a study of mild (N=8), moderate (N=8), or severe hepatic impairment (N=6), both clearance and total exposure were similar to age and sex-matched healthy controls (N=8). The mean half-life of oliceridine was increased in subjects with moderate (4.3 hours) or severe (5.8 hours) hepatic impairment, as compared with healthy subjects (2.1 hours), or patients with mild hepatic impairment (2.6 hours). The estimated volume of distribution of oliceridine was significantly higher in subjects with moderate or severe hepatic impairment (212 and 348 L, respectively), as compared to healthy subjects (126 L) or patients with mild hepatic impairment (167 L).

Based on these data, the initial dose of OLINVYK does not need to be reduced in patients with mild or moderate hepatic impairment, but these patients may require less frequent dosing. Use caution when dosing OLINVYK in patients with severe hepatic impairment. Consider reducing the initial dose, and administer subsequent doses only after a careful review of the patient’s severity of pain and overall clinical status.

'''Drug Interaction Studies'''

In vitro studies suggest that oliceridine is metabolized primarily by the CYP3A4 and CYP2D6 P450 hepatic enzymes, with minor contributions from CYP2C9 and CYP2C19. Inhibition studies using selective inhibitors of all the major CYP enzymes show that only the inhibition of CYP3A4 and CYP2D6 significantly affects the metabolism of oliceridine in these assays, suggesting that the contribution of CYP2C9 and CYP2C19 to the metabolism of oliceridine is minor.

The effect of concomitant administration of a CYP2D6 inhibitor on the pharmacokinetics of OLINVYK, although not studied, may be similar to that noted in subjects who are CYP2D6 poor metabolizers. The plasma clearance of oliceridine in CYP2D6 poor metabolizers is approximately 50% of plasma clearance in subjects who are nonpoor CYP2D6 metabolizers.

In healthy subjects CYP2D6 poor metabolizers (n=4) given a single 0.25 mg dose of OLINVYK after 5 days of itraconazole 200 mg QD (a strong CYP3A4 inhibitor), the total exposure (AUC) of OLINVYK was increased by approximately 80%; however, the peak concentration was not significantly affected. The mean clearance of oliceridine was reduced to approximately 30% of that observed in nonpoor metabolizers of CYP2D6.

Oliceridine does not inhibit any P450 enzymes at clinically relevant concentrations.
|nonClinToxic='''Carcinogenesis, Mutagenesis, Impairment of Fertility'''
'''Carcinogenesis:'''

Long-term animal studies have not been completed to evaluate the carcinogenic potential of oliceridine.

'''Mutagenesis:'''

Oliceridine was negative in an in vitro Ames bacterial reverse mutation assay, the in vitro chromosomal aberration assay using human peripheral blood lymphocytes, and the in vivo rat micronucleus assay.

'''Impairment of Fertility:'''

In a fertility and early embryonic development study, oliceridine administered to female rats via continuous intravenous infusion at 6, 12, or 24 mg/kg/day for 14 days prior to cohabitation and through GD 15 for a total of 29-42 days resulted in prolonged estrous cycle lengths and decreased number of implantations and viable embryos at doses ≥12 mg/kg/day (≥3 times the estimated plasma exposure at the MRHD of 27 mg/day on an AUC basis).

Oliceridine did not alter male fertility at any dose tested. Males were dosed at 6, 12, or 24 mg/kg/day, producing plasma exposures up to 8 times the estimated plasma exposure at the MRHD, for 28 days prior to cohabitation, throughout the mating period and up to the time of scheduled necropsy for a total of 64-65 days of dosing.

'''Animal Toxicology and/or Pharmacology'''
Continuous intravenous infusion of oliceridine to rats for 14 days followed by one-day withdrawal from the treatment resulted in opioid withdrawal stress-related gastric lesions including erosions/ulcers in the glandular stomach, mucosal congestion/hemorrhage and degeneration/necrosis in the nonglandular stomach at all doses tested including the low dose producing plasma exposure 2 times the estimated human exposure at the MRHD on an AUC basis. The effect is believed to be due to acute withdrawal stress, as similar findings were not noted in rats sacrificed immediately after the last dose of oliceridine.
|clinicalStudies=The efficacy of OLINVYK was established in two randomized, double-blind, placebo- and morphine-controlled studies of patients with moderate to severe acute pain following orthopedic surgery-bunionectomy or plastic surgery-abdominoplasty. In each study, pain intensity was measured using a patient-reported numeric rating scale (11-point numerical scale ranging from 0-10, where zero corresponds to no pain and 10 corresponds to worst pain imaginable).

In each study, patients were randomized to one of three OLINVYK treatment regimens, a placebo-control regimen, or a morphine-control regimen. Each blinded treatment regimen consisted of a loading dose, incremental doses delivered as needed via patient-controlled analgesia (PCA) device, and supplemental doses, beginning 1 hour after the initial dose, and hourly thereafter, as needed. The loading dose for all OLINVYK treatment regimens was 1.5 mg; demand doses were 0.1, 0.35 or 0.5 mg, according to the assigned treatment group; supplemental doses were 0.75 mg. The loading dose for the morphine treatment regimen was 4 mg; the demand dose was 1 mg; supplemental doses were 2 mg. The placebo-control regimen was volume-matched. A lockout interval of 6 minutes was used for all PCA regimens. For Studies 1 and 2, patients may have received rescue pain medication (pre-defined in the protocols as etodolac 200 mg every 6 hours, as needed) if the patient requested rescue pain medication and reported a Numeric Rating Scale score ≥4.
|howSupplied=OLINVYK (oliceridine) injection is a clear, colorless, preservative free solution for intravenous use supplied as follows:

NDC# 71308-011-10: 1 mg/mL, sterile solution in single-dose, 2 mL clear glass vials with gray stoppers topped with overseals with gray plastic flip-off caps (carton of 10 vials)

NDC# 71308-021-10: 2 mg/2 mL (1 mg/mL), sterile solution in single-dose, 2 mL clear glass vials with gray stoppers topped with overseals with orange plastic flip-off caps (carton of 10 vials)

NDC# 71308-301-10: 30 mg/30 mL (1 mg/mL), sterile solution in single-patient-use, 30 mL clear glass vials with gray stoppers topped with overseals with purple plastic flip-off caps (carton of 10 vials). For PCA Use Only.
|storage=Store at controlled room temperature 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F)
|fdaPatientInfo='''Addiction, Abuse, and Misuse'''

Inform patients that the use of OLINVYK, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death.

'''Life-Threatening Respiratory Depression'''

Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting OLINVYK or when the dosage is increased, and that it can occur even at recommended dosages.

'''Hyperalgesia and Allodynia'''

Advise patients to inform their healthcare provider if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain.

'''Serotonin Syndrome'''

Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop after discharge from the hospital. Instruct patients to inform their healthcare provider if they are taking or plan to take serotonergic medications.

'''Constipation'''

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention
|alcohol=Alcohol-Oliceridine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=Olinvyk
}}

Viltolarsen

2025-04-30T18:38:29Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=viltolarsen |aOrAn=a |drugClass=exon 53 of the dystrophin pre-mRNA |indicationType=treatment |indication=Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. This indication is approved under accelerated approval based on an increase in dystrophin production in skeletal muscle observed in patients treated..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=viltolarsen
|aOrAn=a
|drugClass=exon 53 of the dystrophin pre-mRNA
|indicationType=treatment
|indication=Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. This indication is approved under accelerated approval based on an increase in dystrophin production in skeletal muscle observed in patients treated with VILTEPSO. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
|adverseReactions=Upper respiratory infections
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. This indication is approved under accelerated approval based on an increase in dystrophin production in skeletal muscle observed in patients treated with VILTEPSO. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

'''DOSAGE'''
The recommended dosage of VILTEPSO is 80 mg/kg administered once weekly as a 60-minute intravenous infusion.

If a dose of VILTEPSO is missed, it should be administered as soon as possible after the scheduled dose time.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Viltolarsen in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Viltolarsen in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Viltolarsen in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Viltolarsen in pediatric patients.
|contraindications=None
|warnings='''Kidney Toxicity'''
Kidney toxicity was observed in animals who received viltolarsen. Although kidney toxicity was not observed in the clinical studies with VILTEPSO, the clinical experience with VILTEPSO is limited, and kidney toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. Kidney function should be monitored in patients taking VILTEPSO. Because of the effect of reduced skeletal muscle mass on creatinine measurements, serum creatinine may not be a reliable measure of kidney function in DMD patients. Serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio should be measured before starting VILTEPSO. Consider also measuring glomerular filtration rate using an exogenous filtration marker before starting VILTEPSO. During treatment, monitor urine dipstick every month, and serum cystatin C and urine protein-to-creatinine ratio every three months. Only urine expected to be free of excreted VILTEPSO should be used for monitoring of urine protein. Urine obtained on the day of VILTEPSO infusion prior to the infusion, or urine obtained at least 48 hours after the most recent infusion, may be used. Alternatively, use a laboratory test that does not use the reagent pyrogallol red, as this reagent has the potential to cross react with any VILTEPSO that is excreted in the urine and thus lead to a false positive result for urine protein.

If a persistent increase in serum cystatin C or proteinuria is detected, refer to a pediatric nephrologist for further evaluation.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials with VILTEPSO, 32 patients have been exposed to VILTEPSO once weekly, ranging between 40 mg/kg (0.5 times the recommended dosage) and 80 mg/kg (the recommended dosage), including 16 patients treated for greater than 12 months and 8 patients treated for greater than 24 months as part of an ongoing open-label extension study. All patients were male and had genetically confirmed DMD.

Study 1 was a multicenter, 2-period, dose-finding study conducted in the United States and Canada in males 4 years to less than 10 years of age on a stable corticosteroid regimen for at least 3 months. During the initial period (first 4 weeks) of Study 1, patients were randomized (double-blind) to VILTEPSO or placebo. All patients then received 20 weeks of VILTEPSO 40 mg/kg once weekly (0.5 times the recommended dose) (N=8), or 80 mg/kg once weekly (N=8).

Study 2 was a multicenter, parallel-group, open-label, dose-finding study conducted in Japan. Eligible patients included ambulatory and non-ambulatory males 5 years to less than 18 years of age who were assigned to receive intravenous VILTEPSO 40 mg/kg once weekly (0.5 times the recommended dose) (N=8) or 80 mg/kg once weekly (N=8) for 24 weeks.

Adverse reactions reported in ≥10% of patients treated with VILTEPSO 80 mg/kg/wk in pooled Studies 1 and 2 are displayed in Table 1. The most common adverse reactions (incidence ≥15% in patients treated with VILTEPSO) were upper respiratory tract infection, injection site reaction, cough, and pyrexia. Patients in the pooled analysis were treated with VILTEPSO for 20 to 24 weeks.
|useInLaborDelivery=There are no human or animal data available to assess the use of VILTEPSO during pregnancy. In the U.S. general population, major birth defects occur in 2 to 4%, and miscarriage occurs in 15 to 20% of clinically recognized pregnancies.
|useInNursing=There are no human or animal data to assess the effect of VILTEPSO on milk production, the presence of viltolarsen in milk, or the effects of VILTEPSO on the breastfed infant.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for VILTEPSO and any potential adverse effects on the breastfed infant from VILTEPSO or from the underlying maternal condition.
|useInPed=VILTEPSO is indicated for the treatment of DMD in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping, including pediatric patients.

'''Juvenile Animal Toxicity Data'''

Viltolarsen (0, 15, 60, 240, or 1200 mg/kg) was administered to juvenile male mice by subcutaneous injection on postnatal day (PND) 7 and by intravenous injection weekly from PND 14 to PND 70. The highest dose resulted in deaths because of renal toxicity. In surviving animals at 240 and 1200 mg/kg, there was a dose-dependent increase in the incidence and severity of renal tubular effects (including degeneration), which were not accompanied by clinical pathology correlates. Reduced body weight gain and delayed sexual maturation were observed at the highest dose tested. At the no-effect dose for renal toxicity (60 mg/kg), plasma exposures were similar to that in humans at the recommended human dose of 80 mg/kg/week.
|useInGeri=DMD is largely a disease of children and young adults; therefore, there is no geriatric experience with VILTEPSO.
|useInRenalImpair=VILTEPSO has not been studied in patients with renal impairment. Viltolarsen is mostly excreted unchanged in the urine, and renal impairment may increase its exposure. However, because of the effect of reduced skeletal muscle mass on creatinine measurements in DMD patients, no specific dosage adjustment can be recommended for DMD patients with renal impairment based on estimated glomerular filtration rate. Patients with known renal function impairment should be closely monitored during treatment with VILTEPSO.
|administration=VILTEPSO is administered via intravenous infusion using a peripheral or central venous catheter. Flush the intravenous access line with 0.9% Sodium Chloride Injection, USP, after infusion. Filtration of VILTEPSO is not required.

Infuse VILTEPSO over 60 minutes. Do not mix other medications with VILTEPSO or infuse other medications concomitantly via the same intravenous access line. VILTEPSO should be mixed with 0.9% Sodium Chloride Injection, USP, only.
|monitoring=Serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio should be measured before starting VILTEPSO. Consider measurement of glomerular filtration rate prior to initiation of VILTEPSO. Monitoring for kidney toxicity during treatment is recommended. Obtain the urine samples prior to infusion of VILTEPSO or at least 48 hours after the most recent infusion
|mechAction=VILTEPSO is designed to bind to exon 53 of dystrophin pre-mRNA resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 53 skipping. Exon 53 skipping is intended to allow for production of an internally truncated dystrophin protein in patients with genetic mutations that are amenable to exon 53 skipping.
|PD=After treatment with VILTEPSO 80 mg/kg once weekly, all patients evaluated (N=8) were found to produce mRNA for a truncated dystrophin protein, as measured by reverse transcription polymerase chain reaction (RT-PCR), and demonstrated exon 53 skipping, as measured by DNA sequence analysis.

In Study 1, all patients who received VILTEPSO 80 mg/kg once weekly for 20 to 24 weeks showed an increase from baseline in dystrophin protein expression, as quantified by a validated Western blot method (mean 5.3%; median 3.8%; range 0.7% to 13.9% of normal levels when normalized to myosin heavy chain; p-value 0.01). Mass spectrometry, immunofluorescence staining, and RT-PCR results were supportive of the Western blot data. Expected localization of truncated dystrophin to the sarcolemma in muscle fibers of patients treated with viltolarsen was confirmed by immunofluorescence staining.
|PK=The pharmacokinetics of viltolarsen was evaluated in DMD patients following administration of intravenous (IV) doses ranging from 1.25 mg/kg/week (0.016 times the recommended dosage) to 80 mg/kg/week (the recommended dosage). Viltolarsen exposure increased proportionally with dose, with minimal accumulation with once-weekly dosing. Inter-subject variability (as %CV) for Cmax and AUC ranged from 16% to 27% respectively.

VILTEPSO is administered as an IV infusion over 60 minutes. Bioavailability is assumed to be 100%, and median Tmax was around 1 hour (end of infusion).

'''Distribution'''

The mean viltolarsen steady-state volume of distribution was 300 mL/kg (%CV=14 at a dose of 80 mg/kg. Viltolarsen plasma protein binding ranged from 39% to 40% and is not concentration dependent.

'''Elimination'''

'''Metabolism'''

Data from in vitro metabolism indicate that viltolarsen is metabolically stable. No metabolites were detected in plasma or urine.

'''Excretion'''

VILTEPSO is excreted mainly as an unchanged drug in the urine. Viltolarsen elimination half-life was 2.5 (%CV=8) hours, and plasma clearance was 217 mL/hr/kg (%CV=22).

'''Specific Populations'''

'''Age, Sex & Race'''

The pharmacokinetics of viltolarsen have been evaluated only in male pediatric DMD patients.There is no experience with VILTEPSO in patients 65 years of age or older. No marked differences in any PK parameters were observed between White and Asian patients.

'''Patients with Renal or Hepatic Impairment'''

VILTEPSO has not been studied in patients with renal or hepatic impairment. Viltolarsen was found to be metabolically stable, and hepatic metabolism does not contribute to the elimination of viltolarsen. In addition, viltolarsen was mainly excreted unchanged in the urine. Viltolarsen is eliminated renally, and renal impairment is expected to result in increasing exposure of viltolarsen. However, because of the effect of reduced skeletal muscle mass on creatinine measurements in DMD patients, no specific dosage adjustment can be recommended for DMD patients with renal impairment based on glomerular filtration rate estimated by serum creatinine.

'''In Vitro Drug Interaction Studies'''

Viltolarsen did not inhibit CYP3A4/5, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, UGT1A1, or UGT2B7. Viltolarsen did not induce CYP1A2, CYP2B6, or CYP3A4.

Viltolarsen is not metabolized by CYP enzymes and is not a substrate of transporters BCRP, BSEP, MDR1, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2-K. Viltolarsen did not inhibit the transporters tested (OATP1B1, OATP1B3, OAT3, BCRP, MDR1, BSEP, OAT1, OCT1, OCT2, MATE1, and MATE2-K).

Based on in vitro data, viltolarsen has a low potential for drug-drug interactions with major CYP enzymes and drug transporters in humans.
|nonClinToxic='''Carcinogenesis'''

Carcinogenicity studies of viltolarsen have not been conducted.

'''Mutagenesis'''

Viltolarsen was negative for genotoxicity in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster lung cells) and in vivo (mouse bone marrow micronucleus) assays.

'''Impairment of Fertility'''

Intravenous administration of viltolarsen (0, 60, 240, or 1000 mg/kg) to male mice weekly prior to and during mating to untreated females did not have adverse effects on fertility. Plasma exposure (AUC) at the highest dose was approximately 18 times that in humans at the recommended human dose of 80 mg/kg/week.
|clinicalStudies=The effect of VILTEPSO on dystrophin production was evaluated in one study in DMD patients with a confirmed mutation of the DMD gene that is amenable to exon 53 skipping (Study 1; NCT02740972).

Study 1 was a multicenter, 2-period, dose-finding study conducted in the United States and Canada.

During the initial period (first 4 weeks) of Study 1, patients were randomized (double blind) to VILTEPSO or placebo. All patients then received 20 weeks of open-label VILTEPSO 40 mg/kg once weekly (0.5 times the recommended dosage) (N=8) or 80 mg/kg once weekly (N=8). Study 1 enrolled ambulatory male patients 4 years to less than 10 years of age (median age 7 years) on a stable corticosteroid regimen for at least 3 months.

Efficacy was assessed based on change from baseline in dystrophin protein level (measured as % of the dystrophin level in healthy subjects, i.e., % of normal) at Week 25. Muscle biopsies (left or right biceps brachii) were collected from patients at baseline and following 24 weeks of VILTEPSO treatment, and analyzed for dystrophin protein level by Western blot normalized to myosin heavy chain (primary endpoint) and mass spectrometry (secondary endpoint).

In patients who received VILTEPSO 80 mg/kg once weekly, mean dystrophin levels increased from 0.6% (SD 0.8) of normal at baseline to 5.9% (SD 4.5) of normal by Week 25, with a mean change in dystrophin of 5.3% (SD 4.5) of normal levels (p=0.01) as assessed by validated Western blot (normalized to myosin heavy chain); the median change from baseline was 3.8%. All patients demonstrated an increase in dystrophin levels over their baseline values. As assessed by mass spectrometry (normalized to filamin C), mean dystrophin levels increased from 0.6% (SD 0.2) of normal at baseline to 4.2% (SD 3.7) of normal by Week 25, with a mean change in dystrophin of 3.7% (SD 3.8) of normal levels (nominal p=0.03, not adjusted for multiple comparisons); the median change from baseline was 1.9%.
|howSupplied=VILTEPSO injection is supplied in single-dose vials. The solution is clear and colorless.

*Single-dose vials containing 250 mg/5 mL (50 mg/mL) viltolarsen
|storage=Store VILTEPSO at 2°C to 8°C (36°F to 46°F). Do not freeze.
|fdaPatientInfo='''Kidney Toxicity'''

Inform patients nephrotoxicity has occurred with drugs similar to VILTEPSO. Advise patients of the importance of monitoring for kidney toxicity by their healthcare providers during treatment with VILTEPSO
|alcohol=Alcohol-Viltolarsen interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=VILTEPSO
}}

Satralizumab-mwge

2025-04-30T18:22:31Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=satralizumab-mwge |aOrAn=a |drugClass=interleukin inhibitors |indication=ENSPRYNG is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. |adverseReactions=The following clinically significant adverse reactions are described elsewhere in the labeling: *Infections *Elevated Liver Enzym..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=satralizumab-mwge
|aOrAn=a
|drugClass=interleukin inhibitors
|indication=ENSPRYNG is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.
|adverseReactions=The following clinically significant adverse reactions are described elsewhere in the labeling:

*Infections
*Elevated Liver Enzymes
*Decreased Neutrophil Counts
*Hypersensitivity Reactions
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=ENSPRYNG is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.

For subcutaneous use only.

Prior to every use of ENSPRYNG, advise patients to consult with their healthcare professional (HCP) if they suspect an active infection, including localized infections. In case of active infection, delay use of ENSPRYNG until the infection is resolved

The recommended loading dosage of ENSPRYNG for the first three administrations is 120 mg by subcutaneous injection at Weeks 0, 2, and 4, followed by a maintenance dosage of 120 mg every 4 weeks.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Satralizumab-mwge in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Satralizumab-mwge in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Satralizumab-mwge in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Satralizumab-mwge in pediatric patients.
|contraindications=ENSPRYNG is contraindicated in patients with:

*A known hypersensitivity to satralizumab or any of the inactive ingredients
*Active Hepatitis B infection
*Active or untreated latent tuberculosis
|warnings='''Infections'''
An increased risk of infections, including serious and potentially fatal infections, has been observed in patients treated with IL-6 receptor antagonists, including ENSPRYNG.

The most common infections reported in a randomized clinical trial of patients treated with ENSPRYNG who were not on other chronic immunosuppressant therapies (Study 1), and that occurred more often than in patients receiving placebo, were nasopharyngitis (12%) and cellulitis (10%). The most common infections in patients who were on an additional concurrent immunosuppressant, and that occurred more often than in patients receiving placebo, were nasopharyngitis (31%), upper respiratory infection (19%), and pharyngitis (12%).

Delay ENSPRYNG administration in patients with an active infection, including localized infections, until the infection is resolved.

'''Hepatitis B Virus (HBV) Reactivation'''

Risk of HBV reactivation has been observed with other immunosuppressant therapies. Patients with chronic HBV infection were excluded from clinical trials. Perform HBV screening in all patients before initiation of treatment with ENSPRYNG. Do not administer ENSPRYNG to patients with active hepatitis. For patients who are chronic carriers of HBV [HBsAg+] or are negative for HBsAg and positive for HB core antibody [HBcAb+], consult liver disease experts before starting and during treatment with ENSPRYNG.

'''Tuberculosis'''

Tuberculosis has occurred in patients treated with other interleukin-6 receptor antagonists. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating ENSPRYNG. Consider anti-tuberculosis therapy prior to initiation of ENSPRYNG in patients with a history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consult infectious disease experts regarding whether initiating anti-tuberculosis therapy is appropriate before starting treatment. Patients should be monitored for the development of symptoms and signs of tuberculosis with ENSPRYNG, even if initial tuberculosis testing is negative.

'''Vaccinations'''

Live or live-attenuated vaccines should not be given concurrently with ENSPRYNG because clinical safety has not been established. Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of ENSPRYNG for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of ENSPRYNG for non-live vaccines.

'''Elevated Liver Enzymes'''
Mild and moderate elevations of liver enzymes have been observed in patients treated with ENSPRYNG at a higher incidence than in patients receiving placebo.

ALT and AST levels should be monitored every 4 weeks for the first 3 months of treatment, followed by every 3 months for one year, and thereafter, as clinically indicated.

'''Decreased Neutrophil Counts'''
Decreases in neutrophil counts were observed in patients treated with ENSPRYNG at a higher incidence than placebo.

Neutrophil counts should be monitored 4 to 8 weeks after initiation of therapy, and thereafter at regular clinically determined intervals [see Dosage and Administration (2.4)].

'''Hypersensitivity Reactions'''
Hypersensitivity reactions, including rash, urticaria, and fatal anaphylaxis, have occurred with other interleukin-6 receptor antagonists.
|clinicalTrials=Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

The safety of ENSPRYNG was evaluated in two randomized, placebo-controlled clinical trials [Study 1 evaluated ENSPRYNG without concurrent immunosuppressive therapy (IST) and Study 2 evaluated ENSPRYNG with concurrent IST], which included 41 anti-AQP4 seropositive patients treated with ENSPRYNG in Study 1 and 26 anti-AQP4 seropositive patients treated with ENSPRYNG in Study 2. In the double-blind, controlled period, the median exposure time on ENSPRYNG treatment was approximately 2 years in Study 1 and approximately 3 years in Study 2. The median exposure time on placebo treatment was approximately 1 year in both Study 1 and Study 2.

Adverse reactions that occurred in Study 1 and Study 2 in more than 5% of patients treated with ENSPRYNG, and at a greater incidence than in patients who received placebo, are shown in Table 3 and Table 4, respectively. The most common adverse reactions (15% or greater with ENSPRYNG in either) were nasopharyngitis, headache, upper respiratory tract infection, gastritis, rash, arthralgia, extremity pain, fatigue, and nausea.
|useInLaborDelivery=There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ENSPRYNG during pregnancy. Healthcare providers are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-833-277-9338.
|useInNursing=No information is available on the presence of satralizumab-mwge in human milk, the effects of the satralizumab-mwge on the breastfed infant, or the effects of the satralizumab-mwge on milk production. Satralizumab-mwge was excreted in the milk of lactating monkeys administered satralizumab-mwge throughout pregnancy. Human IgG is excreted in human milk and the potential for absorption in the infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ENSPRYNG and any potential adverse effects on the breastfed infant from ENSPRYNG or from the underlying maternal condition.
|useInPed=Safety and effectiveness in pediatric patients have not been established.
|useInGeri=Clinical studies of ENSPRYNG did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. However, population pharmacokinetic analyses in patients with NMOSD did not show that age affected the pharmacokinetics of satralizumab-mwge. In general, caution should be used when dosing the elderly, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.
|administration=*ENSPRYNG is intended for patient self-administration by subcutaneous injection under the guidance of a health care professional (HCP). After proper training in subcutaneous injection technique, a patient may self-inject ENSPRYNG or the patient's caregiver may administer ENSPRYNG, if the HCP determines that it is appropriate. See ENSPRYNG "Instructions for Use" (IFU) for more detailed instructions on the preparation and administration of ENSPRYNG.
*Patients or caregivers should seek immediate medical attention if the patient develops symptoms of a serious allergic reaction and should not administer further doses until evaluated by a HCP [see Contraindications (4) and Warning and Precautions (5.4)].
Prior to use, remove the prefilled syringe from the refrigerator and allow to sit at room temperature outside of the carton for 30 minutes. Do not warm ENSPRYNG in any other way.
*Inspect visually for particulate matter and discoloration prior to administration. ENSPRYNG solution should be clear and colorless to slightly yellow. Do not use ENSPRYNG if the solution is cloudy, discolored, or contains particles, or if any part of the prefilled syringe appears to be damaged.
*Instruct patients to inject the full amount in the syringe (1 mL), which provides 120 mg of ENSPRYNG, according to the directions provided in the IFU.
*Administer ENSPRYNG by subcutaneous injection in the abdomen or thigh. Rotate injection sites with each administration. Do not give injection into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.
|monitoring=*Monitor ALT and AST levels every 4 weeks for the first 3 months of treatment with ENSPRYNG, followed by every 3 months for one year, and thereafter as clinically necessary.

*If an ALT or AST elevation of greater than 5 times the ULN occurs, discontinue ENSPRYNG as follows:

*If associated with any bilirubin elevation, discontinue ENSPRYNG, and reinitiation is not recommended.
*If not associated with any bilirubin elevation above the ULN, when the ALT or AST level has returned to the normal range and following a benefit-risk assessment of the patient, treatment with ENSPRYNG can be restarted per the schedule.
|mechAction=The precise mechanism by which satralizumab-mwge exerts therapeutic effects in NMOSD is unknown but is presumed to involve inhibition of IL-6-mediated signaling through binding to soluble and membrane-bound IL-6 receptors.
|PD=The relationship between any of the pharmacodynamic effects of ENSPRYNG and clinical outcomes in NMOSD is unknown.
|PK=The pharmacokinetics of ENSPRYNG have been characterized both in Japanese and Caucasian healthy volunteers, and in NMOSD patients. The pharmacokinetics in NMOSD patients using the recommended dose were characterized using population pharmacokinetic analysis methods based on a database of 154 patients.

The concentration-time course of ENSPRYNG in patients with NMOSD was accurately described by a two-compartment population pharmacokinetic model with parallel linear and target-mediated (Michaelis-Menten) elimination and first-order subcutaneous absorption. ENSPRYNG clearance and volume parameters allometrically scaled by body weight (through power function with the fixed power coefficient of 0.75 and 1 for clearance and volume parameters, respectively). Body weight was shown to be a significant covariate, with clearance and Vc for patients weighing 123 kg (97.5th percentile of the weight distribution) increased by 71.3% and 105%, respectively, compared to a patient weighing 60 kg.

Steady state pharmacokinetics were achieved after the loading period (8 weeks) as follows [mean (±SD)]: Cmin: 19.7 (12.2) mcg/mL, Cmax: 31.5 (14.9) mcg/mL, and AUC: 737 (386) mcg.mL/day.

'''Absorption'''

The bioavailability of satralizumab-mwge was 85%.

'''Distribution'''

Satralizumab-mwge undergoes biphasic distribution. The central volume of distribution was 3.46 L and the peripheral volume of distribution was 2.07 L. The inter-compartmental clearance was 0.336 L/day.

'''Elimination'''

The total clearance of satralizumab-mwge is concentration-dependent. Linear clearance (accounting for approximately half of the total clearance at steady state using the recommended dose in NMOSD patients) is estimated to be 0.0601 L/day. The associated terminal t1/2 is approximately 30 days (range 22 – 37 days) based on data pooled from Study 1 and Study 2.

'''Metabolism'''

The metabolism of satralizumab-mwge has not been directly studied, as antibodies are cleared principally by catabolism.

'''Excretion'''

Monoclonal antibodies, including satralizumab-mwge, are not eliminated via renal or hepatic pathways.

'''Specific Populations'''

Population pharmacokinetic analyses in patients with NMOSD showed that age, gender, and race did not meaningfully influence the pharmacokinetics of satralizumab-mwge.

'''Patients with Renal or Hepatic Impairment'''

No formal studies of the effect of renal impairment or hepatic impairment on the pharmacokinetics of satralizumab-mwge were conducted.

'''Drug Interaction Studies'''

No formal drug-drug interaction studies have been performed with ENSPRYNG.

Based on population pharmacokinetic analyses of the available data, the impact of commonly used small molecule drugs on the pharmacokinetics of satralizumab-mwge remains inconclusive.

Suppression of IL-6 signaling by treatment with ENSPRYNG, from the low baseline levels seen in Study 1 and Study 2, is expected to have a minor impact on exposure of concomitant medications metabolized by CYP450 enzymes. The clinical significance of this is unknown.
|nonClinToxic='''Carcinogenesis'''

Carcinogenicity studies of satralizumab-mwge were not conducted.

'''Mutagenesis'''

Genetic toxicology studies of satralizumab-mwge were not conducted. As an antibody, satralizumab-mwge is not expected to interact directly with DNA.

'''Impairment of Fertility'''

In monkeys administered satralizumab-mwge (0, 2, 10, or 50 mg/kg) weekly by subcutaneous injection for 26 weeks, no effects on sperm, estrus cycle, or male and female reproductive organs were observed. At the high dose, plasma exposures (Cave) were approximately 100 times that in humans at the recommended monthly maintenance dose of 120 mg.
|clinicalStudies=The efficacy of ENSPRYNG for the treatment of NMOSD in adult patients was established in two studies. Study 1 was a randomized (2:1), placebo-controlled trial in 95 patients without concurrent IST (Study 1, NCT02073279) in which 64 patients were anti-AQP4 antibody positive and 31 patients were anti-AQP4 antibody negative.

Study 2 was a randomized (1:1), placebo-controlled trial in 76 adult patients with concurrent IST (Study 2, NCT02028884). Of these, 52 adult patients were anti-AQP4 antibody positive and 24 adult patients were anti-AQP4 antibody negative.

Patients met the following eligibility criteria:

Study 1: Clinical evidence of 1 relapse in the previous 12 months
Study 2: Clinical evidence of at least 2 relapses in the previous 2 years, at least one of which must have occurred in the previous year
EDSS score of 0 to 6.5 (both studies)
Study 1: Patients were excluded if previously treated with IST within an interval specified for each such therapy
Study 2: One of the following baseline treatments at a stable dose as a monotherapy for 8 weeks prior to baseline: azathioprine, mycophenolate mofetil, oral corticosteroids
In Study 1, 41 anti-AQP4 antibody positive adult patients were randomized to and received ENSPRYNG and 23 received placebo. Females accounted for 76% of the ENSPRYNG group and 96% of the placebo group. The remaining baseline demographic characteristics were balanced between the treatment groups. The mean age was 44 years. Fifty percent were White, 22% were Black or African-American, and 20% were Asian. The mean EDSS score was 3.8.

In Study 2, 26 anti-AQP4 antibody positive adult patients were randomized to and received ENSPRYNG and 26 received placebo. All patients were receiving either concurrent azathioprine (42%), oral corticosteroids (52%), or mycophenolate mofetil (6%) during the trial. The baseline demographic and disease characteristics were balanced between the treatment groups. Females accounted for 100% of the study population. Forty-six percent of patients were White and 52% were Asian. The mean age was 46 years. The mean EDSS score was 4.0.

All potential relapses were adjudicated by a blinded Clinical Endpoint Committee (CEC). The primary efficacy endpoint for both studies was the time to the first CEC-confirmed relapse.

In Study 1, the time to the first CEC-confirmed relapse was significantly longer in ENSPRYNG-treated patients compared to patients who received placebo (risk reduction 55%; hazard ratio 0.45; p = 0.0184). In the anti-AQP4 antibody positive population, there was a 74% risk reduction; hazard ratio 0.26; p = 0.0014. There was no evidence of a benefit in the anti-AQP4 antibody negative patients.

In Study 2, the time to the first CEC-confirmed relapse was significantly longer in patients treated with ENSPRYNG compared to patients who received placebo (risk reduction 62%; hazard ratio 0.38; p = 0.0184). In the anti-AQP4 antibody positive population, there was a 78% risk reduction; hazard ratio 0.22; p = 0.0143 (Table 5; Figure 2). There was no evidence of a benefit in the anti-AQP4 antibody negative patients.
|howSupplied=ENSPRYNG (satralizumab-mwge) injection is available as a sterile, preservative-free, clear, colorless to slightly yellow solution in single-dose prefilled syringe (PFS) with needle safety device.

ENSPRYNG PFS is not made with natural rubber latex. Each ENSPRYNG carton contains one single-dose 120 mg/mL prefilled syringe (NDC 50242-007-01).
|storage=*Refrigerate at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake.

*Prior to administration, ENSPRYNG, if unopened, can be removed from and returned to the refrigerator, if necessary. The total combined time out of refrigeration should not exceed 8 days at a temperature that does not exceed 30°C (86°F).
|fdaPatientInfo='''Infections'''

Inform patients that an increased risk of infections, including serious and potentially fatal infections, has been observed in patients treated with IL-6 receptor antagonists, including ENSPRYNG. Instruct patients to contact their healthcare provider immediately when symptoms suggesting infection (e.g., fever, chills, constant cough, or sore throat) appear during treatment [see Warning and Precautions (5.1)].

'''Vaccinations'''

Advise patients to complete any required vaccinations at least 4 weeks prior to initiation of ENSPRYNG for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of ENSPRYNG for non-live vaccines [see Warnings and Precautions 5.1].

'''Elevated Liver Enzymes'''

Inform patients on the importance of liver enzyme testing.

'''Decreased Neutrophil Counts'''

Inform patients on the importance of neutrophil count testing [see Warnings and Precautions (5.3)].

'''Hypersensitivity Reactions'''

Inform patients about the signs and symptoms of hypersensitivity reactions and anaphylaxis and advise them to contact their healthcare provider immediately if these symptoms occur [see Warnings and Precautions (5.4)].

'''Instruction on Injection Technique'''

Instruct patients and caregivers to read the Instructions for Use before the patient starts using ENSPRYNG, and each time the patient gets a refill as there may be new information they need to know.

Perform the first injection under the guidance of a qualified healthcare professional. If a patient or caregiver is to administer subcutaneous ENSPRYNG, instruct him/her in injection techniques and assess his/her ability to inject subcutaneously to ensure proper administration of subcutaneous ENSPRYNG and the suitability for home use.

Instruct patients to remove the prefilled syringe from the refrigerator prior to use and allow to sit at room temperature outside of the carton for 30 minutes. Do not warm ENSPRYNG in any other way.

Advise patients to consult their healthcare provider if the full dose is not received.

A puncture-resistant container for disposal of syringes should be used and should be kept out of the reach of children. Instruct patients or caregivers in the technique as well as proper prefilled syringe disposal, and caution against reuse of these items.

'''Pregnancy Exposure Registry'''

Encourage patients to enroll in the ENSPRYNG Pregnancy Registry if they become pregnant while taking ENSPRYNG. The Registry monitors fetal outcomes of pregnant women exposed to ENSPRYNG.
|alcohol=Alcohol-Satralizumab-mwge interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=ENSPRYNG
}}

Clascoterone

2025-04-30T09:55:50Z

Alara E. Dagsali:

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=Clascoterone
|aOrAn=a
|drugClass=androgen receptor antagonist
|indicationType=treatment
|indication=WINLEVI (clascoterone) cream is an androgen receptor inhibitor indicated for the topical treatment of acne vulgaris in patients 12 years of age and older.
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=Cleanse the affected area gently. After the skin is dry, apply a thin uniform layer of WINLEVI cream twice per day, in the morning and the evening, to the affected area. Avoid accidental transfer of WINLEVI cream into eyes, mouth or other mucous membranes. If contact with mucous membranes occurs, rinse thoroughly with water.
WINLEVI cream is for topical use only. WINLEVI cream is not for ophthalmic, oral or vaginal use.

Cream 1%. Each gram of WINLEVI cream contains 10 mg of clascoterone in a white to almost white cream.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Clascoterone in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Clascoterone in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Clascoterone in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Clascoterone in pediatric patients.
|contraindications=None
|warnings='''Local Skin Reactions'''
WINLEVI cream may induce local irritation (erythema/redness, pruritus, scaling/ dryness). Concomitant use with other potentially irritating topical products (medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect and products with high concentrations of alcohol, astringents, spices or lime) should be limited.
The product should not be applied to cuts, abrasions, eczematous or sunburned skin.
'''Hypothalamic-pituitary-adrenal (HPA) Axis Suppression'''
Hypothalamic-pituitary-adrenal (HPA) axis suppression was observed and may occur during or after treatment with clascoterone. In the PK trial, all subjects returned to normal HPA axis function at follow-up 4 weeks after stopping treatment. Conditions which augment systemic absorption include use over large surface areas, prolonged use, and the use of occlusive dressings.
If HPA axis suppression develops, an attempt should be made to withdraw the drug.
Pediatric patients may be more susceptible to systemic toxicity.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In two identical multicenter, randomized, double-blind, vehicle-controlled trials, 1421 subjects 12 years and older with facial acne vulgaris applied WINLEVI cream or vehicle twice daily for 12 weeks. Overall, 62% of the subjects were female, and 38% were male, 91% of the patients were Caucasian, and the mean age was 19.7 years.
Local skin reactions (edema, erythema/redness, pruritus, scaling/dryness, skin atrophy, stinging/burning, striae rubrea, telangiectasia) were observed during the 12-week treatment and occurred in a similar percentage of subjects treated with vehicle. Local skin reactions reported by ≥ 1% of subjects treated with WINLEVI cream
|useInLaborDelivery=There are no available data on WINLEVI cream use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, subcutaneous administration of clascoterone to pregnant rats and rabbits during organogenesis at doses 8 or 39 times the maximum recommended human dose (MRHD), respectively, increased malformations in rats and post-implantation loss and resorptions in rabbits.
The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
|useInNursing=There are no data regarding the presence of clascoterone or metabolite in human milk, the effects on the breastfed infant or the effects on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of clascoterone to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for clascoterone and any potential adverse effects on the breastfed child from clascoterone or from the underlying maternal condition.
|useInPed=Safety and effectiveness of WINLEVI cream for the topical treatment of acne vulgaris have been established in 641 pediatric patients, aged 12 to 18 years in two identical multicenter, randomized, double-blind, vehicle-controlled, 12-week trials and 2 open-label pharmacokinetic studies .
Safety and effectiveness of WINLEVI cream for the topical treatment of acne vulgaris has not been established in pediatric patients under 12 years of age.
Hypothalamic-pituitary-adrenal (HPA) axis suppression was observed in 2/22 (9%) adolescent subjects. All subjects returned to normal HPA axis function at follow-up 4 weeks after stopping the treatment. Children may be more susceptible to systemic toxicity when treated with clascoterone.
|useInGeri=Clinical studies of WINLEVI cream did not include sufficient numbers of subjects aged 65 years of age and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
|mechAction=Clascoterone is an androgen receptor inhibitor. The mechanism of action of WINLEVI cream for the topical treatment of acne vulgaris is unknown.
|PD='''Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression'''

HPA axis suppression was evaluated in adult (n=20) and adolescent (n=22) subjects with acne vulgaris following twice daily application of WINLEVI cream for 2 weeks in the pharmacokinetic study described in Section 12.3. HPA axis suppression indicated by 30-minute post-stimulation serum cortisol level of ≤18 mcg/dL was observed in 1/20 (5%) of adult subjects and 2/22 (9%) of adolescent subjects at Day 14. All subjects returned to normal HPA axis function at follow-up 4 weeks after the end of treatment.

'''Potassium'''

Shifts from normal to elevated potassium levels were observed in 5% of clascoterone-treated subjects and 4% of vehicle-treated subjects.

'''Cardiac Electrophysiology'''

At approximately 2-times the systemic exposure observed with the maximum dose, WINLEVI cream does not prolong the QT interval to any clinically relevant extent.
|PK=Absorption

Following topical treatment of WINLEVI cream for 2 weeks with a mean dose of approximately 6 grams applied twice daily to adult subjects with moderate to severe acne vulgaris (n=20), systemic concentrations of clascoterone were at steady state by Day 5. On Day 14, the mean ± SD maximum plasma concentration (C max) was 4.5 ± 2.9 ng/mL, the mean ± SD area under the plasma concentration-time over the dosing interval (AUC ꞇ) was 37.1 ± 22.3 h*ng/mL and the mean ± SD average plasma concentration (C avg) was 3.1 ± 1.9 ng/mL.

Distribution

Plasma protein binding of clascoterone is 84% to 89% and is independent of concentrations, in vitro.

Elimination

Metabolism

Following topical treatment with WINLEVI cream, the plasma concentrations of cortexolone, a possible primary metabolite of clascoterone, were detectable and generally below or near the lower limit of quantitation (0.5 ng/mL) in subjects ≥12 years of age with acne vulgaris.

The in vitro study indicated that incubation of 10 µmol/L clascoterone with human cryopreserved hepatocytes generated cortexolone as the possible primary metabolite and other unidentified metabolites, including conjugated metabolites.

Excretion

Excretion of clascoterone has not been fully characterized in humans.

Specific Populations

Pediatric Patients

In adolescent subjects ≥ 12 to <18 years of age (n=22) after 2 weeks of twice daily treatment with mean dose of approximately 6 grams of WINLEVI cream (or mean dose of approximately 4 grams in younger, smaller subjects), steady-state concentrations of clascoterone were achieved by Day 5. Clascoterone systemic exposure in adolescents was similar to those observed in adults.

Drug Interaction Studies

Clinical Studies

No clinical studies evaluating the drug interaction potential of WINLEVI cream have been conducted.

In Vitro Studies

CYP Enzymes:Clascoterone inhibited CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 with an IC 50value of >40 µM. Clascoterone up to 30 µM did not induce CYP 1A2, 2B6, or 3A4. These findings suggest that WINLEVI cream has no clinically meaningful effect on the PK of drugs metabolized by CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4.
|nonClinToxic=Clascoterone cream (0.1%, 1%, or 5%) was not carcinogenic after daily topical administration in a 2-year carcinogenicity study in rats. An increased incidence of the non-neoplastic finding of atrophy of the skin and subcutis at the application site was reported in males and females treated with 1% and 5% clascoterone cream.
Clascoterone was not mutagenic in the Ames reverse mutation assay and was not clastogenic in the in vitro human lymphocyte chromosomal aberration assay. In rats, clascoterone administered via subcutaneous injection did not induce micronuclei in the bone marrow at 500 or 1000 mg/kg but a slight increase in micronuclei occurred in 2 of 5 rats at 2000 mg/kg. The response was considered equivocal. Overall, the weight of evidence indicates that clascoterone does not represent a genotoxic risk.
In a fertility and early embryonic development study in rats, clascoterone was administered subcutaneously at doses of 0.5, 2.5, or 12.5 mg/kg/day from 2 – 4 weeks before mating through mating. Clascoterone increased pre-implantation loss at 12.5 mg/kg/day (163 times the MRHD based on AUC comparison). Clascoterone had no effects on mating or fertility in rats at doses up to 12.5 mg/kg/day (163 times the MRHD based on AUC comparison). No effects were noted on development at doses up to 2.5 mg/kg/day (33 times the MRHD based on AUC comparison).
|clinicalStudies=The safety and efficacy of WINLEVI cream 1% applied twice daily for 12 weeks for the treatment of acne vulgaris were assessed in two identically-designed, multicenter, randomized, double-blind, vehicle-controlled clinical trials (Trial 1 [NCT02608450] and Trial 2 [NCT02608476]) enrolling 1440 subjects with facial acne vulgaris. The trials enrolled subjects 9 years or older with Investigator's Global Assessment (IGA) of moderate or severe facial acne vulgaris (score of 3 or 4), 30 to 75 inflammatory lesions (papules, pustules and nodules), and 30 to 100 non-inflammatory lesions (open and closed comedones).
A total of 1421 subjects 12 years and older with facial acne vulgaris were enrolled. Of these subjects, 641 (45%) were 12 to 17 years of age, and 780 (55%) were 18 years of age or older. In addition, 62% of the subjects were female, and 91% were Caucasian. At baseline, subjects had a mean inflammatory lesion count of 42.4 and a mean non-inflammatory lesion count of 61.4. Additionally, approximately 83% of subjects had an IGA score of 3 ("moderate").
Efficacy was assessed at Week 12 by the proportion of subjects in each treatment group with at least a 2-point reduction in IGA compared to baseline and an IGA score of 0 (clear) or 1 (almost clear), absolute change and percent change from baseline in non-inflammatory and inflammatory lesions. The IGA success rate and mean absolute and percent reduction from baseline in acne lesion counts after 12 weeks of treatment for subjects 12 years of age and older are presented
|howSupplied=WINLEVI cream 1% is supplied in an epoxy-lined aluminum blind-end tube with a polypropylene cap closure: 60-gram tube
|storage=Store the product in a refrigerator between 36°F and 46°F (2°C and 8°C). Do not freeze.
|fdaPatientInfo=*Advise the patient to read the FDA-approved patient labeling (Patient Information).
*Avoid applying WINLEVI Cream to damaged skin (such as cuts, abrasions), eczematous areas, and sunburned skin.
*Avoid concomitant use of other potentially irritating topical products (medicated or not).
|alcohol=Alcohol-Clascoterone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=WINLEVI
}}

Clascoterone

2025-04-30T09:54:06Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=Clascoterone |aOrAn=a |drugClass=androgen receptor antagonist |indicationType=treatment |indication=WINLEVI (clascoterone) cream is an androgen receptor inhibitor indicated for the topical treatment of acne vulgaris in patients 12 years of age and older. |blackBoxWarningTitle='''TITLE''' |blackBoxWarningBody=''Conditi..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=Clascoterone
|aOrAn=a
|drugClass=androgen receptor antagonist
|indicationType=treatment
|indication=WINLEVI (clascoterone) cream is an androgen receptor inhibitor indicated for the topical treatment of acne vulgaris in patients 12 years of age and older.
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=Cleanse the affected area gently. After the skin is dry, apply a thin uniform layer of WINLEVI cream twice per day, in the morning and the evening, to the affected area. Avoid accidental transfer of WINLEVI cream into eyes, mouth or other mucous membranes. If contact with mucous membranes occurs, rinse thoroughly with water.
WINLEVI cream is for topical use only. WINLEVI cream is not for ophthalmic, oral or vaginal use.

Cream 1%. Each gram of WINLEVI cream contains 10 mg of clascoterone in a white to almost white cream.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Clascoterone in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Clascoterone in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Clascoterone in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Clascoterone in pediatric patients.
|contraindications=None
|warnings=‘’’Local Skin Reactions’’’
WINLEVI cream may induce local irritation (erythema/redness, pruritus, scaling/ dryness). Concomitant use with other potentially irritating topical products (medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect and products with high concentrations of alcohol, astringents, spices or lime) should be limited.
The product should not be applied to cuts, abrasions, eczematous or sunburned skin.
‘’’Hypothalamic-pituitary-adrenal (HPA) Axis Suppression’’’
Hypothalamic-pituitary-adrenal (HPA) axis suppression was observed and may occur during or after treatment with clascoterone. In the PK trial, all subjects returned to normal HPA axis function at follow-up 4 weeks after stopping treatment. Conditions which augment systemic absorption include use over large surface areas, prolonged use, and the use of occlusive dressings.
If HPA axis suppression develops, an attempt should be made to withdraw the drug.
Pediatric patients may be more susceptible to systemic toxicity.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In two identical multicenter, randomized, double-blind, vehicle-controlled trials, 1421 subjects 12 years and older with facial acne vulgaris applied WINLEVI cream or vehicle twice daily for 12 weeks. Overall, 62% of the subjects were female, and 38% were male, 91% of the patients were Caucasian, and the mean age was 19.7 years.
Local skin reactions (edema, erythema/redness, pruritus, scaling/dryness, skin atrophy, stinging/burning, striae rubrea, telangiectasia) were observed during the 12-week treatment and occurred in a similar percentage of subjects treated with vehicle. Local skin reactions reported by ≥ 1% of subjects treated with WINLEVI cream
|useInLaborDelivery=There are no available data on WINLEVI cream use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, subcutaneous administration of clascoterone to pregnant rats and rabbits during organogenesis at doses 8 or 39 times the maximum recommended human dose (MRHD), respectively, increased malformations in rats and post-implantation loss and resorptions in rabbits.
The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
|useInNursing=There are no data regarding the presence of clascoterone or metabolite in human milk, the effects on the breastfed infant or the effects on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of clascoterone to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for clascoterone and any potential adverse effects on the breastfed child from clascoterone or from the underlying maternal condition.
|useInPed=Safety and effectiveness of WINLEVI cream for the topical treatment of acne vulgaris have been established in 641 pediatric patients, aged 12 to 18 years in two identical multicenter, randomized, double-blind, vehicle-controlled, 12-week trials and 2 open-label pharmacokinetic studies .
Safety and effectiveness of WINLEVI cream for the topical treatment of acne vulgaris has not been established in pediatric patients under 12 years of age.
Hypothalamic-pituitary-adrenal (HPA) axis suppression was observed in 2/22 (9%) adolescent subjects. All subjects returned to normal HPA axis function at follow-up 4 weeks after stopping the treatment. Children may be more susceptible to systemic toxicity when treated with clascoterone.
|useInGeri=Clinical studies of WINLEVI cream did not include sufficient numbers of subjects aged 65 years of age and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
|mechAction=Clascoterone is an androgen receptor inhibitor. The mechanism of action of WINLEVI cream for the topical treatment of acne vulgaris is unknown.
|PD='''Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression'''

HPA axis suppression was evaluated in adult (n=20) and adolescent (n=22) subjects with acne vulgaris following twice daily application of WINLEVI cream for 2 weeks in the pharmacokinetic study described in Section 12.3. HPA axis suppression indicated by 30-minute post-stimulation serum cortisol level of ≤18 mcg/dL was observed in 1/20 (5%) of adult subjects and 2/22 (9%) of adolescent subjects at Day 14. All subjects returned to normal HPA axis function at follow-up 4 weeks after the end of treatment.

'''Potassium'''

Shifts from normal to elevated potassium levels were observed in 5% of clascoterone-treated subjects and 4% of vehicle-treated subjects.

'''Cardiac Electrophysiology'''

At approximately 2-times the systemic exposure observed with the maximum dose, WINLEVI cream does not prolong the QT interval to any clinically relevant extent.
|PK=Absorption

Following topical treatment of WINLEVI cream for 2 weeks with a mean dose of approximately 6 grams applied twice daily to adult subjects with moderate to severe acne vulgaris (n=20), systemic concentrations of clascoterone were at steady state by Day 5. On Day 14, the mean ± SD maximum plasma concentration (C max) was 4.5 ± 2.9 ng/mL, the mean ± SD area under the plasma concentration-time over the dosing interval (AUC ꞇ) was 37.1 ± 22.3 h*ng/mL and the mean ± SD average plasma concentration (C avg) was 3.1 ± 1.9 ng/mL.

Distribution

Plasma protein binding of clascoterone is 84% to 89% and is independent of concentrations, in vitro.

Elimination

Metabolism

Following topical treatment with WINLEVI cream, the plasma concentrations of cortexolone, a possible primary metabolite of clascoterone, were detectable and generally below or near the lower limit of quantitation (0.5 ng/mL) in subjects ≥12 years of age with acne vulgaris.

The in vitro study indicated that incubation of 10 µmol/L clascoterone with human cryopreserved hepatocytes generated cortexolone as the possible primary metabolite and other unidentified metabolites, including conjugated metabolites.

Excretion

Excretion of clascoterone has not been fully characterized in humans.

Specific Populations

Pediatric Patients

In adolescent subjects ≥ 12 to <18 years of age (n=22) after 2 weeks of twice daily treatment with mean dose of approximately 6 grams of WINLEVI cream (or mean dose of approximately 4 grams in younger, smaller subjects), steady-state concentrations of clascoterone were achieved by Day 5. Clascoterone systemic exposure in adolescents was similar to those observed in adults.

Drug Interaction Studies

Clinical Studies

No clinical studies evaluating the drug interaction potential of WINLEVI cream have been conducted.

In Vitro Studies

CYP Enzymes:Clascoterone inhibited CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 with an IC 50value of >40 µM. Clascoterone up to 30 µM did not induce CYP 1A2, 2B6, or 3A4. These findings suggest that WINLEVI cream has no clinically meaningful effect on the PK of drugs metabolized by CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4.
|nonClinToxic=Clascoterone cream (0.1%, 1%, or 5%) was not carcinogenic after daily topical administration in a 2-year carcinogenicity study in rats. An increased incidence of the non-neoplastic finding of atrophy of the skin and subcutis at the application site was reported in males and females treated with 1% and 5% clascoterone cream.
Clascoterone was not mutagenic in the Ames reverse mutation assay and was not clastogenic in the in vitro human lymphocyte chromosomal aberration assay. In rats, clascoterone administered via subcutaneous injection did not induce micronuclei in the bone marrow at 500 or 1000 mg/kg but a slight increase in micronuclei occurred in 2 of 5 rats at 2000 mg/kg. The response was considered equivocal. Overall, the weight of evidence indicates that clascoterone does not represent a genotoxic risk.
In a fertility and early embryonic development study in rats, clascoterone was administered subcutaneously at doses of 0.5, 2.5, or 12.5 mg/kg/day from 2 – 4 weeks before mating through mating. Clascoterone increased pre-implantation loss at 12.5 mg/kg/day (163 times the MRHD based on AUC comparison). Clascoterone had no effects on mating or fertility in rats at doses up to 12.5 mg/kg/day (163 times the MRHD based on AUC comparison). No effects were noted on development at doses up to 2.5 mg/kg/day (33 times the MRHD based on AUC comparison).
|clinicalStudies=The safety and efficacy of WINLEVI cream 1% applied twice daily for 12 weeks for the treatment of acne vulgaris were assessed in two identically-designed, multicenter, randomized, double-blind, vehicle-controlled clinical trials (Trial 1 [NCT02608450] and Trial 2 [NCT02608476]) enrolling 1440 subjects with facial acne vulgaris. The trials enrolled subjects 9 years or older with Investigator's Global Assessment (IGA) of moderate or severe facial acne vulgaris (score of 3 or 4), 30 to 75 inflammatory lesions (papules, pustules and nodules), and 30 to 100 non-inflammatory lesions (open and closed comedones).
A total of 1421 subjects 12 years and older with facial acne vulgaris were enrolled. Of these subjects, 641 (45%) were 12 to 17 years of age, and 780 (55%) were 18 years of age or older. In addition, 62% of the subjects were female, and 91% were Caucasian. At baseline, subjects had a mean inflammatory lesion count of 42.4 and a mean non-inflammatory lesion count of 61.4. Additionally, approximately 83% of subjects had an IGA score of 3 ("moderate").
Efficacy was assessed at Week 12 by the proportion of subjects in each treatment group with at least a 2-point reduction in IGA compared to baseline and an IGA score of 0 (clear) or 1 (almost clear), absolute change and percent change from baseline in non-inflammatory and inflammatory lesions. The IGA success rate and mean absolute and percent reduction from baseline in acne lesion counts after 12 weeks of treatment for subjects 12 years of age and older are presented
|howSupplied=WINLEVI cream 1% is supplied in an epoxy-lined aluminum blind-end tube with a polypropylene cap closure: 60-gram tube
|storage=Store the product in a refrigerator between 36°F and 46°F (2°C and 8°C). Do not freeze.
|fdaPatientInfo=*Advise the patient to read the FDA-approved patient labeling (Patient Information).
*Avoid applying WINLEVI Cream to damaged skin (such as cuts, abrasions), eczematous areas, and sunburned skin.
*Avoid concomitant use of other potentially irritating topical products (medicated or not).
|alcohol=Alcohol-Clascoterone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=WINLEVI
}}

Somapacitan-beco

2025-04-30T08:53:05Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=somapacitan-beco |aOrAn=a |drugClass=binds to the growth hormone receptor and induces intracellular signalling to up-regulate insulin-like growth factor I (IGF-1) |indicationType=treatment |indication=SOGROYA is indicated for the: *Treatment of pediatric patients aged 2.5 years and older who have growth failure due to inadequate secretion of endogenous growth hormone (GH). *Repla..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=somapacitan-beco
|aOrAn=a
|drugClass=binds to the growth hormone receptor and induces intracellular signalling to up-regulate insulin-like growth factor I (IGF-1)
|indicationType=treatment
|indication=SOGROYA is indicated for the:
*Treatment of pediatric patients aged 2.5 years and older who have growth failure due to inadequate secretion of endogenous growth hormone (GH).
*Replacement of endogenous GH in adults with growth hormone deficiency (GHD).
The following clinically significant adverse drug reactions are described elsewhere in the labeling:
|adverseReactions=The following clinically significant adverse drug reactions are described elsewhere in the labeling:
*Increased mortality in patients with acute critical illness
Severe hypersensitivity
*Increased risk of neoplasms
*Glucose intolerance and diabetes mellitus
*Intracranial hypertension
*Fluid retention
*Hypoadrenalism
*Hypothyroidism
*Slipped capital femoral epiphysis in pediatric patients
*Progression of preexisting scoliosis in pediatric patients
*Pancreatitis
*Lipohypertrophy/Lipoatrophy
*Sudden death in pediatric patients with Prader-Willi syndrome
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=SOGROYA is indicated for the:
*Treatment of pediatric patients aged 2.5 years and older who have growth failure due to inadequate secretion of endogenous growth hormone (GH).

*Replacement of endogenous GH in adults with growth hormone deficiency (GHD).

‘’’Dosage and Monitoring for Pediatric Patients with GHD’’’
*Recommended dosage of SOGROYA is 0.16 mg/kg based on actual body weight once weekly for treatment-naïve patients and patients switching from daily growth hormone (somatropin).
*Individualize dosage for each patient based on the growth response.
*When switching from daily human growth hormone to once-weekly SOGROYA, choose the preferred day for the weekly dose. Take the final dose of daily treatment on the day before (or at least 8 hours before) the first dose of SOGROYA.
*When switching from a weekly human growth hormone to once-weekly SOGROYA, continue once weekly dosing schedule.
*Assess compliance and evaluate other causes of poor growth such as hypothyroidism, undernutrition, advanced bone age, and antibodies to recombinant human growth hormone if patients experience failure to increase height velocity, particularly during the first year of treatment.
*Patients who were treated with SOGROYA for GH deficiency in childhood and whose epiphyses are closed should be reevaluated before continuing SOGROYA.

‘’’ Dosage, Titration, and Monitoring for Adult Patients with GHD
*Initiate SOGROYA with a dosage of 1.5 mg once weekly for treatment naïve patients and patients switching from daily growth hormone (somatropin).
*Increase the weekly dosage every 2 to 4 weeks by approximately 0.5 mg to 1.5 mg until the desired response is achieved.
*Titrate the dosage based on clinical response and serum insulin-like growth factor-1 (IGF-1) concentrations. Draw IGF-1 samples 3 to 4 days after the prior dose.
*Decrease the dosage as necessary on the basis of adverse reactions and/or serum IGF-1 concentrations above the age- and sex-specific normal range.
*The maximum recommended dosage is 8 mg once weekly.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Somapacitan-beco in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Somapacitan-beco in adult patients.
|fdaLIADPed=‘’’Dosage and Monitoring for Pediatric Patients with GHD’’’
*Recommended dosage of SOGROYA is 0.16 mg/kg based on actual body weight once weekly for treatment-naïve patients and patients switching from daily growth hormone (somatropin).
*Individualize dosage for each patient based on the growth response.
*When switching from daily human growth hormone to once-weekly SOGROYA, choose the preferred day for the weekly dose. Take the final dose of daily treatment on the day before (or at least 8 hours before) the first dose of SOGROYA.
*When switching from a weekly human growth hormone to once-weekly SOGROYA, continue once weekly dosing schedule.
*Assess compliance and evaluate other causes of poor growth such as hypothyroidism, undernutrition, advanced bone age, and antibodies to recombinant human growth hormone if patients experience failure to increase height velocity, particularly during the first year of treatment.
*Patients who were treated with SOGROYA for GH deficiency in childhood and whose epiphyses are closed should be reevaluated before continuing SOGROYA.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Somapacitan-beco in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Somapacitan-beco in pediatric patients.
|contraindications=SOGROYA is contraindicated in patients with:
*Acute critical illness after open-heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure because of the risk of increased mortality with use of pharmacologic doses of SOGROYA.
*Hypersensitivity to SOGROYA or any of its excipients. Systemic hypersensitivity reactions have been reported postmarketing with somatropin.
*Pediatric patients with closed epiphyses.
*Active malignancy.
*Active proliferative or severe non-proliferative diabetic retinopathy.
*Pediatric patients with Prader-Willi syndrome who are severely obese, have a history of upper airway obstruction or sleep apnea or have severe respiratory impairment due to risk of sudden death.
|warnings=‘’’Increased Mortality in Patients with Acute Critical Illness’’’
Increased mortality has been reported after treatment with somatropin in patients with acute critical illness due to complications following open-heart surgery, abdominal surgery and multiple accidental trauma, as well as patients with acute respiratory failure. The safety of continuing SOGROYA treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. SOGROYA is not indicated for the treatment of non-GH deficient adults.
‘’’Severe Hypersensitivity’’’
Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin. Inform patients and/or caregivers that such reactions are possible, and that prompt medical attention should be sought if an allergic reaction occurs. SOGROYA is contraindicated in patients with known hypersensitivity to somatropin or any excipients in SOGROYA..
‘’’Increased Risk of Neoplasms’’’
Active Malignancy
There is an increased risk of malignancy progression with somatropin treatment in patients with active malignancy. Any preexisting malignancy should be inactive, and its treatment complete prior to instituting therapy with SOGROYA. Discontinue SOGROYA if there is evidence of recurrent activity.
Risk of Second Neoplasm in Pediatric Patients
In childhood cancer survivors who were treated with radiation to the brain/head for their first neoplasm and who developed subsequent growth hormone deficiency (GHD) and were treated with somatropin, an increased risk of second neoplasm has been reported. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. Monitor all patients with a history of GHD secondary to an intracranial neoplasm while on somatropin therapy for progression or recurrence of the tumor.
New Malignancy During Treatment
Because children with certain rare genetic causes of short stature have an increased risk of developing malignancies, thoroughly consider the risks and benefits of starting SOGROYA in these patients. If treatment with SOGROYA is initiated, carefully monitor these patients for development of neoplasms.
There is risk of malignant changes of preexisting nevi with somatropin treatment in patients. Monitor patients on SOGROYA therapy carefully for increased growth or potential malignant changes of preexisting nevi. Advise patients/caregivers to report marked changes in behavior, onset of headaches, vision disturbances, and/or changes in the appearance of preexisting nevi.
‘’’Glucose Intolerance and Diabetes Mellitus’’’
Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses. New onset type 2 diabetes mellitus has been reported in patients taking somatropin. Patients with undiagnosed pre-diabetes and diabetes mellitus may experience worsened glycemic control and become symptomatic. Monitor glucose levels periodically in all patients receiving SOGROYA, especially in those with risk factors for diabetes mellitus, such as obesity, Turner syndrome, or a family history of diabetes mellitus. Patients with preexisting type 1 or type 2 diabetes mellitus or pre-diabetes should be monitored closely. The doses of antidiabetic agents may require adjustment when SOGROYA is initiated.
‘’’Intracranial Hypertension’’’
Intracranial hypertension with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in patients treated with somatropin. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin therapy. In all reported cases, intracranial hypertension-associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose.
Perform fundoscopic examination before initiating treatment with SOGROYA to exclude preexisting papilledema and periodically thereafter. If papilledema is identified prior to initiation, evaluate the etiology and treat the underlying cause before initiating SOGROYA. If papilledema is observed by fundoscopy during SOGROYA treatment, treatment should be stopped. If intracranial hypertension is confirmed, treatment with SOGROYA can be restarted at a lower dose after intracranial hypertension-associated signs and symptoms have resolved.
‘’’Fluid Retention’’’
Fluid retention during SOGROYA replacement therapy may occur. Clinical manifestations of fluid retention (e.g. edema and nerve compression syndromes including carpal tunnel syndrome/paresthesia) are usually transient and dose dependent.
‘’’Hypoadrenalism’’’
Patients receiving somatropin therapy who have or are at risk for corticotropin deficiency may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of SOGROYA treatment. Monitor patients with known hypoadrenalism for reduced serum cortisol levels and/or need for glucocorticoid dose increases.
‘’’Hypothyroidism’’’
Undiagnosed/untreated hypothyroidism may prevent an optimal response to SOGROYA. In patients with GH deficiency, central (secondary) hypothyroidism may first become evident or worsen during treatment with somatropin therapy. Therefore, patients should have periodic thyroid function tests and thyroid hormone replacement therapy should be initiated or appropriately adjusted when indicated.
‘’’Slipped Capital Femoral Epiphysis in Pediatric Patients’’’
Slipped capital femoral epiphysis may occur more frequently in patients undergoing rapid growth. Evaluate pediatric patients with the onset of a limp or complaints of persistent hip or knee pain.
‘’’Progression of Preexisting Scoliosis in Pediatric Patients’’’
Somatropin increases growth rate, and progression of preexisting scoliosis can occur in patients who experience rapid growth. Somatropin has not been shown to increase the occurrence of scoliosis. Monitor patients with a history of scoliosis for disease progression.
‘’’Pancreatitis’’’
Cases of pancreatitis have been reported in patients receiving somatropin. The risk may be greater in pediatric patients compared with adults. Consider pancreatitis in patients who develop persistent severe abdominal pain.
‘’’Lipohypertrophy/Lipoatrophy’’’
When SOGROYA is administered subcutaneously at the same site over a long period of time, tissue lipohypertrophy or lipoatrophy may result. Rotate injection sites when administering SOGROYA to reduce this risk.
‘’’Sudden Death in Pediatric Patients with Prader-Willi Syndrome’’’
There have been reports of fatalities after initiating therapy with somatropin in pediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than females. SOGROYA is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome.
‘’’Laboratory Tests’’’
Serum levels of inorganic phosphorus and alkaline phosphatase may increase after SOGROYA therapy. Serum levels of parathyroid hormone may increase with somatropin treatment.
|clinicalTrials=‘’’Pediatric Patients with GHD’’’
SOGROYA was studied in a 52-week randomized, open-label, active-controlled, parallel-group clinical study in 200 treatment naïve, prepubertal pediatric patients with growth hormone deficiency. Table 2 shows common adverse reactions that occurred in ≥5% of patients treated with either SOGROYA or somatropin in this trial.

‘’’Adult Patients with GHD’’’
More SOGROYA treated patients shifted from normal baseline levels to elevated phosphate and creatine phosphokinase levels at the end of the trial compared to the placebo group (17.5% vs 4.9% and 9.2% vs. 6.6%, respectively); these laboratory changes occurred intermittently, and were non-progressive.
|drugInteractions='''Glucocorticoid'''
Microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. GH inhibits 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Initiation of SOGROYA may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations.

'''Cytochrome P450-Metabolized Drugs'''
Limited published data indicate that GH treatment increases cytochrome P450 (CP450)-mediated antipyrine clearance. SOGROYA may alter the clearance of compounds known to be metabolized by CP450 liver enzymes.

'''Oral Estrogen'''
Oral estrogens may reduce the serum IGF-1 response to SOGROYA.

'''Insulin and/or Other Hypoglycemic Agents'''
Treatment with SOGROYA may decrease insulin sensitivity, particularly at higher doses.
|useInLaborDelivery=There are no available data on the use of SOGROYA during pregnancy; however, published studies describing the use of short-acting recombinant growth hormone (rhGH) during pregnancy over several decades have not identified any drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, subcutaneously administered somapacitan-beco was not teratogenic in rats or rabbits during organogenesis at doses approximately 12 times the clinical exposure at the maximum recommended human dose (MRHD) of 8 mg/week. No adverse developmental outcomes were observed in a pre- and post-natal development study with administration of somapacitan-beco to pregnant rats from organogenesis through lactation at approximately 275 times the clinical exposure at the MRHD (see Data).
The background risk of birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
|useInNursing=There is no information on the presence of somapacitan-beco in human milk, the effects on the breastfed infant, or the effects on milk production. Somapacitan-beco-related material was secreted into milk of lactating rats. When a substance is present in animal milk, it is likely that the substance will be present in human milk. Available published data describing administration of short-acting recombinant growth hormone (rhGH) to lactating women for 7 days reported that short-acting rhGH did not increase the normal breastmilk concentration of growth hormone and no adverse effects were reported in breastfed infants. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SOGROYA and any potential adverse effects on the breastfed infant from SOGROYA or from the underlying maternal condition.
|useInPed=The safety and effectiveness of SOGROYA have been established for the treatment of growth failure due to inadequate secretion of endogenous growth hormone (GH) in pediatric patients 2.5 years of age and older. The use of SOGROYA for this indication is supported by evidence from a 52 week randomized, multi-center, open-label, active-controlled, parallel-group phase 3 trial in 200 treatment-naïve, pediatric patients with GHD. The safety profile from the pediatric trial was similar to that reported in adults
Risks in pediatric patients associated with growth hormone use include:
*Sudden death in pediatric patients with Prader-Willi Syndrome. SOGROYA is not indicated for the treatment of pediatric patients with growth failure secondary to genetically confirmed Prader-Willi syndrome
*Increased risk of second neoplasm in pediatric cancer survivors treated with radiation to the brain and/or head
*Slipped capital femoral epiphysis in pediatric patients
*Progression of preexisting scoliosis in pediatric patients
*Pancreatitis
The safety and effectiveness of SOGROYA for the treatment of growth failure due to inadequate secretion of endogenous growth hormone have not been established in pediatric patients less than 2.5 years of age.
|useInGeri=In clinical studies a total of 52 (15.6%) of the 333 SOGROYA-treated patients were 65 years or older and 3 (0.9%) were 75 years or older. Subjects older than 65 years appeared to have higher exposure than younger subjects at the same dose level. Elderly patients may be more sensitive to the action of somapacitan-beco, and therefore may be at increased risk for adverse reactions. Initiate SOGROYA with a dose of 1 mg once weekly and use smaller increments when increasing the dose.
|useInHepaticImpair=Adult patients: No dose adjustment of SOGROYA is required for patients with mild hepatic impairment. Higher somapacitan-beco exposure was observed in patients with moderate hepatic impairment. In patients with moderate hepatic impairment, initiate SOGROYA with a dose of 1 mg once weekly and use smaller increments when increasing the dose. The maximum dose should not exceed 4 mg once weekly. Somapacitan-beco was not studied in patients with severe hepatic impairment. Therefore, use of SOGROYA is not recommended in patients with severe hepatic impairment.
Pediatric patients: Based on the hepatic impairment study in adults, no dose adjustment of SOGROYA is recommended for patients with mild hepatic impairment. Higher systemic exposure of SOGROYA is expected in pediatric patients with moderate and severe hepatic impairment; therefore, SOGROYA is not recommended in these pediatric patients
|overdose=Acute overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Overdose with SOGROYA is likely to cause fluid retention. Long-term overdosage could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess endogenous growth hormone.
|mechAction=Somapacitan-beco binds to a dimeric GH receptor in the cell membrane of target cells resulting in intracellular signal transduction and a host of pharmacodynamic effects. Some of these pharmacodynamic effects are primarily mediated by insulin-like growth factor-1 (IGF-1) produced in the liver, while others are primarily a consequence of the direct effects of somapacitan-beco.
|PD=IGF-1 was measured to assess the pharmacodynamic (PD) properties of somapacitan-beco. Somapacitan-beco normalizes the mean IGF-1 standard deviation score (SDS) level from a baseline value below -2 to a value within the reference range (-2 to +2) in treatment-naïve adult patients with GHD.
In adult patients with GHD (n=26), somapacitan-beco induces a less than dose proportional IGF-1 response at steady state. Maximum IGF-1 concentrations were observed within 2 to 4 days after dosing. Similar to the somapacitan-beco exposure time course, a steady state IGF-1 response was reached after 1 to 2 weekly doses with limited cumulative IGF-1 response.
In pediatric patients with GHD aged 2.5 to 11 years, somapacitan-beco produces a dose linear IGF-1 response, with a change of 0.02 mg/kg on average resulting in a change in IGF-1 standard deviation score (SDS) of 0.32. Approximately 97% of pediatric patients achieved an average IGF-1 SDS level within normal range after 52 weeks of treatment with once weekly Sogroya in Study NCT03811535. IGF-1 SDS levels were -2.03 at baseline and the IGF-1 SDS level change from baseline was 2.36.
|PK=Somapacitan-beco has pharmacokinetic properties compatible with once weekly administration. The reversible binding to endogenous albumin delays elimination of somapacitan and thereby prolongs the in vivo half-life and duration of action.
The pharmacokinetics (PK) of somapacitan-beco following subcutaneous administration have been investigated at clinically relevant doses (e.g., 0.01 to 0.32 mg/kg in healthy adults, 0.02 to 0.12 mg/kg in adults with GHD, and 0.02 to 0.16 mg/kg in pediatric patient with GHD)‎.
Overall, somapacitan-beco displays non-linear pharmacokinetics, however in the clinically relevant dose range of somapacitan-beco in adults with GHD, somapacitan-beco pharmacokinetics are approximately linear. After subcutaneous administration of 0.02 – 0.16 mg/kg/week somapacitan-beco in pediatric patients with GHD, a non-linear dose-exposure relationship with a greater than dose proportional increase in exposure was observed.
‘’’Absorption’’’
In adults with GHD, a maximum concentration of somapacitan-beco is reached 4 to 24 hours post dose.
Steady state exposure is achieved following 1 to 2 weeks of once weekly administration of subcutaneous somapacitan-beco.
In pediatric patients with GHD, maximum somapacitan-beco concentrations occurred 8 to 25 hours after dosing at doses from 0.02 mg/kg/week to 0.16 mg/kg/week and increased with increasing dose level. Steady state was achieved following 1 to 2 weekly administration.
‘’’Distribution’’’
Somapacitan-beco is extensively bound (>99%) to plasma proteins.
Based on population PK analyses, the estimated volume of distribution (V/F) of somapacitan-beco in adult GHD patients is approximately 14.6 L and 1.7 L in pediatric patients with GHD.
‘’’Elimination’’’
The plasma elimination half-life of somapacitan-beco is approximately 2 to 3 days in adult patients with GHD. Following a dose of 0.16 mg/kg/week, the terminal half-life of somapacitan-beco was about 34 hours in pediatric patients with GHD. Somapacitan-beco was cleared within one week after treatment discontinuation.
‘’’Metabolism’’’: Somapacitan-beco is metabolized via proteolytic cleavage of the linker sequence between the peptide backbone and albumin binder sidechain.
Excretion: The primary excretion routes of somapacitan-beco-related material are via the urine and feces. Approximately 81% of the dose is excreted in the urine and approximately 13% is excreted in the feces. No intact somapacitan-beco is excreted indicating full breakdown of somapacitan-beco prior to excretion.
Specific Populations
‘’’Body weight’’’: Adults with GHD -The exposure of somapacitan-beco decreases with increasing body weight. However, the somapacitan-beco dose range of 0.1 to 8 mg/week provides adequate systemic exposure to reach target IGF-1 levels over the weight range of 34.5-150.5 kg evaluated in the clinical trials.
‘’’Pediatric patients with GHD’’’: Based on pharmacokinetic analysis, gender and race do not have a clinically meaningful effect on the pharmacokinetics. The exposure of somapacitan-beco decreases with increasing body weight. However, the somapacitan-beco dose of 0.16 mg/kg/week provides adequate systemic exposure for pediatrics to reach target IGF-1 levels over the weight range of 9.9 to 61.8 kg evaluated in the clinical trials.
‘’’Geriatric patients’’’: Adult patients greater than 65 years of age and geriatric patients have a higher exposure than younger subjects at the same somapacitan-beco dose.
Female patients receiving estrogen: Female patients and in particular female patients on oral estrogen, have lower exposure than males at the same somapacitan-beco dose .
Hepatic impairment: A somapacitan-beco dose of 0.08 mg/kg at steady state resulted in comparable somapacitan-beco exposure between patients with normal hepatic function and mild hepatic impairment (Child-Pugh A). However, higher exposure was observed in patients with moderate hepatic impairment (Child-Pugh B) (ratios to normal hepatic function were 4.69 and 3.52-fold increase for AUC0-168h and Cmax, respectively). Lower somapacitan-beco stimulated
|nonClinToxic=Long term studies in animals with somapacitan-beco to evaluate carcinogenic potential have not been conducted.

Somapacitan-beco was not mutagenic or clastogenic in a standard battery of genotoxicity tests (bacterial mutagenicity (Ames), human lymphocyte chromosome aberration, rat bone marrow micronucleus).

In rat studies evaluating male and female fertility, somapacitan-beco was administered by subcutaneous injection at doses of 1, 2, and 4 mg/kg twice weekly. Males were dosed from four weeks before pairing until termination and females were dosed beginning two weeks prior to mating through gestation day 7. No adverse effects were observed on male or female fertility in rats at doses up to 4 mg/kg (29 times the MRHD, based on AUC).
|clinicalStudies=‘’’Pediatric Patients with Growth Hormone Deficiency (GHD)’’’

A randomized, open-label, active-controlled, parallel-group phase 3 study was conducted in 200 treatment-naïve, pediatric patients with growth hormone deficiency (GHD) (NCT03811535). The primary efficacy endpoint was annualized height velocity at Week 52.
One hundred thirty two patients (132) received 0.16 mg/kg/week SOGROYA, and 68 received 0.034 mg/kg/day daily somatropin. The patients ranged in age from 2.5 to 11 years with a mean of 6.4 years. Of these patients, 74.5% were male and 25.5% were female. Fifty-seven percent (57%) of patients were Caucasian, 37% of patients were Asian, 0.5% of patients were Black or African American, 5.0% were not reported, and 0.5% were categorized as “other.” The mean baseline height standard deviation score (SDS) of -2.99 (1.02) in SOGROYA group and -3.47 (1.52) in daily somatropin group.
Treatment with once-weekly SOGROYA for 52 weeks resulted in an annualized height velocity of 11.2 cm/year. Patients treated with daily somatropin achieved an annualized height velocity of 11.7 cm/year after 52 weeks of treatment.

‘’’Adults with Growth Hormone Deficiency (GHD)’’’
In a 35-week, double-blind, placebo-controlled study, treatment-naïve adult patients with GHD were randomized (2:1:2) and exposed to once-weekly SOGROYA 10 mg/1.5mL (n=120) or placebo (n=60) or a daily somatropin product 10 mg/1.5mL (n=119) for a 34-week treatment period (NCT02229851).
In this study, patients were 51.7% female and had a mean age of 45.1 years. Most patients were 23 to 64 years old and most (69.7%) had adult onset GHD. The mean BMI was 27.4 kg/m2. Overall, 66.7% were White, 28.7% were Asian and 2.3% were Black or African American; 4.5% identified as Hispanic or Latino ethnicity.
Treatment with SOGROYA demonstrated superiority compared to placebo in reduction in truncal fat percentage (%) as assessed by dual X-ray absorptiometry, with a change of -1.06% for SOGROYA and +0.47% for placebo after 34 weeks (see Table 6). Patients treated with daily somatropin achieved a change in truncal fat % of -2.23% after 34 weeks
|howSupplied=SOGROYA (somapacitan-beco) injection is a clear to slightly opalescent and colorless to slightly yellow solution available as one 1.5 mL single-patient-use prefilled pen per carton:
*SOGROYA 5 mg/1.5 mL (3.3 mg/mL) pen (teal) NDC 0169-2035-11
*SOGROYA 10 mg/1.5 mL (6.7 mg/mL) pen (yellow) NDC 0169-2030-11
*SOGROYA 15 mg/1.5 mL (10 mg/mL) pen (red) NDC 0169-2037-11
SOGROYA 5 mg/1.5 mL, 10 mg/1.5 mL, and 15 mg/1.5 mL pens are compatible with FlexPro® PenMate®. The FlexPro PenMate is an accessory device that is dispensed separately with its enclosed Instructions for Use.
|storage=Before and during use: Store in a refrigerator at 36°F to 46°F (2°C to 8°C) with the cap on and in the original carton to protect from light. Do not freeze. Do not use SOGROYA if it has been frozen. Discard prefilled pen if kept above 86°F (30°C). Avoid direct or excessive heat. Avoid sunlight. Refer to storage conditions for SOGROYA .
Write the date of first use in the space provided on the carton.
Always remove and safely discard the needle after each injection and store the SOGROYA prefilled pen without an injection needle attached. Always use a new needle for each injection to prevent contamination.
|fdaPatientInfo=Advise patients and/or caregivers to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Advise patients and/or caregivers to administer SOGROYA once weekly.
‘Hypersensitivity’ - Advise patients and/or caregivers that severe and/or serious systemic hypersensitivity reactions (anaphylaxis and angioedema) have been reported, and to seek prompt medical attention should an allergic reaction ocur
‘Neoplasms’ – Advise patients to report marked changes in skin pigmentation or changes in the appearance of preexisting nevi.
‘Glucose Intolerance/ Diabetes Mellitus’ – Advise patients that new onset pre- /diabetes mellitus or exacerbation of preexisting diabetes mellitus can occur and monitoring of blood glucose during treatment with SOGROYA may be needed.
‘Intracranial Hypertension’ - Advise patients to report to their healthcare provider any visual changes, headache, and nausea and/or vomiting.
‘Fluid Retention’ - Advise patients that fluid retention during SOGROYA replacement therapy may frequently occur. Inform patients of the clinical manifestations of fluid retention (e.g. edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paresthesia) and to report to their healthcare provider any of these signs or symptoms occur during treatment with SOGROYA.
‘Hypoadrenalism ‘- Advise patients who have or who are at risk for corticotropin deficiency that hypoadrenalism may develop and to report to their healthcare provider if they experience hyperpigmentation, extreme fatigue, dizziness, weakness, or weight loss.
‘Hypothyroidism’ - Advise patients/caregivers that undiagnosed/untreated hypothyroidism may prevent an optimal response to SOGROYA. Advise patients/caregivers they may require periodic thyroid function tests.
‘Pancreatitis’ - Advise patients that pancreatitis may develop and to report to their healthcare provider any new onset abdominal pain.
‘Lipohypertrophy/ Lipoatrophy ‘ – Advise patients that lipohypertrophy or lipoatrophy can occur if SOGROYA is administered subcutaneously at the same site over a long period of time. Advise patients to rotate injection sites when administering SOGROYA to reduce this risk
|alcohol=Alcohol-Somapacitan-beco interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=SOGROYA
}}

Copper cu 64 dotatate injection

2025-04-30T05:56:25Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=copper cu 64 dotatate injection |aOrAn=a |drugClass=somatostatin receptor-positive neuroendocrine tumors (NETs) |indicationType=diagnosis |indication=Detectnet is indicated for use with positron emission tomography (PET) for localization of somatostatin receptor positive neuroendocrine tumors (NETs) in adult patients. |adverseReactions=The following clinically significant adverse r..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=copper cu 64 dotatate injection
|aOrAn=a
|drugClass=somatostatin receptor-positive neuroendocrine tumors (NETs)
|indicationType=diagnosis
|indication=Detectnet is indicated for use with positron emission tomography (PET) for localization of somatostatin receptor positive neuroendocrine tumors (NETs) in adult patients.
|adverseReactions=The following clinically significant adverse reactions are described elsewhere in the labeling:
*Hypersensitivity reactions
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=Detectnet is indicated for use with positron emission tomography (PET) for localization of somatostatin receptor positive neuroendocrine tumors (NETs) in adult patients.

'''Dosage'''
'''Radiation Safety – Drug Handling'''
Handle Detectnet with appropriate safety measures to minimize radiation exposure. Use waterproof gloves, effective radiation shielding and appropriate safety measures when preparing and handling Detectnet.

Radiopharmaceuticals should be used by or under the control of physicians who are qualified by specific training and experience in the safe use and handling of radionuclides, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radionuclides.

'''Recommended Dosage and Administration Instructions'''
Recommended Dosage

In adults, the recommended amount of radioactivity to be administered for PET imaging is 148 MBq (4 mCi) administered as an intravenous injection over a period of approximately 1 minute.

'''Administration'''

Use Detectnet within 2 hours after calibration time.
Use aseptic technique and radiation shielding when withdrawing and administering Detectnet.
Inspect Detectnet visually for particulate matter and discoloration before administration. Do not use the drug if the solution contains particulate matter or is discolored.
Calculate the necessary volume to administer based on measured activity, volume, calibration time, and date.
Use a dose calibrator to measure the patient dose immediately prior to administration of Detectnet.
After injection of Detectnet, administer an intravenous flush of 0.9% sodium chloride injection, USP.
Dispose of any unused drug in a safe manner in compliance with applicable regulations.
'''Patient Preparation'''
Somatostatin Analogs

Image patients just prior to dosing with somatostatin analogs.

For patients on long-acting somatostatin analogs, a wash-out period of 28 days is recommended prior to imaging.

For patients on short-acting somatostatin analogs, a washout period of 2 days is recommended prior to imaging.

'''Patient Hydration'''

Instruct patients to drink water to ensure adequate hydration prior to administration of Detectnet and to continue to drink and void frequently during the first hours following administration to reduce radiation exposure [see Warnings and Precautions ( 5.1)] .

'''Pregnancy Status'''

Assessment of pregnancy status is recommended in females of reproductive potential before administering Detectnet.

'''Image Acquisition'''
For Detectnet PET imaging, a whole-body acquisition from the skull vertex to mid-thigh is recommended. Image acquisition can begin between 45 to 90 minutes after the intravenous administration of Detectnet. Adapt Detectnet uptake time and scan duration according to the equipment used and the patient and tumor characteristics, to obtain the optimal image quality.

'''Image Interpretation'''
Copper Cu 64 dotatate binds to somatostatin receptors. Based upon the intensity of the signals, PET images obtained using copper Cu 64 dotatate injection indicate the presence and density of somatostatin receptors in tissues. Uptake can also be seen in a variety of non-NET tumors that contain somatostatin receptors or as a normal physiologic variant. NET tumors that do not bear somatostatin receptors will not be visualized.

'''Radiation Dosimetry'''
Estimated radiation absorbed doses per injected activity for organs and tissues of adult patients following an intravenous administration of copper Cu 64 dotatate injection
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Copper cu 64 dotatate injection in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Copper cu 64 dotatate injection in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Copper cu 64 dotatate injection in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Copper cu 64 dotatate injection in pediatric patients.
|contraindications=None
|warnings='''Radiation Risk'''
Diagnostic radiopharmaceuticals, including Detectnet, contribute to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk of cancer. Ensure safe handling and preparation procedures to protect patients and health care workers from unintentional radiation exposure. Advise patients to hydrate before and after administration and to void frequently after administration.

'''Hypersensitivity Reactions'''
Hypersensitivity reactions following administration of somatostatin receptor imaging agents predominantly consisted of cutaneous reactions such as rash and pruritus. Reactions reversed either spontaneously or with routine symptomatic management. Less frequently hypersensitivity reactions included angioedema or cases with features of anaphylaxis.

'''Risk for Image Misinterpretation'''
The uptake of copper Cu 64 dotatate reflects the level of somatostatin receptor density in NETs, however, uptake can also be seen in a variety of other tumors that also express somatostatin receptors. Increased uptake might also be seen in other non-cancerous pathologic conditions that express somatostatin receptors including thyroid disease or in subacute inflammation, or might occur as a normal physiologic variant (e.g. uncinate process of the pancreas).

A negative scan after the administration of Detectnet in patients who do not have a history of NET disease does not rule out disease.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In safety and efficacy trials, 71 subjects received a single dose of Detectnet. Of these 71 subjects, 21 were healthy volunteers and the remainder were patients with known or suspected NET.

The following adverse reactions occurred at a rate of < 2%:

*Gastrointestinal Disorders:nausea, vomiting
*Vascular Disorders:flushing

In published clinical experience, 126 patients with known history of NET received a single dose of copper Cu 64 dotatate injection. Four patients were reported to have experienced nausea immediately after injection.
|postmarketing=The following adverse reactions have been identified during postapproval use of other somatostatin receptor imaging agents. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug.

Immune System Disorders:Hypersensitivity reactions, predominantly rash, pruritus, less frequently angioedema or features of anaphylaxis
|drugInteractions='''Somatostatin Analogs'''

Non-radioactive somatostatin analogs and copper Cu 64 dotatate competitively bind to somatostatin receptors (SSTR2). Image patients just prior to dosing with somatostatin analogs. For patients on long-acting somatostatin analogs, a wash-out period of 28 days is recommended prior to imaging. For patients on short-acting somatostatin analogs, a washout period of 2 days is recommended prior to imaging
|useInLaborDelivery=All radiopharmaceuticals, including Detectnet have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. Advise a pregnant woman of the potential risks of fetal exposure to radiation from administration of Detectnet.

There are no data on Detectnet use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. No animal reproduction studies have been conducted with copper Cu 64 dotatate injection.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
|useInNursing=There are no data on the presence of copper Cu 64 dotatate in human milk, the effect on the breastfed infant, or the effect on milk production. Lactation studies have not been conducted in animals.

Advise a lactating woman to interrupt breastfeeding for 12 hours after Detectnet administration in order to minimize radiation exposure to a breastfed infant.
|useInPed=The safety and effectiveness of Detectnet have not been established in pediatric patients.
|useInGeri=Clinical studies of Detectnet did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
|administration=*Use Detectnet within 2 hours after calibration time.
*Use aseptic technique and radiation shielding when withdrawing and administering Detectnet.
*Inspect Detectnet visually for particulate matter and discoloration before administration. Do not use the drug if the solution contains particulate matter or is discolored.
*Calculate the necessary volume to administer based on measured activity, volume, calibration time, and date.
*Use a dose calibrator to measure the patient dose immediately prior to administration of Detectnet.
*After injection of Detectnet, administer an intravenous flush of 0.9% sodium chloride injection, USP.
*Dispose of any unused drug in a safe manner in compliance with applicable regulations.
|overdose=In the event of a radiation overdose, the absorbed dose to the patient should be reduced where possible by increasing the elimination of the radionuclide from the body by reinforced hydration and frequent bladder voiding. A diuretic might also be considered. If possible, estimation of the radioactive dose given to the patient should be performed.
|mechAction=Copper Cu 64 dotatate binds to somatostatin receptors with highest affinity for subtype 2 receptors (SSTR2). It binds to cells that express somatostatin receptors including malignant neuroendocrine cells, which overexpress SSTR2 receptors. Copper Cu 64 is a positron (β +) emitting radionuclide with an emission yield that allows positron emission tomography (PET) imaging.
|PD=The relationship between copper Cu 64 dotatate plasma concentrations and successful imaging was not explored in clinical trials.
|PK='''Distribution'''

After 1 to 3 hours of a single dose administration of copper Cu 64 dotatate injection, the maximum radioactivity is observed in adrenal glands, kidney, pituitary glands, spleen, and liver.

'''Elimination'''

'''Metabolism'''

The metabolism of copper Cu 64 dotatate is unknown.

'''Excretion'''

Following a single intravenous dose (4.15 ± 0.13 mCi) of Detectnet (n = 6), between 16% to 40% radioactivity of the injected dose was recovered in urine over a 6-hour collection time.

'''Specific Populations'''

The effect of hepatic impairment or renal impairment on copper Cu 64 dotatate pharmacokinetics has not been studied.
|nonClinToxic=Carcinogenicity and mutagenicity studies have not been conducted with copper Cu 64 dotatate injection; however, radiation is a carcinogen and mutagen.

No animal studies were conducted to determine the effects of copper Cu 64 dotatate on fertility or embryology.
|clinicalStudies=The efficacy of Detectnet was established in two single-center, open-label studies. Study 1 prospectively evaluated a total of 63 subjects, including 42 patients with known or suspected NET based on histology, conventional imaging, or clinical evaluations and 21 healthy volunteers. Of the 42 patients, 37 (88%) had a history of NETs at the time of Detectnet imaging. Among the total study population of 63 subjects, 28 (44%) were men and 35 (56%) were women with most subjects being white (86%). The mean age of the subjects was 54 years (range 25 to 82 years).

Detectnet images from each subject were interpreted as either positive or negative for NET by three independent readers who were blinded to clinical information and other imaging results. PET imaging results were compared to a composite reference standard consisting of a single oncologist’s blinded assessment of subject diagnosis based on available histopathology results, reports of conventional imaging (MRI, contrast CT, bone scintigraphy, F 18 fludeoxyglucose PET/CT, F 18 sodium fluoride PET/CT, In 111 pentetreotide SPECT/CT, Ga 68 dotatate PET/CT) performed within 8 weeks prior to Detectnet imaging, and clinical and laboratory data including chromogranin A and serotonin levels. The proportion of subjects positive for disease per composite reference who were identified as positive by Detectnet imaging was used to quantify positive percent agreement. The proportion of subjects without disease per composite reference who were identified as negative by Detectnet imaging was used to quantify negative percent agreement. Table 5 shows the performance of Detectnet in the detection of NET for Study 1.
|howSupplied=Detectnet (NDC 69945-064-01) is supplied as a sterile, clear, colorless to yellow solution in a 10 mL single-dose vial containing 148 MBq (4 mCi) (37 MBq (1 mCi) per mL) of copper Cu 64 dotatate at calibration date and time.

The sealed vial is contained in a shielded (lead) container for radiation protection. The product is shipped in a Type A package.

Discard unused portion from the single-patient use vial.
|storage=Store Detectnet in an upright position within the lead shielding to protect handlers from exposure to radiation.

Store Detectnet at controlled room temperature 20 °C to 25 °C (68 °F to 77 °F). Do not use and discard Detectnet 2 hours after the calibration date and time.

This radiopharmaceutical is for distribution and use by persons under license by the U.S. Nuclear Regulatory Commission or the relevant regulatory authority of an Agreement State. Store and dispose of Detectnet in compliance with the appropriate regulations of the government agency authorized to license the use of this radionuclide.
|fdaPatientInfo='''Radiation Risk'''

Advise patients to drink water to ensure adequate hydration prior to their PET study and recommend they drink and urinate as often as possible during the first hours following the administration of Detectnet, in order to reduce radiation exposure.

'''Pregnancy'''

Advise a pregnant woman of the potential risks of fetal exposure to radiation doses with Detectnet .

'''Lactation'''

Advise a lactating woman to interrupt breastfeeding for 12 hours after Detectnet administration in order to minimize radiation exposure to a breastfed infant.
|alcohol=Alcohol-Copper cu 64 dotatate injection interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=DETECTNET
}}

Pralsetinib

2025-04-29T21:13:57Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=pralsetinib |aOrAn=a |drugClass=RET receptor tyrosine kinase inhibitor |indicationType=treatment |indication=of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test. |adverseReactions=*Interstitial Lung Disease/Pneumonitis *Hypertension *Hepatotoxicity *Hemorrhagic Events *Tumor Lysis Syndrome *Risk of Im..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=pralsetinib
|aOrAn=a
|drugClass=RET receptor tyrosine kinase inhibitor
|indicationType=treatment
|indication=of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test.
|adverseReactions=*Interstitial Lung Disease/Pneumonitis
*Hypertension
*Hepatotoxicity
*Hemorrhagic Events
*Tumor Lysis Syndrome
*Risk of Impaired Wound Healing
*Embryo-Fetal Toxicity
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult='''Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer'''
GAVRETO is indicated for the treatment of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test.

'''RET Fusion-Positive Thyroid Cancer'''
GAVRETO is indicated for the treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

'''Dosage'''
The recommended dosage of GAVRETO is 400 mg orally once daily on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking GAVRETO)Continue treatment until disease progression or until unacceptable toxicity.

If a dose of GAVRETO is missed, it can be taken as soon as possible on the same day. Resume the regular daily dose schedule for GAVRETO the next day.

Do not take an additional dose if vomiting occurs after GAVRETO but continue with the next dose as scheduled.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Pralsetinib in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Pralsetinib in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Pralsetinib in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Pralsetinib in pediatric patients.
|contraindications=None
|warnings='''Interstitial Lung Disease/Pneumonitis'''
Severe, life-threatening, and fatal interstitial lung disease (ILD) / pneumonitis can occur in patients treated with GAVRETO. Pneumonitis occurred in 12% of patients who received GAVRETO, including 3.3% with Grade 3-4, and 0.2% with fatal reactions.

Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Withhold GAVRETO and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Withhold, reduce dose or permanently discontinue GAVRETO based on severity of confirmed ILD

'''Hypertension'''
Hypertension occurred in 35% of patients, including Grade 3 hypertension in 18% of patients. Overall, 8% had their dose interrupted and 4.8% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications.

Do not initiate GAVRETO in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating GAVRETO. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue GAVRETO based on the severity

'''Hepatoxicity'''
Serious hepatic adverse reactions occurred in 1.5% of patients treated with GAVRETO. Increased AST occurred in 49% of patients, including Grade 3 or 4 in 7% and increased ALT occurred in 37% of patients, including Grade 3 or 4 in 4.8%. The median time to first onset for increased AST was 15 days (range: 5 days to 2.5 years) and for increased ALT was 24 days (range: 7 days to 3.7 years).

Monitor AST and ALT prior to initiating GAVRETO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue GAVRETO based on severity.

'''Hemorrhagic Events'''
Serious, including fatal, hemorrhagic events can occur with GAVRETO. Grade ≥ 3 hemorrhagic events occurred in 4.1% of patients treated with GAVRETO including one patient with a fatal hemorrhagic event.

Permanently discontinue GAVRETO in patients with severe or life-threatening hemorrhage.

'''Tumor Lysis Syndrome'''
Cases of tumor lysis syndrome (TLS) have been reported in patients with medullary thyroid carcinoma receiving GAVRETO. Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated.

'''Risk of Impaired Wound Healing'''
Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, GAVRETO has the potential to adversely affect wound healing.

Withhold GAVRETO for at least 5 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of GAVRETO after resolution of wound healing complications has not been established.

'''Embryo-Fetal Toxicity'''
Based on findings from animal studies and its mechanism of action, GAVRETO can cause fetal harm when administered to a pregnant woman. Oral administration of pralsetinib to pregnant rats during the period of organogenesis resulted in malformations and embryolethality at maternal exposures below the human exposure at the clinical dose of 400 mg once daily.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with GAVRETO and for 2 weeks after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with GAVRETO and for 1 week after the last dose.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population in the WARNINGS AND PRECAUTIONS reflect exposure to GAVRETO as a single agent at 400 mg orally once daily in 540 patients in ARROW.
Among 540 patients who received GAVRETO, 71% were exposed for 6 months or longer and 57% were exposed for greater than one year. The most common adverse reactions (≥ 25%) were musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia, and cough. The most common Grade 3-4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased leukocytes, decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased calcium (corrected), decreased platelets, increased alkaline phosphatase, increased potassium, decreased potassium and increased bilirubin.
|drugInteractions='''Strong or Moderate CYP3A and/or P-gp Inhibitors'''
Concomitant use with a strong or moderate CYP3A inhibitor and/or a P-gp inhibitor increases pralsetinib exposure which may increase the risk of adverse reactions related to GAVRETO. Avoid coadministration of GAVRETO with a strong or moderate CYP3A and/or P-gp inhibitor. If coadministration with any of the above inhibitors cannot be avoided, reduce the GAVRETO dose

'''Strong or Moderate CYP3A Inducers'''
Concomitant use with a strong CYP3A inducer decreases pralsetinib exposure which may decrease efficacy of GAVRETO. Avoid concomitant use of GAVRETO with strong or moderate CYP3A inducers. If coadministration of GAVRETO with strong or moderate CYP3A inducers cannot be avoided, increase the GAVRETO dose
|useInLaborDelivery=Based on findings from animal studies and its mechanism of action, GAVRETO can cause fetal harm when administered to a pregnant woman. There are no available data on GAVRETO use in pregnant women to inform drug-associated risk. Oral administration of pralsetinib to pregnant rats during the period of organogenesis resulted in malformations and embryolethality at maternal exposures below the human exposure at the clinical dose of 400 mg once daily (see Data). Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
|useInNursing=There are no data on the presence of pralsetinib or its metabolites in human milk or their effects on either the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with GAVRETO and for 1 week after the last dose.
|useInPed=The safety and effectiveness of GAVRETO have been established in pediatric patients aged 12 years and older for RET fusion-positive thyroid cancer. Use of GAVRETO in this age group is supported by evidence from an adequate and well-controlled study of GAVRETO in adults with additional population pharmacokinetic data demonstrating that age and body weight had no clinically meaningful effect on the pharmacokinetics of pralsetinib, that the exposure of pralsetinib is expected to be similar between adults and pediatric patients age 12 years and older, and that the course of RET fusion-positive thyroid cancer is sufficiently similar in adults and pediatric patients to allow extrapolation of data in adults to pediatric patients
|useInGeri=Of the 540 patients in ARROW who received the recommended dose of GAVRETO at 400 mg once daily, 31% were 65 years or and over, while 7% were 75 years and over.

No overall differences in pharmacokinetics (PK), safety or effectiveness were observed between patients aged 65 years or older and younger patients.
|useInGender=Based on animal data, GAVRETO can cause embryolethality and malformations at doses resulting in exposures below the human exposure at the clinical dose of 400 mg daily.

'''Pregnancy Testing'''

Verify pregnancy status of females of reproductive potential prior to initiating GAVRETO.

'''Contraception'''

GAVRETO can cause fetal harm when administered to a pregnant woman.

'''Females'''

Advise females of reproductive potential to use effective non-hormonal contraception during treatment with GAVRETO and for 2 weeks after the last dose. GAVRETO may render hormonal contraceptives ineffective.

'''Males'''

Advise males with female partners of reproductive potential to use effective contraception during treatment with GAVRETO and for 1 week after the last dose.

'''Infertility'''

Based on histopathological findings in the reproductive tissues of male and female rats and a dedicated fertility study in which animals of both sexes were treated and mated to each other, GAVRETO may impair fertility .
|useInHepaticImpair=No dose adjustment is required for patients with mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 × ULN and any AST), moderate (total bilirubin > 1.5 to 3 × ULN and any AST) or severe hepatic impairment (total bilirubin > 3 × ULN and any AST)
|administration=The recommended dosage of GAVRETO is 400 mg orally once daily on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking GAVRETO)
|monitoring=Permanently discontinue GAVRETO in patients who are unable to tolerate 100 mg taken orally once daily.
|mechAction=Pralsetinib is a kinase inhibitor of wild-type RET and oncogenic RET fusions (CCDC6-RET) and mutations (RET V804L, RET V804M and RET M918T) with half maximal inhibitory concentrations (IC50s) less than 0.5 nM. In purified enzyme assays, pralsetinib inhibited DDR1, TRKC, FLT3, JAK1-2, TRKA, VEGFR2, PDGFRB, and FGFR1 at higher concentrations that were still clinically achievable at Cmax. In cellular assays, pralsetinib inhibited RET at approximately 14-, 40-, and 12-fold lower concentrations than VEGFR2, FGFR2, and JAK2, respectively.

Certain RET fusion proteins and activating point mutations can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to uncontrolled cell proliferation. Pralsetinib exhibited anti-tumor activity in cultured cells and animal tumor implantation models harboring oncogenic RET fusions or mutations including KIF5B-RET, CCDC6-RET, RET M918T, RET C634W, RET V804E, RET V804L and RET V804M. In addition, pralsetinib prolonged survival in mice implanted intracranially with tumor models expressing KIF5B-RET or CCDC6-RET.
|PD=Pralsetinib exposure-response relationships and the time course of pharmacodynamics response have not been fully characterized.

'''Cardiac Electrophysiology'''

The QT interval prolongation potential of pralsetinib was assessed in 34 patients with RET -altered solid tumors administered GAVRETO at the recommended dosage. No large mean increase in QTc (> 20 ms) was detected in the study.
|PK=At 400 mg GAVRETO once daily under fasting conditions, the steady state geometric mean [% coefficient of variation (CV%)] of maximum observed plasma concentration (Cmax) and area under the concentration-time curve (AUC0-24h) of pralsetinib was 2470 (55.1%) ng/mL and 36700 (66.3%) h∙ng/mL, respectively. Pralsetinib Cmax and AUC increased inconsistently over the dose range of 60 mg to 600 mg once daily (0.15 to 1.5 times the recommended dose). Pralsetinib plasma concentrations reached steady state by 3 to 5 days. The mean accumulation ratio was approximately 2-fold after once-daily repeated oral administration.

'''Absorption'''

The median time to peak concentration (Tmax) ranged from 2 to 4 hours following single doses of pralsetinib 60 mg to 600 mg.

''Food Effect'''

Following administration of a single dose of 200 mg GAVRETO with a high-fat meal, (approximately 800 to 1000 calories with 50 to 60% of calories from fat), the mean (90% CI) Cmax of pralsetinib was increased by 104% (65%, 153%), the mean (90% CI) AUC0-INF was increased by 122% (96%,152%), and the median Tmax was delayed from 4 to 8.5 hours, compared to the fasted state.

'''Distribution'''

The mean (CV%) apparent volume of distribution (Vd/F) of pralsetinib is 303 L (68%). Protein binding of pralsetinib is 97.1% and is independent of concentration. The blood-to-plasma ratio is 0.6 to 0.7.

'''Elimination'''

The mean (±standard deviation) plasma elimination half-life (T½) of pralsetinib is 15.7 hours (9.8) following single doses and 20 hours (11.7) following multiple doses of pralsetinib. The mean (CV%) apparent oral clearance (CL/F) of pralsetinib is 10.9 L/h (66%) at steady state.

'''Metabolism'''

Pralsetinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2, in vitro. Following a single oral dose of 310 mg of radiolabeled pralsetinib to healthy subjects, pralsetinib metabolites from oxidation and glucuronidation were detected as 5% or less.

'''Excretion'''

Approximately 73% (66% as unchanged) of the total administered radioactive dose [14C] pralsetinib was recovered in feces and 6% (4.8% as unchanged) was recovered in urine.

'''Specific Populations'''

No clinically significant differences in the PK of pralsetinib were observed based on age (19 to 87 years), sex, race (370 White, 22 Black, or 61 Asian), and body weight (32.1 to 128 kg). Mild and moderate renal impairment (CLcr 30 - 89 mL/min) had no effect on the exposure of pralsetinib. Pralsetinib has not been studied in patients with severe renal impairment (CLcr < 15 mL/min).

'''Patients with Hepatic Impairment'''

Mild (total bilirubin ≤ ULN and AST > ULN, or total bilirubin > 1 to 1.5 × ULN and any AST), moderate (total bilirubin > 1.5 to 3 × ULN and any AST) or severe (total bilirubin > 3 × ULN and any AST) hepatic impairment had no effect on the PK of pralsetinib. .

'''Drug Interaction Studies'''

Clinical Studies and Model-Informed Approach

CYP3A Inhibitors: Coadministration of multiple doses of CYP3A inhibitors increases pralsetinib Cmax and AUC.
|nonClinToxic='''Carcinogenesis, Mutagenesis, Impairment of Fertility'''
Carcinogenicity studies with pralsetinib have not been conducted. Pralsetinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay with or without metabolic activation and was not clastogenic in either an in vitro micronucleus assay in TK6 cells or an in vivo bone marrow micronucleus assay in rats.

In a dedicated fertility and early embryonic development study conducted in treated male rats mated to treated female rats, although pralsetinib did not have clear effects on male or female mating performance or ability to become pregnant, at the 20 mg/kg dose level (approximately 2.9 times the human exposure (AUC) at the clinical dose of 400 mg based on toxicokinetic data from the 13-week rat toxicology study) 82% of female rats had totally resorbed litters, with 92% post-implantation loss (early resorptions); post-implantation loss occurred at doses as low as 5 mg/kg (approximately 0.35 times the human exposure (AUC) at the clinical dose of 400 mg based on toxicokinetic data from the 13-week rat toxicology study). In a separate fertility and early embryonic development study in which male rats administered 20 mg/kg pralsetinib were mated to untreated female rats, there were no clear pralsetinib-related effects on intrauterine survival of embryos or on male reproductive performance at a dose approximately 1.7 times the human exposure (AUC) at the clinical dose of 400 mg. In a 13-week repeat-dose toxicology study, male rats exhibited histopathological evidence of tubular degeneration/atrophy in the testis with secondary cellular debris and reduced sperm in the lumen of the epididymis, which correlated with lower mean testis and epididymis weights and gross observations of soft and small testis. Female rats exhibited degeneration of the corpus luteum in the ovary. For both sexes, these effects were observed at pralsetinib doses ≥ 10 mg/kg/day, approximately 1 times the human exposure based on AUC at the clinical dose of 400 mg.

'''Animal Toxicology and/or Pharmacology'''
In 28-day rat and monkey toxicology studies, once daily oral administration of pralsetinib resulted in histologic necrosis and hemorrhage in the heart of preterm decedents at exposures ≥ 1.3 times and ≥ 3.1 times, respectively, the human exposure based on AUC at the clinical dose of 400 mg. Pralsetinib induced hyperphosphatemia (rats) and multi-organ mineralization (rats and monkeys) in 13-week toxicology studies at exposures approximately 2.8 times and ≥ 0.13 times, respectively, the human exposure based on AUC at the clinical dose of 400 mg.
|clinicalStudies='''Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer'''
The efficacy of GAVRETO was evaluated in patients with RET fusion-positive metastatic NSCLC in a multicenter, non-randomized, open-label, multi-cohort clinical trial (ARROW, NCT03037385). The study enrolled, in separate cohorts, patients with metastatic RET fusion-positive NSCLC who had progressed on platinum-based chemotherapy and treatment-naïve patients with metastatic NSCLC. Identification of a RET gene fusion was determined by local laboratories using next generation sequencing (NGS), fluorescence in situ hybridization (FISH), and other tests. Among the 237 patients in the efficacy population(s) described in this section, samples from 40% of patients were retrospectively tested with the Life Technologies Corporation Oncomine Dx Target Test (ODxTT). Patients with asymptomatic central nervous system (CNS) metastases, including patients with stable or decreasing steroid use within 2 weeks prior to study entry, were enrolled. Patients received GAVRETO 400 mg orally once daily until disease progression or unacceptable toxicity.

The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), as assessed by a blinded independent central review (BICR) according to RECIST v1.1.

'''RET Fusion-Positive Thyroid Cancer'''
The efficacy of GAVRETO was evaluated in RET fusion-positive metastatic thyroid cancer patients in a multicenter, open-label, multi-cohort clinical trial (ARROW, NCT03037385). All patients with RET fusion-positive thyroid cancer were required to have disease progression following standard therapy, measurable disease by RECIST version 1.1, and have RET fusion status as detected by local testing (89% NGS tumor samples and 11% using FISH).

The median age was 61 years (range: 46 to 74); 67% were male, 78% were White, 22% were Asian, 11% were Hispanic/Latino. All patients (100%) had papillary thyroid cancer. ECOG performance status was 0-1 (100%), all patients (100%) had metastatic disease, and 56% had a history of CNS metastases. Patients had received a median of 2 prior therapies (range 1-8). Prior systemic treatments included prior radioactive iodine (100%) and prior sorafenib and/or lenvatinib (56%).
|howSupplied=GAVRETO (pralsetinib) 100 mg, light blue, opaque, immediate release, hydroxypropyl methylcellulose (HPMC) hard capsule printed with "BLU-667" on the capsule shell body and "100 mg" on the capsule shell cap are supplied as follows:

*Bottles of 60 capsules (NDC 50242-210-60).
*Bottles of 90 capsules (NDC 50242-210-90).
*Bottles of 120 capsules (NDC 50242-210-12).
|storage=Store at 20°C to 25°C (68°F to 77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from moisture.
|fdaPatientInfo=Advise the patient to read the FDA-approved patient labeling (Patient Information).

'''ILD/Pneumonitis'''

Advise patients to contact their healthcare provider if they experience new or worsening respiratory symptoms

'''Hypertension'''

Advise patients that they will require regular blood pressure monitoring and to contact their healthcare provider if they experience symptoms of increased blood pressure or elevated readings.

'''Hepatotoxicity'''

Advise patients that hepatotoxicity can occur and to immediately contact their healthcare provider for signs or symptoms of hepatotoxicity.

'''Hemorrhagic Events'''

Advise patients that GAVRETO may increase the risk for bleeding and to contact their healthcare provider if they experience any signs or symptoms of bleeding.

'''Tumor Lysis Syndrome'''

Advise patients to contact their healthcare provider promptly to report any signs and symptoms of TLS.

'''Risk of Impaired Wound Healing'''

Advise patients that GAVRETO may impair wound healing. Advise patients that temporary interruption of GAVRETO is recommended prior to any elective surgery.

'''Embryo-Fetal Toxicity'''

Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.

Advise females of reproductive potential to use effective non-hormonal contraception during the treatment with GAVRETO and for 2 weeks after the last dose.

Advise males with female partners of reproductive potential to use effective contraception during treatment with GAVRETO and for 1 week after the last dose.

'''Lactation'''

Advise women not to breastfeed during treatment with GAVRETO and for 1 week after the last dose.

'''Infertility'''

Advise males and females of reproductive potential that GAVRETO may impair fertility.

'''Drug Interactions'''

Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products.

'''Administration'''

Advise patients to take GAVRETO on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking GAVRETO).
|alcohol=Alcohol-Pralsetinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=GAVRETO
}}

Atoltivimab, maftivimab, and odesivimab-ebgn

2025-04-29T20:54:34Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=atoltivimab, maftivimab, and odesivimab-ebgn |aOrAn=a |drugClass=fixed-dose combination of three monoclonal antibodies |indicationType=treatment |indication=of infection caused by Orthoebolavirus zairense in adult and pediatric patients, including neonates born to a mother who is RT-PCR positive for Orthoebolavirus zairense infection |adverseReactions=Hypersensitivity Reactions Inc..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=atoltivimab, maftivimab, and odesivimab-ebgn
|aOrAn=a
|drugClass=fixed-dose combination of three monoclonal antibodies
|indicationType=treatment
|indication=of infection caused by Orthoebolavirus zairense in adult and pediatric patients, including neonates born to a mother who is RT-PCR positive for Orthoebolavirus zairense infection
|adverseReactions=Hypersensitivity Reactions Including Infusion-Associated Events
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=INMAZEB is indicated for the treatment of infection caused by Orthoebolavirus zairense in adult and pediatric patients, including neonates born to a mother who is RT-PCR positive for Orthoebolavirus zairense infection

'''DOSAGE'''
INMAZEB is a combination of three human monoclonal antibodies co-formulated in a 1:1:1 ratio of atoltivimab, maftivimab, and odesivimab. INMAZEB is available as two different strength presentations, containing either 16.67 mg of each antibody per mL or 33.33 mg of each antibody per mL

The recommended dosage of INMAZEB is 50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg diluted and administered as a single intravenous infusion
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Atoltivimab, maftivimab, and odesivimab-ebgn in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Atoltivimab, maftivimab, and odesivimab-ebgn in adult patients.
|fdaLIADPed=Same as adult version.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Atoltivimab, maftivimab, and odesivimab-ebgn in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Atoltivimab, maftivimab, and odesivimab-ebgn in pediatric patients.
|contraindications=None
|warnings='''Hypersensitivity Reactions Including Infusion-Associated Events'''
Hypersensitivity reactions including infusion-associated events have been reported during and post-infusion with INMAZEB. These may include acute, life-threatening reactions during and after the infusion. Monitor all patients for signs and symptoms including, but not limited to, hypotension, chills and elevation of fever, during and following INMAZEB infusion. In the case of severe or life-threatening hypersensitivity reactions, discontinue the administration of INMAZEB immediately and administer appropriate emergency care

Infusion could not be completed in 1% of subjects who received INMAZEB due to infusion-associated adverse events. The rate of infusion of INMAZEB may be slowed or interrupted if the patient develops any signs of infusion-associated events or other adverse events
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates may not reflect the rates observed in practice.

Overall, 382 adult and pediatric subjects with Orthoebolavirus zairense infection received INMAZEB in one clinical trial (the PALM trial) and as part of an expanded access program conducted in the Democratic Republic of Congo during a Orthoebolavirus zairense outbreak in 2018-2019. In the PALM trial, the safety of INMAZEB was evaluated in a multi-center, open-label, randomized controlled trial, in which 154 subjects (115 adult subjects and 39 pediatric subjects) received INMAZEB [50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg (3 mL/kg)] intravenously as a single infusion and 168 subjects received an investigational control. All subjects received optimized standard of care treatment. During the same outbreak, INMAZEB [50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg (3 mL/kg)] was given to 228 subjects (190 adult subjects and 38 pediatric subjects) in the expanded access program.

The safety data described below is derived from the PALM trial.
|drugInteractions=No vaccine-therapeutic interaction studies have been performed in human subjects using INMAZEB. However, because of the potential for INMAZEB to inhibit replication of a live vaccine virus indicated for prevention of Orthoebolavirus zairense infection and possibly reduce the efficacy of the vaccine, avoid the concurrent administration of a live vaccine during treatment with INMAZEB. The interval between live vaccination following initiation of INMAZEB therapy should be in accordance with current vaccination guidelines. The efficacy of INMAZEB among subjects who reported receipt of a recombinant live vaccine prior to their enrollment in the PALM clinical trial was similar to subjects who did not receive a vaccine.
|useInLaborDelivery=Orthoebolavirus zairense infection is life-threatening for both the mother and fetus and treatment should not be withheld due to pregnancy. Available data from the PALM trial and an expanded access program in which pregnant women with Orthoebolavirus zairense infection were treated with INMAZEB demonstrate the high rate of maternal and fetal/neonatal morbidity consistent with published literature regarding the risk associated with underlying maternal Orthoebolavirus zairense infection. These data are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal/fetal outcome. Animal reproduction studies with INMAZEB have not been conducted. Human monoclonal antibodies, such as INMAZEB, are transported across the placenta; therefore, INMAZEB has the potential to be transferred from the mother to the developing fetus.
|useInNursing=The Centers for Disease Control and Prevention recommend that patients with confirmed Orthoebolavirus zairense not breastfeed their infants to reduce the risk of postnatal transmission of Orthoebolavirus zairense infection.

There are no data on the presence of atoltivimab, maftivimab, and odesivimab-ebgn in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to atoltivimab, maftivimab, or odesivimab-ebgn are unknown.
|useInPed=The safety and effectiveness of INMAZEB for the treatment of infection caused by Orthoebolavirus zairense have been established in pediatric patients from birth to less than 18 years of age. Use of INMAZEB for this indication is supported by evidence from a multi-center, open label, randomized controlled trial of INMAZEB in adults and pediatric subjects that included 39 pediatric subjects birth to less than 18 years of age, including neonates born to a mother who is RT-PCR positive for Orthoebolavirus zairense infection. The 28-day mortality and safety in adult and pediatric subjects treated with INMAZEB were similar. An additional 38 pediatric subjects from birth to less than 18 years of age received INMAZEB in an expanded access program.
|useInGeri=Clinical studies of INMAZEB did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 154 subjects with Orthoebolavirus zairense infection who received INMAZEB in the randomized controlled trial, 5 (3.2%) were 65 years or older. The limited clinical experience has not identified differences in responses between the elderly and younger subjects.
|administration=INMAZEB must be prepared and administered under the supervision of a healthcare provider. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. INMAZEB should be clear to slightly opalescent, colorless to pale yellow solution that is free from visible particulates. Discard the vial if the solution is cloudy, discolored or contains particulate matter.
|monitoring=Monitor all patients for signs and symptoms including, but not limited to, hypotension, chills and elevation of fever, during and following INMAZEB infusion. In the case of severe or life-threatening hypersensitivity reactions, discontinue the administration of INMAZEB immediately and administer appropriate emergency care
|IVCompat=Preparation for Intravenous Infusion:

*The recommended dosage is based on 50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg. For example, a patient weighing 50 kg the recommended dosage is 2,500 mg of atoltivimab, 2,500 mg of maftivimab, and 2,500 mg of odesivimab.

*Determine the number of vials needed based on the calculated dose in volume (mL).
–The number of vials needed depends on the INMAZEB strength used. Refer to Table 1 for the corresponding volume per kg needed to withdraw from each available strength presentation to prepare dose.
–Multiple INMAZEB vials may be needed. Each vial contains 14.5 mL of INMAZEB solution, regardless of the strength presentation. For example, for a 50 kg patient, the volume of INMAZEB needed is 150 mL (11 vials) if using the 16.67 mg/16.67 mg/16.67 mg per mL solution or 75 mL (6 vials) if using the 33.33 mg/33.33 mg/33.33 mg per mL solution.
|mechAction=INMAZEB is an antiviral drug combination of three recombinant human IgG1κ monoclonal antibodies (atoltivimab, maftivimab, and odesivimab) that inhibit Orthoebolavirus zairense
|PD=Atoltivimab, maftivimab, and odesivimab exposure-response relationships and the time course of pharmacodynamic response are unknown.
|PK=No pharmacokinetic data are available in patients with Orthoebolavirus zairense infection. The pharmacokinetics of atoltivimab, maftivimab, and odesivimab in 18 healthy subjects 21 to 60 years of age are linear and dose-proportional over the range of 1 mg of atoltivimab, 1 mg of maftivimab, and 1 mg of odesivimab per kg to 50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg (0.02 to 1 times the approved recommended dosage) of INMAZEB following a single intravenous (IV) infusion. Pharmacokinetic parameters for the individual antibodies of INMAZEB
|nonClinToxic=Carcinogenicity, genotoxicity, and fertility studies have not been conducted with INMAZEB.
|clinicalStudies=The efficacy of INMAZEB was evaluated in PALM, a multi-center, open-label, randomized controlled trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID; NCT03719586). The trial was conducted in the Democratic Republic of Congo, where an outbreak began in August 2018, and enrolled 681 subjects of all ages, including pregnant women, with documented Orthoebolavirus zairense infection and symptoms of any duration who were receiving optimized standard of care (oSOC). Subjects were randomized to receive INMAZEB (50 mg of atoltivimab, 50 mg of maftivimab, and 50 mg of odesivimab per kg) intravenously as a single infusion, an investigational control 50 mg/kg intravenously every third day, for a total of 3 doses, or other investigational drugs. Eligible subjects had a positive reverse transcriptase-polymerase chain reaction (RT-PCR) for the nucleoprotein (NP) gene of Orthoebolavirus zairense and had not received other investigational treatments (with the exception of experimental vaccines) within the previous 30 days. Neonates ≤7 days of age were eligible if the mother had documented infection. Neonates born to a mother who had cleared Orthoebolavirus zairense following a course of her assigned investigational medication were also eligible to be enrolled at investigator discretion regarding the likelihood that the neonate was infected. Randomization was stratified by reverse transcription-PCR cycle threshold calculated using NP targets (CtNP ≤22.0 vs >22.0; corresponding to high and low viral load, respectively) and Ebola Treatment Unit (ETU) site. All subjects received oSOC consisting of a minimum of intravenous fluids, daily clinical laboratory testing, correction of hypoglycemia and electrolyte imbalances, and broad-spectrum antibiotics and antimalarials, as indicated.

The primary efficacy endpoint was 28-day mortality. The primary analysis population includes all subjects who were randomized and concurrently eligible to receive either INMAZEB or the investigational control during the same time period of the trial.
|howSupplied=INMAZEB (atoltivimab, maftivimab, and odesivimab-ebgn) injection is a clear to slightly opalescent and colorless to pale yellow solution. It is supplied in a carton containing one single dose vial of:

*241.7 mg of atoltivimab, 241.7 mg of maftivimab, and 241.7 mg of odesivimab per 14.5 mL (16.67 mg/16.67 mg/16.67 mg per mL) (NDC 61755-018-01)
*483.3 mg of atoltivimab, 483.3 mg of maftivimab, and 483.3 mg of odesivimab per 14.5 mL (33.33 mg/33.33 mg/33.33 mg per mL) (NDC 61755-019-01)
|storage=Store INMAZEB vial refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze or shake.
|fdaPatientInfo='''Hypersensitivity Reactions Including Infusion-Associated Events'''
Inform patients that hypersensitivity reactions including infusion-associated events have been reported during and post-infusion with INMAZEB and to immediately report if they experience any symptoms of systemic hypersensitivity reactions

'''Lactation'''
Instruct patients with Orthoebolavirus zairense infection not to breastfeed because of the risk of passing Orthoebolavirus zairense to the baby
|alcohol=Alcohol-Atoltivimab, maftivimab, and odesivimab-ebgn interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=INMAZEB
}}

Lonafarnib b

2025-04-29T20:42:40Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=lonafarnib |aOrAn=a |drugClass=direct farnesyl transferase inhibitor |indication=ZOKINVY is indicated in patients 12 months of age and older with a body surface area (BSA) of 0.39 m2 and above: *To reduce the risk of mortality in Hutchinson-Gilford Progeria Syndrome (HGPS) *For the treatment of processing-deficient Progeroid Laminopathies with either: - Heterozygous LMNA mut..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=lonafarnib
|aOrAn=a
|drugClass=direct farnesyl transferase inhibitor
|indication=ZOKINVY is indicated in patients 12 months of age and older with a body surface area (BSA) of 0.39 m2 and above:

*To reduce the risk of mortality in Hutchinson-Gilford Progeria Syndrome (HGPS)

*For the treatment of processing-deficient Progeroid Laminopathies with either:
- Heterozygous LMNA mutation with progerin-like protein accumulation
- Homozygous or compound heterozygous ZMPSTE24 mutations
|adverseReactions=Vomiting, Diarrhea, Nausea, Abdominal Pain, Constipation, Fatigue, Infection,
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=ZOKINVY is indicated in patients 12 months of age and older with a body surface area (BSA) of 0.39 m2 and above:

*To reduce the risk of mortality in Hutchinson-Gilford Progeria Syndrome (HGPS)

*For the treatment of processing-deficient Progeroid Laminopathies with either:
- Heterozygous LMNA mutation with progerin-like protein accumulation
- Homozygous or compound heterozygous ZMPSTE24 mutations
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Lonafarnib b in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Lonafarnib b in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Lonafarnib b in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Lonafarnib b in pediatric patients.
|contraindications=ZOKINVY is contraindicated in patients taking:
*Strong CYP3A inhibitors
*Strong or moderate CYP3A inducers
*Midazolam
*Lovastatin, simvastatin, or atorvastatin
|warnings='''QTc Interval Prolongation'''
ZOKINVY prolongs the QTc interval. Prolongation of the QTc interval increases the risk of Torsade de pointes, other serious arrhythmias, and sudden death.

Avoid use of ZOKINVY in patients with a history of cardiac arrhythmias, as well as in other circumstances that may increase the risk of the occurrence of Torsade de pointes or sudden death, including symptomatic bradycardia, hypokalemia, or hypomagnesemia. Avoid use of ZOKINVY in combination with other drugs known or suspected to prolong the QTc interval.

Monitor ECGs prior to initiating ZOKINVY, during treatment, and as clinically indicated. If QTc interval is greater than 500 msec, withhold ZOKINVY until QTc interval is less than 470 msec, then resume ZOKINVY at same dosage.

Obtain serum electrolytes prior to initiating ZOKIVNY and during treatment as clinically indicated. Correct serum electrolyte abnormalities.

'''Risk of Reduced Efficacy or Adverse Reactions Due to Drug Interactions'''
Coadministration of ZOKINVY with other drugs may result in clinically significant drug interactions.These drug interactions can lead to:
*Reduced efficacy of ZOKINVY
*Increased risk of adverse reactions from ZOKINVY or co-administered drugs

'''Laboratory Abnormalities'''
Some patients treated with ZOKINVY developed laboratory abnormalities

These included:
*Electrolyte abnormalities (43%), such as hyperkalemia, hypokalemia, hyponatremia, or hypercalcemia

*Myelosuppression (35%), such as reductions in absolute neutrophil count, white blood cell counts, lymphocytes, hemoglobin, or hematocrit

*Increased liver enzymes, such as aspartate aminotransferase (35%), or alanine aminotransferase (27%)

These laboratory abnormalities often improved while continuing ZOKINVY, but it is not possible to exclude ZOKINVY as a cause of the abnormalities. Periodically monitor electrolytes, complete blood counts, and liver enzymes, and manage abnormalities accordingly.

'''Nephrotoxicity'''
Lonafarnib caused nephrotoxicity in rats at plasma drug exposures approximately equal to that achieved with the human dose. Monitor renal function at regular intervals during ZOKINVY therapy.

'''Retinal Toxicity'''
Lonafarnib caused rod-dependent, low-light vision decline in monkeys at plasma drug exposures similar to that achieved with the human dose. Perform ophthalmological evaluation at regular intervals and at the onset of any new visual changes during ZOKINVY therapy.

'''Impaired Fertility'''
Lonafarnib caused impaired fertility in female rats at 1.2 times the human dose based on plasma drug exposure.

Lonafarnib caused impaired fertility and testicular toxicity in male rats at 1.5 times the human dose based on plasma drug exposureand toxicity in the male reproductive tract in monkeys at doses lower than the human dose based on plasma drug exposure.

Advise females and males of reproductive potential of the animal fertility findings, and that the impact on pubertal development and the potential for impaired fertility with ZOKINVY therapy in humans have not been adequately evaluated

'''Embryo-Fetal Toxicity'''
Based on findings from animal reproduction studies, ZOKINVY can cause embryo-fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of lonafarnib in pregnant rats during organogenesis produced embryo-fetal toxicity at plasma drug exposures that were approximately equal to the recommended human dose. In pregnant rabbits, oral administration of lonafarnib during organogenesis produced skeletal malformations and variations at exposures lower than the human exposure. Advise pregnant women of the risk to a fetus. Advise females of reproductive potential to avoid becoming pregnant and to use appropriate effective contraception during treatment with ZOKINVY
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 84 subjects were treated with at least one dose of ZOKINVY with or without additional therapy, of which 8 were treated at a dosage of at least 115 mg/m2 twice daily for greater than or equal to 10 years.

The safety profile of ZOKINVY is based on 128 patient-years of treatment exposure (62 patients with HGPS and 1 patient with processing-deficient Progeroid Laminopathy with LMNA heterozygous mutation) and pooled results from two Phase 2 open-label, single-arm trials (n=63: 28 patients from Study 1 and 35 treatment naïve patients from Study 2). In Study 1, ZOKINVY treatment was initiated at 115 mg/m2 twice daily and increased to 150 mg/m2 twice daily after approximately 4 months for a total treatment duration of 24 to 30 months. Treatment naïve patients in Study 2 received ZOKINVY 150 mg/m2 twice daily for up to 36 months. In both studies, ZOKINVY was administered orally via capsules or the capsule contents were mixed with Ora Blend SF or Ora-Plus and administered orally as a suspension.

In these two studies, a total of 63 patients received ZOKINVY for a median duration of 2.2 years, with approximately 1.9 years at the recommended dose of 150 mg/m2 twice daily. The population was 2 to 17 years old, with a similar proportion of males (33 [52%] patients) and females (30 [48%] patients). Most patients had classic HGPS (60 [95%] patients) compared to non-classic HGPS (2 [3%] patients) and 1 (2%) patient had Progeroid Laminopathy with LMNA heterozygous mutation.
|drugInteractions='''Risk of Reduced Efficacy or Adverse Reactions Due to Drug Interactions'''
Coadministration of ZOKINVY with other drugs may result in clinically significant drug interactions.These drug interactions can lead to:
*Reduced efficacy of ZOKINVY
*Increased risk of adverse reactions from ZOKINVY or co-administered drugs
|useInLaborDelivery=Based on findings from animal studies, ZOKINVY can cause embryofetal harm when administered to a pregnant woman. There are no human data on ZOKINVY use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Advise pregnant women of the risk to a fetus.

In animal reproduction studies, oral administration of lonafarnib to pregnant rats during organogenesis produced embryo-fetal toxicity at exposures that were 1.2-times the human exposure at the recommended dose of 150 mg/m2 twice daily. In pregnant rabbits, oral administration of lonafarnib during organogenesis produced skeletal malformations and variations at exposures lower than the human exposure at 150 mg/m2 twice daily, and maternal toxicity at 26 times the human exposure at 150 mg/m2 twice daily.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
|useInNursing=There are no data on the presence of ZOKINVY in human milk, the effects on the breastfed infant, or the effects on milk production. Lonafarnib is excreted in rat milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZOKINVY and any potential adverse effects of the breastfed infant from ZOKINVY or from the underlying maternal condition.
|useInPed=The safety and effectiveness of ZOKINVY for the treatment of HGPS and processing-deficient Progeroid Laminopathies (with either heterozygous LMNA mutation with progerin-like protein accumulation or homozygous or compound heterozygous ZMPSTE24 mutations) have been established in pediatric patients 12 months of age and older. Use of ZOKINVY for these indications is supported by adequate and well-controlled studies in pediatric patients 2 years of age and older. The safety and effectiveness of ZOKINVY in pediatric patients less than 12 months of age have not been established.
|useInGender='''Female'''
'''Contraception'''
ZOKINVY can cause embryo-fetal harm when administered to pregnant women. Advise females of reproductive potential to use appropriate effective contraception during treatment with ZOKINVY.

'''Infertility'''
Based on findings in rats, ZOKINVY may reduce fertility in females and males of reproductive potential
|othersTitle=Adult Use
|useInOthers=The safety and effectiveness of ZOKINVY for the treatment of HGPS and processing-deficient Progeroid Laminopathies (with either heterozygous LMNA mutation with progerin-like protein accumulation or homozygous or compound heterozygous ZMPSTE24 mutations) have been established in adults. Use of ZOKINVY in adults for these indications is based on adequate and well-controlled studies in pediatric patients 2 years of age and older
|administration=Administer ZOKINVY orally with the morning and evening meals.

'''Patients Able to Swallow Capsules'''
Administer ZOKINVY capsules whole with a sufficient amount of water. Do not chew the capsules.

'''Patients Unable to Swallow Capsules'''
*The entire contents of ZOKINVY capsules can be mixed with Ora Blend SF® or Ora-Plus® or, for patients unable to access or tolerate Ora Blend SF or Ora-Plus, the contents of ZOKINVY capsules can be mixed with orange juice or applesauce

*Do not mix with juice containing grapefruit or Seville oranges

*The mixture must be prepared fresh for each dose and be taken within approximately 10 minutes of mixing.
|monitoring=*Withhold ZOKINVY until QTc interval is less than 470 msec, then resume ZOKINVY at same dosage.
Monitor electrocardiograms (ECGs) prior to initiating ZOKINVY, during treatment, and as clinically indicated.

*For patients who have increased their dose of ZOKINVY to 150 mg/m2 twice daily and are experiencing repeated episodes of vomiting and/or diarrhea resulting in dehydration or weight loss. The dose of ZOKINVY can be reduced to the starting dose of 115 mg/m2 twice daily

*When initiating ZOKINVY in a patient who is concurrently on a moderate CYP3A inhibitor. The patient may be at increased risk of adverse reactions.
Monitor the patient closely for adverse reactions for at least the first 7 days after initiating ZOKINVY.
If the patient experiences an adverse reaction during the first 7 days of the starting dose or thereafter, consider an alternative therapy that is not a moderate CYP3A inhibitor.
|mechAction=Lonafarnib inhibits farnesyltransferase to prevent farnesylation and subsequent accumulation of progerin and progerin-like proteins in the inner nuclear membrane.
|PD='''Cardiac Electrophysiology'''
The effect of lonafarnib on the QTc interval was evaluated in a randomized, double-blind, placebo- and positive-controlled (moxifloxacin 400 mg single dose), multiple-dose, QTc study in 64 healthy subjects. Subjects received 200 mg lonafarnib twice daily for 9 consecutive days and a single 200 mg dose in the morning on Day 10, with food.

The largest mean increase in QTc interval was 19 msec (upper bound of 90% confidence interval = 27 msec) on Day 10 at 48 hours after administration of the morning dose of lonafarnib 200 mg. The Cmax on Day 10 was 2233 ng/mL, which is similar to the mean Cmax of 2695 ng/mL observed in the HGPS patient population.
|PK='''Absorption'''
The absolute bioavailability of lonafarnib following oral administration has not been determined. Following oral administration of lonafarnib 75 mg and 100 mg twice daily in healthy subjects under fasted conditions, the geometric mean (CV%) maximum peak plasma concentrations of lonafarnib were 834 (32%) ng/mL and 964 (32%) ng/mL, respectively.

'''Distribution'''
In vitro plasma protein binding of lonafarnib was greater than or equal to 99% over the concentration range between 0.5 to 40.0 μg/mL. The apparent volumes of distribution were 87.8 L and 97.4 L, respectively, at steady state following oral administration of lonafarnib 100 mg and 75 mg twice daily in healthy subjects.

'''Elimination'''
The mean half-life was approximately 4 to 6 hours following oral administration of lonafarnib 100 mg twice daily in healthy subjects.
|nonClinToxic=Nonclinical toxi:
'''Carcinogenesis'''
Carcinogenicity studies have not been conducted with lonafarnib.

'''Mutagenesis'''
Lonafarnib was not genotoxic in the bacterial mutagenicity (Ames) assay, in vitro chromosomal aberration assay in mammalian cells, or in vivo micronucleus assay in mice.

'''Impairment of Fertility'''
Lonafarnib produced impaired fertility in male rats at 90 mg/kg/day or higher (1.5 times the AUC in humans at the recommended dose of 150 mg/m2 twice daily), with a nearly complete loss of fertility at 180 mg/kg/day (3 times the AUC in humans). Male rats treated with 180 mg/kg/day exhibited small testes, flaccid testes, and discolored epididymis (84%, 56%, and 24% of males, respectively). No effects on fertility occurred in males at systemic exposures lower than the human AUC at 150 mg/m2 twice daily.

Female rats treated with 30 mg/kg/day lonafarnib or higher (1.2 times the human AUC at the recommended human dose of 150 mg/m2 twice daily) showed a decrease in fertility, as indicated by reductions in the number of corpora lutea and implantation sites and increases in pre- and post-implantation loss. No effects on fertility occurred in females at systemic exposures lower than the human AUC at 150 mg/m2 twice daily
|clinicalStudies=The efficacy of ZOKINVY is based on results from the Observational Cohort Survival Study, which retrospectively compared survival data from two Phase 2 studies in patients with HGPS to those from a natural history cohort.

Study 1 (NCT00425607) was a Phase 2 open-label, single-arm trial that evaluated the efficacy of ZOKINVY in 28 patients (26 with classic HGPS, one with non-classic HGPS, and one with Progeroid Laminopathy with LMNA heterozygous mutation with progerin-like protein accumulation). Patients received ZOKINVY for 24 to 30 months. Patients initiated treatment with ZOKINVY 115 mg/m2 twice daily. After 4 months of treatment, patients who tolerated treatment had an increase in dose to 150 mg/m2 twice daily. Among the 28 patients treated, 27 patients with HGPS (16 females, 11 males) were included in the survival assessment. The median age at treatment initiation for the 27 patients was 7.5 years (range: 3 to 16 years). The body weight range was 6.6 to 17.6 kg and the BSA range was 0.38 to 0.75 m2 (ZOKINVY is not indicated in patients with a BSA less than 0.39 m2 because the appropriate dosage strength is not available for this population).

Following completion of Study 1, 26 patients enrolled in a second Phase 2 open label, single-arm trial (Study 2, NCT00916747) which consisted of two study phases. In the first phase of Study 2, patients received ZOKINVY with additional therapies for about 5 years. In the second phase of Study 2, patients received ZOKINVY 150 mg/m2 twice daily for a period of up to 3 years.

There were 35 treatment naïve patients with HGPS enrolled into the second phase of Study 2. Among the 35 treated patients (22 males, 13 females), 34 (97.1%) patients had classic HGPS and 1 (2.9%) patient had non-classic HGPS. The median age was 6 years (range: 2 to 17 years). The body weight range was 6.7 to 22 kg and the BSA range was 0.42 to 0.90 m2.

Throughout Study 1 and Study 2, ZOKINVY was administered orally via capsules or the capsule contents were mixed with Ora Blend SF or Ora-Plus and administered orally as a suspension.
The retrospective survival analysis was based on the mortality data from 62 treated patients (27 patients in Study 1 and 35 treatment-naïve patients in Study 2) and data from matched, untreated patients in a separate natural history cohort. The lifespan of HGPS patients treated with ZOKINVY increased by an average of 3 months through the first three years of follow-up and 2.5 years through the last follow-up time (11 years) compared to untreated patients.
|howSupplied=ZOKINVY is supplied as:
*50 mg capsules: Size 4 hard capsule, opaque yellow with “LNF” and “50” printed in black.
Bottles of 30 capsules each (NDC 73079-050-30)
*75 mg capsules: Size 3 hard capsule, opaque light orange with “LNF and “75” printed in black.
Bottles of 30 capsules each (NDC 73079-075-30)
|storage=Store at 20°C-25°C (68°F-77°F), excursions permitted to 15°C-30ºC (59°F-86°F)
|fdaPatientInfo='''Dosing'''

* Advise patients and caregivers that ZOKINVY should be taken twice daily with the morning and evening meals.
*Inform patients and caregivers that if a dose is missed, the next dose should be given as soon as possible up to 8 hours prior to the next scheduled dose. If less than 8 hours remain before the next scheduled dose, the patient should skip the missed dose and resume taking ZOKINVY at the next scheduled dose.

'''Preparation and Administration'''

*Advise patients to swallow the capsule whole with water. The capsules should not be chewed.
For patients unable to swallow capsules, advise patients and caregivers that the contents of ZOKINVY can be mixed with Ora Blend SF or Ora-Plus. *For patients unable to access or tolerate Ora Blend SF or Ora-Plus, the contents of ZOKINVY can be mixed with orange juice or applesauce. Advise patients not to mix the contents of ZOKINVY with juice containing grapefruit or Seville oranges. Advise patients and caregivers that the mixture must be prepared fresh for each dose and taken within approximately 10 minutes of mixing.
*Advise patients and caregivers to read and carefully follow the instructions for administering the capsule contents in Ora Blend SF, Ora-Plus, orange juice or applesauce

'''QTc Interval Prolongation'''
*Inform patients and caregivers that ZOKINVY causes QTc interval prolongation and may increase the risk of Torsades de pointes, other ventricular arrhythmias, and sudden death.
*Instruct patients or caregivers to notify their healthcare provider if they experience symptoms such as dizziness, lightheadedness, heart palpitations, or loss of consciousness.
*Instruct patients to inform their healthcare provider if they are taking any other medications that may prolong the QTc interval.

'''Drug Interactions'''
Inform patients and caregivers that ZOKINVY may interact with several drugs. Advise patients and their caregivers to inform their healthcare provider before starting or discontinuing a prescription or non-prescription drug, supplement, or strong CYP3A inhibitor.

'''Nephrotoxicity'''
Inform the patient and caregiver of the risk of kidney damage.

'''Retinal Toxicity'''
Inform the patient and caregiver of the risk of developing difficulty with night vision. Advise patients and caregivers to contact their healthcare provider if they experience a change in vision.

'''Gastrointestinal Adverse Reactions'''
Inform patients and caregivers that gastrointestinal adverse reactions are common with ZOKINVY. These include, but are not limited to, vomiting, diarrhea, and nausea. Advise patients and caregivers to contact their healthcare provider if these adverse reactions persist.

'''Hypertension'''
Inform patients and caregivers that blood pressure may increase while taking ZOKINVY. Symptoms of hypertension may include headaches, shortness of breath, nosebleeds, flushing, dizziness, or chest pain. Advise patients and caregivers to contact their healthcare provider if these adverse reactions occur.

'''Impaired Fertility'''
Inform females and males of reproductive potential that ZOKINVY may impact pubertal development and impair fertility.

'''Embryo-Fetal Toxicity'''
Inform pregnant women and female patients of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ZOKINVY.
|alcohol=Alcohol-Lonafarnib b interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=ZOKINVY
}}

Lumasiran

2025-04-29T19:59:18Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=lumsiran |aOrAn=an |drugClass=inhibits oxalate synthesis |indicationType=treatment |indication=of primary hyperoxaluria type 1 (PH1) to lower urinary and plasma oxalate levels in pediatric and adult patients |adverseReactions=*Injection site reaction *Abdominal pain* |blackBoxWarningTitle='''TITLE''' |blackBoxWarningBody=''<span style="color:#..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=lumsiran
|aOrAn=an
|drugClass=inhibits oxalate synthesis
|indicationType=treatment
|indication=of primary hyperoxaluria type 1 (PH1) to lower urinary and plasma oxalate levels in pediatric and adult patients
|adverseReactions=*Injection site reaction

*Abdominal pain*
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=OXLUMO is indicated for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary and plasma oxalate levels in pediatric and adult patients

'''DOSING'''
The recommended dosing regimen of OXLUMO consists of loading doses (monthly for 3 doses) followed by maintenance doses (beginning 1 month after the last loading dose) administered subcutaneously

Injection: 94.5 mg/0.5 mL clear, colorless-to-yellow solution in a single-dose vial.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Lumasiran in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Lumasiran in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Lumasiran in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Lumasiran in pediatric patients.
|contraindications=None
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of OXLUMO has been evaluated in a placebo-controlled trial and two single-arm clinical trials. Across these trials, 98 patients with PH1 have been treated with OXLUMO, including 71 pediatric patients and 15 patients on hemodialysis. Overall, 92 patients were treated for at least 6 months, 78 patients for at least 12 months, and 29 patients for at least 24 months.

In the randomized, placebo-controlled, double-blind study ILLUMINATE-A in pediatric and adult patients with PH1 aged 6 to 61 years, 26 patients received OXLUMO, and 13 patients received placebo. Of these, 25 patients received ≥5 months of treatment.

In two single-arm studies in patients with PH1, ILLUMINATE-B (patients <6 years of age) and ILLUMINATE-C (pediatric and adult patients with moderately or severely reduced GFR [eGFR ≤45 mL/min/1.73 m2 or pediatric patients <12 months of age with serum creatinine above the upper limit of normal for age] and patients with kidney failure on hemodialysis), the OXLUMO safety profile was similar to that seen in ILLUMINATE-A

In placebo-controlled and open-label clinical studies the most common adverse reaction reported was injection site reaction. Injection site reactions included erythema, swelling, pain, hematoma, pruritus, and discoloration. These symptoms were generally mild and resolved within one day of the injection and did not lead to discontinuation of treatment.
|postmarketing=The following additional adverse reaction has been reported during post-approval use. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency.

Immune system disorder: Hypersensitivity
|useInLaborDelivery=There are no available data with the use of OXLUMO in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

No adverse effects on pregnancy or embryo-fetal development related to OXLUMO were observed in rats at 45 times and in rabbits at 90 times the maximum recommended human dose in women

The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
|useInNursing=There are no data on the presence of OXLUMO in human milk, the effects on the breastfed child, or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for OXLUMO and any potential adverse effects on the breastfed child from OXLUMO or from the underlying maternal condition.
|useInPed=The safety and effectiveness of OXLUMO have been established in pediatric patients aged birth and older. Use of OXLUMO in these age groups is supported by evidence from an adequate and well controlled study of OXLUMO in pediatric patients 6 years or older and adults with PH1 (ILLUMINATE-A), a single-arm clinical study in pediatric patients less than 6 years of age with PH1 (ILLUMINATE-B), and a single-arm clinical study in pediatric and adult patients with PH1 who had advanced chronic kidney disease including patients on hemodialysis (ILLUMINATE-C)
|useInGeri=Clinical studies of OXLUMO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.
|useInRenalImpair=No dose adjustment is necessary in patients with renal impairment including patients with kidney failure treated with hemodialysis. OXLUMO has not been studied in patients on peritoneal dialysis.
|useInHepaticImpair=No dose adjustment is recommended for patients with mild [total bilirubin > upper limit of normal (ULN) to 1.5 × ULN or AST > ULN] or moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN with any AST). OXLUMO has not been studied in patients with severe hepatic impairment (total bilirubin > 3 × ULN with any AST)
|administration=OXLUMO is intended for subcutaneous use and should be administered by a healthcare professional.

Visually inspect the drug product solution. Do not use if it contains particulate matter or if it is cloudy or discolored. OXLUMO is a sterile, preservative-free, clear, colorless-to-yellow solution. It is supplied in a single-dose vial, as a ready-to-use solution that does not require additional reconstitution or dilution prior to administration.

*Use aseptic technique.
*Divide injection volumes greater than 1.5 mL equally into multiple syringes.
*For volumes less than 0.3 mL, a sterile 0.3-mL syringe is recommended. If using a 0.3 mL (30 unit) insulin syringe, 1-unit markings indicate 0.01 mL.
*Administer subcutaneous injection into the abdomen, thigh, or the side or back of the upper arms. Rotate injection sites. Do not inject into scar tissue or areas that are reddened, inflamed, or swollen.

*If injecting into the abdomen, avoid the area around the navel.
*If more than one injection is needed for a single dose of OXLUMO, the injection sites should be at least 2 cm apart.
*Discard unused portion of the drug.
|mechAction=Lumasiran reduces levels of glycolate oxidase (GO) enzyme by targeting the hydroxyacid oxidase 1 (HAO1) messenger ribonucleic acid (mRNA) in hepatocytes through RNA interference. Decreased GO enzyme levels reduce the amount of available glyoxylate, a substrate for oxalate production. As the GO enzyme is upstream of the deficient alanine: glyoxylate aminotransferase (AGT) enzyme that causes PH1, the mechanism of action of lumasiran is independent of the underlying AGXT gene mutation. OXLUMO is not expected to be effective in primary hyperoxaluria type 2 (PH2) or type 3 (PH3) because its mechanism of action does not affect the metabolic pathways causing hyperoxaluria in PH2 and PH3.
|PD=The pharmacodynamic effects of OXLUMO have been evaluated in adult and pediatric patients with PH1 across a range of doses and dosing frequency. Dose-dependent reductions in urinary oxalate levels were observed, resulting in the selection of the recommended body weight-based loading and maintenance dosing regimens. With the recommended dosing regimens, onset of effect was observed within two weeks after the first dose and maximal reductions in urinary oxalate were observed by Month 2 and persisted with continued use of OXLUMO maintenance dosage

'''Cardiac Electrophysiology'''
At the recommended dose, OXLUMO does not lead to clinically relevant QT interval prolongation.
|PK=The pharmacokinetic (PK) properties of OXLUMO were evaluated following administration of single and multiple dosages in patients with PH1
|nonClinToxic=Carcinogenicity studies were conducted in Tg-rasH2 mice and Sprague Dawley rats.

Lumasiran was not carcinogenic in transgenic Tg-rasH2 mice following monthly subcutaneous administration of lumasiran for 26 weeks at doses of 150, 500, or 1500 mg/kg.

In a 2-year carcinogenicity study, lumasiran was not carcinogenic up to the highest dose tested. Sprague Dawley rats were administered subcutaneous doses of 20, 55, or 110 mg/kg lumasiran once every 4 weeks (3, 9, or 18 times the normalized maintenance MRHD, based on body surface area).

Lumasiran was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay, in the in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes, or the in vivo micronucleus assay in rats.

Administration of lumasiran by weekly subcutaneous doses of 0, 5, 15, and 50 mg/kg in male and female rats prior to and during mating and continuing in females once on Day 6 of presumed gestation resulted in no adverse effects upon the male or female fertility endpoints evaluated.
|clinicalStudies='''ILLUMINATE-A'''

ILLUMINATE-A was a randomized, double-blind trial comparing lumasiran and placebo in 39 patients 6 years of age and older with PH1 and an eGFR ≥30 mL/min/1.73 m2 (ILLUMINATE-A; NCT03681184). Patients received 3 loading doses of 3 mg/kg OXLUMO (N=26) or placebo (N=13) administered once monthly, followed by quarterly maintenance doses of 3 mg/kg OXLUMO or placebo. After six months, all patients received OXLUMO.

The median age of patients at first dose was 15 years (range 6 to 61 years), 67% were male, and 77% were White. At baseline, the median 24-hour urinary oxalate excretion corrected for body surface area (BSA) was 1.7 mmol/24 h/1.73 m2, the median plasma oxalate level was 13.1 µmol/L, 33% of patients had eGFR ≥90 mL/min/1.73 m2, 49% had eGFR of 60 to <90 mL/min/1.73 m2, and 18% had eGFR 30 to <60 mL/min/1.73 m2, 56% were on pyridoxine, and 85% reported a history of symptomatic kidney stone events.

The primary endpoint was the percent reduction from baseline in 24-hour urinary oxalate excretion corrected for BSA averaged over Months 3 through 6. The LS mean percent change from baseline in 24-hour urinary oxalate in the OXLUMO group was -65% (95% CI: -71, -59) compared with -12% (95% CI: -20, -4) in the placebo group, resulting in a between-group LS mean difference of 53% (95% CI: 45, 62; p<0.0001).

By Month 6, 52% (95% CI: 31, 72) of patients treated with OXLUMO achieved a normal 24-hour urinary oxalate corrected for BSA (≤0.514 mmol/24 hr/1.73 m2) compared to 0% (95% CI: 0, 25) placebo-treated patients (p=0.001). Reduced urinary oxalate levels were maintained through Month 24 in patients treated with OXLUMO.

'''ILLUMINATE-B'''
ILLUMINATE-B was a single-arm study in 18 patients <6 years of age with PH1 and an eGFR >45 mL/min/1.73 m2 for patients ≥12 months of age or a normal serum creatinine for patients <12 months of age (ILLUMINATE-B; NCT03905694). Dosing was based on body weight

The median age of patients at first dose was 51 months (range 4 to 74 months), 56% were female, and 88% were White. Three patients were less than 10 kg, 12 were 10 kg to <20 kg, and 3 were ≥20 kg. The median spot urinary oxalate: creatinine ratio at baseline was 0.47 mmol/mmol.

The primary endpoint was the percent reduction from baseline in spot urinary oxalate: creatinine ratio averaged over Months 3 through 6. Patients treated with OXLUMO achieved a reduction in spot urinary oxalate: creatinine ratio from baseline of 72% (95% CI: 66, 78) (Figure 2). The reduction in urinary oxalate excretion was maintained with continued OXLUMO treatment through Month 12.

'''ILLUMINATE-C'''
A total of 21 patients were enrolled and treated with OXLUMO in a multi-center, single-arm study in patients with PH1 and an eGFR ≤45 mL/min/1.73 m2 in patients 12 months of age and older or an elevated serum creatinine for age in patients less than 12 months of age, including patients on hemodialysis. ILLUMINATE-C included 2 cohorts. Cohort A included 6 patients who did not require dialysis at the time of study enrollment. Cohort B included 15 patients who were on a stable regimen of hemodialysis; the hemodialysis regimen was to remain stable in these patients for the first 6 months of the study. Patients received the recommended dosing regimen of OXLUMO based on body weight.
Patients requiring peritoneal dialysis were excluded.

The median age of patients at first dose was 9 years (range 0 to 59 years), 57% were male, and 76% were White. For Cohort A, the median plasma oxalate level was 58 µmol/L. For Cohort B, the median pre-dialysis plasma oxalate level was 104 µmol/L.

The primary endpoint was the percent change in plasma oxalate from baseline to Month 6 (average from Month 3 to Month 6) for Cohort A (N=6) and the percent change in pre-dialysis plasma oxalate from baseline to Month 6 (average from Month 3 to Month 6) for Cohort B (N=15). The percent change from baseline to Month 6 in plasma oxalate levels in Cohort A was an LS mean difference of -33% (95% CI: -82, 15) and in Cohort B was -42% (95% CI: -51, -34).

Mean plasma oxalate decreased from 65 µmol/L (95% CI: 21, 108) at baseline to 33 µmol/L (95% CI: 10, 56) at Month 6 in Cohort A, and from 108 µmol/L (95% CI: 92, 125) at baseline to 62 µmol/L (95% CI: 51, 72) at Month 6 in Cohort B. The time course for changes in plasma oxalate
|howSupplied=OXLUMO is a clear, colorless-to-yellow solution available in single-dose vials of 94.5 mg/0.5 mL in cartons containing one vial (NDC 71336-1002-1).
|storage=Store at 2°C to 25°C [36°F to 77°F].

Store OXLUMO in its original container until ready for use.
|alcohol=Alcohol-Lumasiran interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=OXLUMO
}}

Setmelanotide

2025-04-29T19:45:18Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=setmelanotide |aOrAn=a |drugClass=melanocortin-4 receptor (MC4R) agonist |indication=IMCIVREE is indicated for chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to: |adverseReactions=*'''Disturbance in Sexual Arousal''' *'''Depression and Suicidal Ideation''' *'''Hypersensitivity Reactions''' *'''Skin Pigme..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=setmelanotide
|aOrAn=a
|drugClass=melanocortin-4 receptor (MC4R) agonist
|indication=IMCIVREE is indicated for chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to:
|adverseReactions=*'''Disturbance in Sexual Arousal'''
*'''Depression and Suicidal Ideation'''
*'''Hypersensitivity Reactions'''
*'''Skin Pigmentation and Darkening of Pre-Existing Nevi'''
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=IMCIVREE is indicated for chronic weight management in adult and pediatric patients 6 years of age and older with monogenic or syndromic obesity due to:

*Pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency as determined by an FDA-approved test demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS)

*Pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency as determined by an FDA-approved test demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS)

'''DOSAGE in Adults and Pediatric Patients 12 Years of Age and Older'''
In adult and pediatric patients 12 years of age and older, the recommended starting dosage is 2 mg (0.2 mL) injected subcutaneously once daily for 2 weeks, and the recommended target dosage is 3 mg (0.3 mL) injected subcutaneously once daily. Monitor patients for gastrointestinal (GI) adverse reactions

*Not tolerated, reduce the dosage to 1 mg (0.1 mL) once daily. If the 1 mg once daily dosage is tolerated for at least 1 week, increase the dosage to 2 mg (0.2 mL) once daily.
*Tolerated for 2 weeks, increase the dosage to 3 mg (0.3 mL) once daily. If the 3 mg once daily dosage is not tolerated, decrease the dosage to 2 mg (0.2 mL) once daily.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Setmelanotide in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Setmelanotide in adult patients.
|fdaLIADPed='''DOSAGE in Patients 12 Years of Age and Older'''
In adult and pediatric patients 12 years of age and older, the recommended starting dosage is 2 mg (0.2 mL) injected subcutaneously once daily for 2 weeks, and the recommended target dosage is 3 mg (0.3 mL) injected subcutaneously once daily. Monitor patients for gastrointestinal (GI) adverse reactions

*Not tolerated, reduce the dosage to 1 mg (0.1 mL) once daily. If the 1 mg once daily dosage is tolerated for at least 1 week, increase the dosage to 2 mg (0.2 mL) once daily.
*Tolerated for 2 weeks, increase the dosage to 3 mg (0.3 mL) once daily. If the 3 mg once daily dosage is not tolerated, decrease the dosage to 2 mg (0.2 mL) once daily.

''' Recommended Dosage in Pediatric Patients 6 to Less Than 12 Years of Age'''
In pediatric patients aged 6 to less than 12 years, the recommended starting dosage is 1 mg (0.1 mL) injected subcutaneously once daily for 2 weeks, and the recommended target dosage is 3 mg (0.3 mL) injected subcutaneously once daily. Monitor patients for GI adverse reactions

*Not tolerated, reduce the dosage to 0.5 mg (0.05 mL) once daily. If the 0.5 mg once daily dosage is tolerated for at least 1 week, increase the dosage to 1 mg (0.1 mL) once daily.

*Tolerated for 2 weeks, increase the dosage to 2 mg (0.2 mL) once daily. If the 2 mg daily dosage is:

*Not tolerated, reduce the dosage to 1 mg (0.1 mL) once daily.
*Tolerated, increase the dosage to 3 mg (0.3 mL) once daily.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Setmelanotide in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Setmelanotide in pediatric patients.
|contraindications=IMCIVREE is contraindicated in patients with a prior serious hypersensitivity reaction to setmelanotide or any of the excipients in IMCIVREE. Serious hypersensitivity reactions have included anaphylaxis
|warnings='''1.Disturbance in Sexual Arousal'''
Sexual adverse reactions may occur in patients treated with IMCIVREE. Spontaneous penile erections in males (24%) and sexual adverse reactions in females (7% in IMCIVREE-treated patients and 0% in placebo-treated patients from an unapproved population) occurred in clinical studies with IMCIVREE

Inform patients that these events may occur and instruct patients who have an erection lasting longer than 4 hours to seek emergency medical attention.

'''Depression and Suicidal Ideation'''
Some drugs that target the central nervous system, such as IMCIVREE, may cause depression or suicidal ideation. Depression (26%) and suicidal ideation (11%) occurred in adults and pediatric patients in IMCIVREE clinical studies. Patients with a history of depression or suicidal ideation may be at increased risk for recurrent episodes while taking IMCIVREE.

Monitor patients for new onset or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. Consider discontinuing IMCIVREE if patients experience suicidal thoughts or behaviors or if clinically significant or persistent depression symptoms occur.

'''Hypersensitivity Reactions'''
Serious hypersensitivity reactions, including anaphylaxis, have been reported with IMCIVREE. These reactions generally occurred within minutes to hours after injecting IMCIVREE. If hypersensitivity reactions occur, advise patients to promptly seek medical attention and discontinue use of IMCIVREE. IMCIVREE is contraindicated in patients with a prior serious hypersensitivity reaction to setmelanotide or any of the excipients in IMCIVREE.

'''Skin Pigmentation and Darkening of Pre-Existing Nevi'''
Generalized increased skin pigmentation occurred in the majority of patients (69%) treated with IMCIVREE in clinical trials. MCIVREE may also cause darkening of pre-existing nevi due to its pharmacologic effect. This effect is reversible upon discontinuation of the drug.

Perform a full body skin examination prior to initiation and periodically during treatment with IMCIVREE to monitor pre-existing and new skin pigmentary lesions.

'''Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative in Neonates and Low Birth Weight Infants'''

IMCIVREE is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs, including IMCIVREE. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (IMCIVREE contains 10 mg of benzyl alcohol per mL)
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

'''POMC, PCSK1, and LEPR Deficiency'''

The safety of IMCIVREE was evaluated in two 52-week, open-label clinical studies of 27 patients with obesity due to POMC, PCSK1, or LEPR deficiency with POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance

'''Bardet-Biedl Syndrome'''
The safety of IMCIVREE was evaluated in a clinical study, which included a 14 week, randomized, double-blind, placebo-controlled period followed by a 52-week open-label, treatment period, in 44 patients with obesity and a clinical diagnosis of BBS (Study 3) [see Clinical Studies (14)]. The study duration was 66 weeks.

During the 14-week placebo-controlled period in Study 3, the most common reported adverse reactions in IMCIVREE-treated patients when compared to placebo-treated patients were hyperpigmentation disorders (67% vs 0%, respectively) and vomiting (11% vs 0%, respectively).
|postmarketing=The following adverse reactions have been identified during post-approval use of IMCIVREE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

'''Hypersensitivity, including anaphylaxis'''
|drugInteractions=In vitro assessment of drug-drug interactions

Setmelanotide has low potential for pharmacokinetic drug-drug interactions related to cytochrome P450 (CYP), transporters and plasma protein binding.

In vivo assessment of drug-drug interactions

No clinical studies evaluating the drug-drug interaction potential of setmelanotide have been conducted.
|useInLaborDelivery=Discontinue IMCIVREE when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.

IMCIVREE contains the preservative benzyl alcohol. Because benzyl alcohol is rapidly metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs

There are no available data with IMCIVREE in pregnant women to inform a drug-associated risk for major birth defects and miscarriage, or adverse maternal or fetal outcomes. For the general US population, weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. In animal reproduction studies, setmelanotide subcutaneously administered to pregnant rats from before mating to the end of organogenesis was not teratogenic at doses 11 times the maximum recommended human dose (MRHD) of 3 mg. Setmelanotide subcutaneously administered to pregnant rabbits during the period of organogenesis was not teratogenic at clinical doses. Setmelanotide administered subcutaneously to pregnant rats during organogenesis through lactation did not result in adverse developmental effects at doses 7 times the MRHD .
The estimated background risk of birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
|useInNursing=Treatment with IMCIVREE is not recommended for use while breastfeeding.

IMCIVREE from multiple-dose vials contains the preservative benzyl alcohol. Because benzyl alcohol is rapidly metabolized by a lactating woman, benzyl alcohol exposure in the breastfed infant is unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs. There is no information on the presence of setmelanotide or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. However, setmelanotide is present in the milk of rats. When a drug is present in rat milk, it is likely that the drug will be present in human milk.
|useInPed=The safety and effectiveness of IMCIVREE have been established for chronic weight management in pediatric patients aged 6 years and older with obesity due to:

*POMC, PCSK1, or LEPR deficiency with variants in POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain significance (VUS)

*BBS

Use of IMCIVREE for these indications is supported by evidence from 2 one-year, open-label studies that included 9 pediatric patients with POMC, PCSK1, or LEPR deficiency, and from one 66-week study, which included a 14-week, randomized, double-blind, placebo-controlled period followed by a 52-week open-label period, and included 22 pediatric patients with BBS [see Clinical Studies (14.1, 14.2)].

The safety and effectiveness of IMCIVREE have not been established in pediatric patients younger than 6 years old.

IMCIVREE is not approved for use in neonates or infants. Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and low birth weight infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (IMCIVREE contains 10 mg of benzyl alcohol)
|useInGeri=Clinical studies of IMCIVREE did not include patients aged 65 and over. It is not known whether geriatric patients would respond differently than younger adult patients.
|useInRenalImpair=Patients with severe renal impairment have a higher exposure of setmelanotide relative to patients with normal kidney function. Reduce the recommended starting and target dosage of IMCIVREE in adults and pediatric patients 12 years of age and older with severe renal impairment (eGFR 15-29 mL/min/1.73 m2). The use of IMCIVREE in pediatric patients 6 to less than 12 years of age with severe renal impairment is not recommended.

The recommended dosage in patients with mild (eGFR of 60-89 mL/min/1.73 m2) or moderate renal impairment (eGFR of 30-59 mL/min/1.73 m2) is the same as those with normal kidney function.

IMCIVREE is not recommended for use in patients with end stage renal disease.
|administration=*Prior to initiation of IMCIVREE, train patients or their caregivers on proper injection technique. Instruct patients to use a 1-mL syringe with a 28- or 29-gauge needle appropriate for subcutaneous injection.

* Remove IMCIVREE from the refrigerator approximately 15 minutes prior to administration. Alternatively, warm IMCIVREE prior to administration by rolling the vial gently between the palms of the hands for 60 seconds.

* Inspect IMCIVREE visually before use. It should appear clear to slightly opalescent, colorless to slightly yellow. Do not use if particulate matter or discoloration is seen.

*Administer IMCIVREE once daily, at the beginning of the day, without regard to meals.

*Inject IMCIVREE subcutaneously in the abdomen, thigh, or arm, rotating to a different site each day. Do not administer IMCIVREE intravenously or intramuscularly.

*If a dose is missed, resume the once daily regimen as prescribed with the next scheduled dose.
|monitoring='''Obesity Due to POMC, PCSK1, or LEPR Deficiency'''
*Periodically assess response to IMCIVREE therapy. In pediatric patients, evaluate the impact of weight loss on growth and maturation.

* Evaluate weight loss after 12-16 weeks of treatment. If a patient has not lost at least 5% of baseline body weight or 5% of baseline BMI for patients with continued growth potential, discontinue IMCIVREE as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.

'''Obesity and a Clinical Diagnosis of BBS'''
*Periodically assess response to IMCIVREE therapy. In pediatric patients, evaluate the impact of weight loss on growth and maturation.

*Evaluate weight loss after 1 year of treatment. If a patient has not lost at least 5% of baseline body weight or 5% of baseline BMI for patients aged less than 18 years, discontinue IMCIVREE as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.
|mechAction=Setmelanotide is an MC4 receptor agonist with 20-fold less activity at the melanocortin 3 (MC3) and melanocortin 1 (MC1) receptors. MC4 receptors in the brain are involved in regulation of hunger, satiety, and energy expenditure. Based on nonclinical evidence, setmelanotide may re-establish MC4 receptor pathway activity to reduce food intake and promote weight loss through decreased caloric intake and increased energy expenditure in patients with obesity due to POMC, PCSK1, or LEPR deficiency, or BBS associated with insufficient activation of the MC4 receptor. The MC1 receptor is expressed on melanocytes, and activation of this receptor leads to accumulation of melanin and increased skin pigmentation independently of ultraviolet light
|PD=At a dose 2.3 times the maximum recommended dose, IMCIVREE does not prolong the QT interval to any clinically relevant extent.

'''Energy Expenditure'''
Short-term administration of IMCIVREE in 12 otherwise healthy patients with obesity increased resting energy expenditure and shifted substrate oxidation to fat. The safety and effectiveness of IMCIVREE have not been established in such patients and IMCIVREE is not approved to treat such patients
|PK=The mean steady state setmelanotide Cmax,ss, AUCtau, and trough concentration for a 3-mg dose administered subcutaneously once daily was 37.9 ng/mL, 495 h*ng/mL, and 6.77 ng/mL, respectively. Steady-state plasma concentrations of setmelanotide were achieved within 2 days with daily dosing of 1-3 mg setmelanotide. The accumulation of setmelanotide in the systemic circulation during once-daily dosing over 12 weeks was approximately 30%. Setmelanotide AUC and Cmax increased proportionally following multiple-dose subcutaneous administration in the proposed dose range (1-3 mg).

'''Absorption'''
After subcutaneous injection of IMCIVREE, plasma concentrations of setmelanotide reached maximum concentrations at a median tmax of 8 h after dosing.

'''Distribution'''
The mean apparent volume of distribution of setmelanotide after subcutaneous administration of IMCIVREE 3 mg once daily was estimated from the population pharmacokinetics model to be 48.7 L. Protein binding of setmelanotide is 79.1%.

'''Elimination'''
The effective elimination half-life (t½) of setmelanotide was approximately 11 hours. The total apparent steady state clearance of setmelanotide following subcutaneous administration of IMCIVREE 3 mg once daily was estimated from the population PK model to be 4.86 L/h.

'''Metabolism'''
Setmelanotide is expected to be metabolized into small peptides by catabolic pathways.

'''Excretion'''
Approximately 39% of the administered setmelanotide dose was excreted unchanged in urine during the 24-hour dosing interval following subcutaneous administration of 3 mg once daily.

'''Specific Populations'''
No clinically significant differences in the pharmacokinetics of setmelanotide were observed based on sex or disease. The effect of age 65 years or older, pregnancy, or hepatic impairment on the pharmacokinetics of setmelanotide is unknown.

'''Pediatric Patients'''
IMCIVREE has been evaluated in pediatric patients aged 6 to less than 12 years and aged 12 to 17 years. Simulations from the population pharmacokinetic analyses suggest that AUC and Cmax are 100% and 92% higher in pediatric patients 6 to less than 12 years as compared to patients greater than or equal to 17 years. For patients aged 12 to 17 years, the setmelanotide AUC and Cmax were 44% and 37% higher, respectively as compared to patients greater than or equal to 17 years

'''Patients with Renal Impairment'''

Exposure parameters, AUC0-t and AUC0-inf, were approximately 13%-15%, 34%-35%, and 86%-96% higher for patients with mild, moderate, and severe renal impairment, respectively, as compared to patients with normal renal function

Renal impairment did not appear to affect plasma protein binding. The average fraction unbound (fu) was approximately 0.2 and was independent of renal function.
|clinicalStudies=Setmelanotide was not carcinogenic in Tg.rasH2 mice at doses up to 10 mg/kg/day when given subcutaneously for 26 weeks.

Setmelanotide was not mutagenic or clastogenic in a bacterial reverse mutation test, an in vitro chromosome aberration test in human lymphocyte cultures, or an in vivo bone marrow micronucleus study in rats.

There were no effects on the fertility of male rats subcutaneously administered up to 3.0 mg/kg/day setmelanotide, which represents 9 times the MRHD of 3 mg, based on AUC. No effects on the fertility of female rats were observed with subcutaneous administration up to 5 mg/kg/day setmelanotide, which represents 11 times the MRHD of 3 mg, based on AUC.
|howSupplied=*10 mg/mL, clear to slightly opalescent, colorless to slightly yellow solution in a 1-mL multiple-dose vial

*Package of 1 multiple-dose vial: NDC 72829-010-01
|storage=Store unopened IMCIVREE vials in the refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. After removal from the refrigerator, vials may be kept at temperatures ranging from refrigerated to room temperature (2°C to 25°C [36°F to 77°F]) for up to 30 days with brief excursions up to 30°C (86°F). After the vial is punctured (opened), discard after 30 days.
|fdaPatientInfo=Advise the patient or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

'''Disturbance in Sexual Arousal'''
Inform patients that sexual adverse reactions, including spontaneous erection, may occur in patients treated with IMCIVREE. Advise patients to seek emergency medical treatment if an erection lasts longer than 4 hours

'''Depression and Suicidal Ideation'''
Inform patients or caregivers that IMCIVREE may cause depression or suicidal ideation. Advise patients or caregivers to report any new or worsening symptoms of depression, suicidal thoughts or behaviors, or unusual changes in mood or behavior

'''Hypersensitivity Reactions'''
Inform patients that serious hypersensitivity reactions have been reported with use of IMCIVREE. Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking IMCIVREE and seek medical advice promptly if such symptoms occur

'''Skin Pigmentation and Darkening of Pre-Existing Nevi'''
Inform patients or caregivers that skin darkening occurs in the majority of patients treated with IMCIVREE because of its mechanism of action. This change is reversable upon discontinuation of IMCIVREE. Inform patients or caregivers that they should have a full body skin examination before starting and during treatment with IMCIVREE to monitor these changes

'''Pregnancy'''
Advise patients who may become pregnant to inform their healthcare provider of a known or suspected pregnancy

'''Lactation'''
Advise patients that treatment with IMCIVREE is not recommended while breastfeeding

'''Administration'''
Instruct patients and caregivers how to prepare and administer the correct dose of IMCIVREE and assess their ability to inject subcutaneously to ensure the proper administration of IMCIVREE. Instruct patients to use a 1 mL syringe with a 28- or 29-gauge needle appropriate for subcutaneous injection.
|alcohol=Alcohol-Setmelanotide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=IMCIVREE
}}

Naxitamab

2025-04-27T18:02:33Z

Alara E. Dagsali:

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=naxitamab-gqgk
|aOrAn=a
|drugClass=IgG1 monoclonal antibody directed against GD2 disialogangliosides
|indicationType=treatment
|indication=of pediatric patients 1 year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response, or stable disease to prior therapy.
|hasBlackBoxWarning=Yes
|adverseReactions='''Serious Infusion-Related Reactions'''
'''Neurotoxicity'''
'''Myocarditis'''
'''Hypertension'''
'''Orthostatic Hypotension '''
|blackBoxWarningTitle='''SERIOUS INFUSION-RELATED REACTIONS and NEUROTOXICITY'''
|blackBoxWarningBody=''Serious Infusion-Related Reactions:'' (*DANYELZA can cause serious infusion reactions, including cardiac arrest, anaphylaxis, hypotension, bronchospasm, and stridor. Infusion reactions of any Grade occurred in 94-100% of patients. Severe infusion reactions occurred in 32-68% and serious infusion reactions occurred in 4 - 18% of patients in DANYELZA clinical studies
*Premedicate prior to each DANYELZA infusion as recommended and monitor patients for at least 2 hours following completion of each infusion. Reduce the rate, interrupt infusion, or permanently discontinue DANYELZA based on severity)
''Neurotoxicity:'' (*DANYELZA can cause severe neurotoxicity, including severe neuropathic pain, transverse myelitis and reversible posterior leukoencephalopathy syndrome (RPLS). Pain of any Grade occurred in 94-100% of patients in DANYELZA clinical studies
*Premedicate to treat neuropathic pain as recommended. Permanently discontinue DANYELZA based on the adverse reaction and severity)
|fdaLIADAdult=DANYELZA is indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), for the treatment of pediatric patients 1 year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response, or stable disease to prior therapy.
This indication is approved under accelerated approval based on overall response rate and duration of response.
Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

'''Recommended Dosage''':
The recommended dosage of DANYELZA is 3 mg/kg/day (up to 150 mg/day) on Days 1, 3, and 5 of each treatment cycle, administered as an intravenous infusion after dilution in combination with GM-CSF subcutaneously. Treatment cycles are repeated every 4 weeks until complete response or partial response, followed by 5 additional cycles every 4 weeks. Subsequent cycles may be repeated every 8 weeks. Discontinue DANYELZA and GM-CSF for disease progression or unacceptable toxicity.

The recommended dosage regimen for each treatment cycle:
*Days -4 to 0: administer GM-CSF 250 µg/m2/day by subcutaneous injection, beginning 5 days prior to DANYELZA infusion.
*Days 1 to 5: administer GM-CSF 500 µg/m2/day by subcutaneous injection. Administer at least 1 hour prior to DANYELZA administration on Days 1, 3, and 5.
*Days, 1, 3, and 5: administer DANYELZA 3 mg/kg/day (up to 150 mg/day) by intravenous infusion.

'''Missed Dose''':
If a DANYELZA dose is missed, administer the missed dose the following week by Day 10. Administer GM-CSF 500 µg /m2/day on the first day of the DANYELZA infusion, and on the day before and on the day of the second and third infusion, respectively (i.e. a total of 5 days with 500 µg /m2/day).
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Naxitamab in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Naxitamab in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Naxitamab in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Naxitamab in pediatric patients.
|contraindications=DANYELZA is contraindicated in patients with a history of severe hypersensitivity reaction to naxitamab-gqgk. Reactions have included anaphylaxis
|warnings='''Serious Infusion-Related Reactions''':
DANYELZA can cause serious infusion reactions requiring urgent intervention including fluid resuscitation, administration of bronchodilators and corticosteroids, intensive care unit admission, infusion rate reduction or interruption of DANYELZA infusion. Infusion-related reactions included hypotension, bronchospasm, hypoxia, and stridor

Serious infusion-related reactions occurred in 4% of patients in Study 201 and in 18% of patients in Study 12-230. Infusion-related reactions of any Grade occurred in 100% of patients in Study 201 and 94% of patients in Study 12-230. Hypotension of any grade occurred in 100% of patients in Study 201 and 89% of patients in Study 12-230.
In Study 201, 68% of patients experienced Grade 3 or 4 infusion reactions; and in Study 12-230, 32% of patients experienced Grade 3 or 4 infusion reactions. Anaphylaxis occurred in 12% of patients and 2 patients (8%) permanently discontinued DANYELZA due to anaphylaxis in Study 201. One patient in Study 12-230 (1.4%) experienced a Grade 4 cardiac arrest 1.5 hours following completion of DANYELZA infusion.

In Study 201, infusion reactions generally occurred within 24 hours of completing a DANYELZA infusion, most often within 30 minutes of initiation. Infusion reactions were most frequent during the first infusion of DANYELZA in each cycle. Eighty percent of patients required reduction in infusion rate and 80% of patients had an infusion interrupted for at least one infusion-related reaction.

Caution is advised in patients with pre-existing cardiac disease, as this may exacerbate the risk of severe hypotension.

Premedicate with an antihistamine, acetaminophen, an H2 antagonist and corticosteroid as recommended.
Monitor patients closely for signs and symptoms of infusion reactions during and for at least 2 hours following completion of each DANYELZA infusion in a setting where cardiopulmonary resuscitation medication and equipment are available.

Reduce the rate, interrupt infusion, or permanently discontinue DANYELZA based on severity and institute appropriate medical management as needed.

'''Neurotoxicity''':
DANYELZA can cause severe neurotoxicity, including severe neuropathic pain, transverse myelitis, and reversible posterior leukoencephalopathy syndrome.

''Pain''
Pain, including abdominal pain, bone pain, neck pain, and extremity pain, occurred in 100% of patients in Study 201 and 94% of patients in Study 12-230. Grade 3 pain occurred in 72% of patients in Study 201. One patient in Study 201 (4%) required interruption of an infusion due to pain. Pain typically began during the infusion of DANYELZA and lasted a median of less than one day in Study 201 (range less than one day and up to 62 days)
Premedicate with drugs that treat neuropathic pain (e.g., gabapentin) and oral opioids. Administer intravenous opioids as needed for breakthrough pain. Permanently discontinue DANYELZA based on severity

''Transverse Myelitis'':
Transverse myelitis has occurred with DANYELZA. Permanently discontinue DANYELZA in patients who develop transverse myelitis

''Reversible Posterior Leukoencephalopathy Syndrome (RPLS)''
Reversible posterior leukoencephalopathy syndrome (RPLS) (also known as posterior reversible encephalopathy syndrome or PRES) occurred in 2 (2.8%) patients in Study 12-230. Events occurred 2 and 7 days following completion of the first cycle of DANYELZA. Monitor blood pressure during and following DANYELZA infusion and assess for neurologic symptoms. Permanently discontinue DANYELZA in case of symptomatic RPLS.

''Peripheral Neuropathy''
Peripheral neuropathy, including peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, and neuralgia, occurred in 32% of patients in Study 201 and in 25% of patients in Study 12-230. Most signs and symptoms of neuropathy began on the day of the infusion and neuropathy lasted a median of 5.5 days (range 0 to 22 days) in Study 201 and 0 days (range 0 to 22 days) in Study 12-230

''Neurological Disorders of the Eye''
Neurological disorders of the eye including unequal pupils, blurred vision, accommodation disorder, mydriasis, visual impairment, and photophobia occurred in 24% of patients in Study 201 and 19% of patients in Study 12-230. Neurological disorders of the eye lasted a median of 17 days (range 0 to 84 days) in Study 201 with two patients (8%) experiencing an event that had not resolved at the time of data cutoff, and a median of 1 day (range less than one day to 21 days) in Study 12-230. Permanently discontinue DANYELZA based on severity

''Prolonged Urinary Retention''
Urinary retention occurred in 1 (4%) patient in Study 201 and in 3 patients (4%) in Study 12-230. All events in both studies occurred on the day of an infusion of DANYELZA and lasted between 0 and 24 days. Permanently discontinue DANYELZA in patients with urinary retention that does not resolve following discontinuation of opioids

'''Myocarditis''':
Myocarditis has occurred in adolescent patients receiving DANYELZA in clinical trials and expanded access programs. Myocarditis occurred within days of receiving DANYELZA requiring drug interruption. Monitor for signs and symptoms of myocarditis during treatment with DANYELZA. Withhold, reduce the dose, or permanently discontinue DANYELZA based on severity

'''Hypertension''':
Hypertension occurred in 44% of patients in Study 201 and 28% of patients in Study 12-230 who received DANYELZA. Grade 3 or 4 hypertension occurred in 4% of patients in Study 201 and 7% of patients in Study 12- 230. Four patients (6%) in Study 12-230 permanently discontinued DANYELZA due to hypertension. In both studies, most events occurred on the day of DANYELZA infusion and occurred up to 9 days following an infusion of DANYELZA.

Do not initiate DANYELZA in patients with uncontrolled hypertension. Monitor blood pressure during infusion, and at least daily on Days 1 to 8 of each cycle of DANYELZA and evaluate for complications of hypertension including RPLS. Interrupt DANYELZA infusion and resume at a reduced rate, or permanently discontinue DANYELZA based on the severity

'''Orthostatic Hypotension''':
Orthostatic hypotension has occurred in patients receiving DANYELZA in clinical trials and expanded access programs. Severe orthostatic hypotension, including cases requiring hospitalization, have occurred. Cases occurred within hours to 6 days of DANYELZA infusions in any cycle.

In patients with symptoms of orthostatic hypotension, monitor postural blood pressure prior to initiating treatment with DANYELZA and as clinically indicated with subsequent dosing. Withhold, reduce dose, or permanently discontinue DANYELZA based on severity.

'''Embryo-Fetal Toxicity''':
Based on its mechanism of action, DANYELZA may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential, including pregnant women, of the potential risk to a fetus. Advise females of reproductive potential to use effective contraceptive during treatment with DANYELZA and for two months after the last dose.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of DANYELZA in combination with GM-CSF was evaluated in patients with refractory or relapsed highrisk neuroblastoma in bone or bone marrow who had demonstrated a partial response, minor response, or stable disease following initial or subsequent therapy, and in patients who were in second complete remission, from two open-label, single arm studies, Study 201 (n=25) and Study 12-230 (n=72). Patients received DANYELZA 9 mg/kg/cycle administered as three separate intravenous infusions of 3 mg/kg (Day 1, 3 and 5) in the first week of each cycle. Patients also received GM-CSF 250 μg/m2/day subcutaneously on Days -4 to 0 and GM-CSF 500 μg/m2/day subcutaneously on Days 1 to 5

The most common adverse reactions in Studies 201 and 12-230 (≥25% in either study) were infusion-related reaction, pain, tachycardia, vomiting, cough, nausea, diarrhea, decreased appetite, hypertension, fatigue, erythema multiforme, peripheral neuropathy, urticaria, pyrexia, headache, injection site reaction, edema, anxiety, localized edema and irritability. The most common Grade 3 or 4 laboratory abnormalities (≥5% in either study) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased platelet count, decreased potassium, increased alanine aminotransferase, decreased glucose, decreased calcium, decreased albumin, decreased sodium and decreased phosphate.
|postmarketing=The following adverse reactions have been identified during expanded access and post-approval use of DANYELZA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
|useInLaborDelivery=Based on its mechanism of action, DANYELZA may cause fetal harm when administered to pregnant women. There are no available data on the use of DANYELZA in pregnant women and no animal reproduction studies have been conducted with DANYELZA. IgG1 monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. Advise pregnant women of potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
|useInNursing=There are no data on the presence of naxitamab-gqgk in human milk or its effects on the breastfed child, or on milk production, however, human IgG is present in human milk. Because of the potential for serious adverse reactions in a breastfed child from DANYELZA, advise women not to breastfeed during treatment and for 2 months after the last dose of DANYELZA.
|useInPed=The safety and effectiveness of DANYELZA, in combination with GM-CSF for the treatment of relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response or stable disease following prior therapy, have been established in pediatric patients 1 year of age and older.

Safety and effectiveness have not been established in pediatric patients younger than 1 year of age.
|useInGeri=Neuroblastoma is largely a disease of pediatric and young adult patients. Clinical studies of DANYELZA in combination with GM-CSF did not include patients 65 years of age and older.
|useInReproPotential=DANYELZA may cause fetal harm when administered to a pregnant woman
''Pregnancy Testing''
Verify pregnancy status in females of reproductive potential prior to initiating DANYELZA.

''Contraception''
FEMALES
Advise females of reproductive potential to use effective contraception during treatment and for 2 months after the last dose of DANYELZA.
|administration=*Administer DANYELZA as a diluted intravenous infusion as recommended. Do not administer DANYELZA as an intravenous push or bolus
*For the first infusion (Cycle 1, Day 1), administer DANYELZA intravenously over 60 minutes.
For subsequent infusions, administer DANYELZA intravenously over 30 to 60 minutes, as tolerated.
*Observe patients for a minimum of 2 hours following each infusion.
|monitoring=Premedicate with an antihistamine, acetaminophen, an H2 antagonist and corticosteroid as recommended.
Monitor patients closely for signs and symptoms of infusion reactions during and for at least 2 hours following completion of each DANYELZA infusion in a setting where cardiopulmonary resuscitation medication and equipment are available.

Reduce the rate, interrupt infusion, or permanently discontinue DANYELZA based on severity and institute appropriate medical management as needed.
|mechAction=Naxitamab-gqgk binds to the glycolipid GD2. GD2 is a disialoganglioside that is overexpressed on neuroblastoma cells and other cells of neuroectodermal origin, including the central nervous system and peripheral nerves. In vitro, naxitamab-gqgk was able to bind to cell surface GD2 and induce complement dependent cytotoxicity (CDC) and antibody dependent cell-mediated cytotoxicity (ADCC).
|PD=The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of naxitamab-gqgk have not been fully characterized.
|PK=The geometric mean (CV%) maximum plasma concentration (Cmax) of naxitamab-gqgk was 57.4 μg/mL (49%) following DANYELZA 3 mg/kg intravenous infusion over 30 minutes.

'''Elimination''':
The mean terminal half-life of naxitamab-gqgk was 8.2 days.

'''Metabolism''':
Naxitamab-gqgk is expected to be metabolized into small peptides by catabolic pathways.

'''Specific Populations''':
Population pharmacokinetic analyses suggest that age (range: 1 to 34 years), sex and race have no clinically important effect on the clearance (CL) of naxitamab-gqgk. The naxitamab-gqgk systemic exposure (AUC) at 150 mg/day (450 mg per cycle) for patients with body weight over 50 kg is not expected to differ clinically from that of the naxitamabgqgk exposures at 3 mg/kg/day (9 mg/kg per cycle) for patients with body weight of 30 - 50 kg.
|nonClinToxic='''Carcinogenesis, Mutagenesis, Impairment of Fertility''':
No animal studies have been conducted to evaluate the carcinogenic or mutagenic potential of naxitamab-gqgk.

Dedicated studies evaluating the effects of naxitamab-gqgk on fertility in animals have not been conducted.

'''Animal Toxicology and/or Pharmacology''':
Non-clinical studies suggest that naxitamab-gqgk-induced neuropathic pain is mediated by binding of the antibody to the GD2 antigen located on the surface of peripheral nerve fibers and myelin and subsequent induction of immunemediated cytotoxic activity.

In a nude rat model, slight-moderate hyperplasia and erosion of the glandular mucosa of the stomach occurred, occasionally accompanied by diffuse inflammation. Complete recovery of all histopathological findings in the stomachs of male rats was observed; however, only partial recovery was observed in the stomachs of female rats during the four week off-drug period.
|clinicalStudies=The efficacy of DANYELZA in combination with GM-CSF was evaluated in two open-label, single arm trials in patients with high-risk neuroblastoma with refractory or relapsed disease in the bone or bone marrow, Study 201 and Study 12-230.

'''Study 201''':
The efficacy of DANYELZA in combination with GM-CSF was evaluated in Study 201 (NCT03363373), a multicenter open-label, single arm trial, in a subpopulation of patients who had refractory or relapsed high-risk neuroblastoma in the bone or bone marrow and demonstrated a partial response, minor response, or stable disease to prior therapy. Patients with progressive disease were excluded. All patients received at least one systemic therapy to treat disease outside of the bone or bone marrow prior to enrollment. Patients received DANYELZA 9 mg/kg/cycle administered as three separate intravenous infusions of 3 mg/kg on Days 1, 3 and 5 of each cycle. Patients received GM-CSF subcutaneously at 250 μg/m2/day on Days -4 to 0 and at 500 μg/m2/day on Days 1 to 5. Preplanned radiation to the primary site was allowed.

The major efficacy outcome measure was overall response rate (ORR) according to the revised International Neuroblastoma Response Criteria (INRC), as determined by independent pathology and imaging review and confirmed by at least one subsequent assessment. An additional efficacy outcome measure was duration of response (DOR).

Of the 22 patients included in the efficacy analysis, 64% had refractory disease and 36% had relapsed disease; the median age was 5 years (range 3 to 10 years), 59% were male; 45% were White, 50% were Asian and 5% were Black. MYCN amplification was present in 14% of patients and 86% of patients were International Neuroblastoma Staging System (INSS) stage 4 at time of diagnosis. Disease sites included 59% in the bone only, 9% in bone marrow only, and 32% in both. Prior therapies included surgery (91%), chemotherapy (95%), radiation (36%), autologous stem cell transplant (ASCT) (18%), and anti-GD2 antibody treatment (18%).

'''Study 12-230'''
The efficacy of DANYELZA in combination with GM-CSF was evaluated in Study 12-230 (NCT01757626), a single center, open-label, single arm trial, in a subpopulation of patients who had relapsed or refractory high-risk neuroblastoma in bone or bone marrow and demonstrated a partial response, minor response, or stable disease to prior therapy. Patients with progressive disease were excluded. All patients received at least one systemic therapy to treat disease outside of the bone or bone marrow prior to enrollment. Patients were required to have received at least one dose of DANYELZA at a dose of 3 mg/kg or greater per infusion and have evaluable disease at baseline according to independent review per the revised INRC.

Patients received DANYELZA 9 mg/kg/cycle administered as three separate intravenous infusions of 3 mg/kg (on Days 1, 3 and 5) in the first week of each cycle. Patients received GM-CSF subcutaneously at 250 μg/m2/day on Days -4 to 0 and at 500 μg/m2/day on Days 1 to 5. Radiation to non-target bony lesions and soft tissue lesions was permitted at the investigator's discretion; assessment of response excluded sites that received radiation. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), as determined by independent pathology and imaging review according to the revised INRC and confirmed by at least one subsequent assessment.

Of the 38 patients included in the efficacy analysis, 55% had relapsed neuroblastoma and 45% had refractory disease; 50% were male, the median age was 5 years (range 2 to 23 years), 74% were White, 8% Asian and 5% were Black, 5% Native American/American Indian/Alaska Native, 3% other races and 5% was not available. MYCN-amplification was present in 16% of patients and most patients were International Neuroblastoma Staging System (INSS) stage 4 (95%). Fifty percent (50%) of patients had disease involvement in the bone only, 11% only in bone marrow, and 39% in both. Prior therapies included surgery (100%), chemotherapy (100%), radiation (47%), autologous stem cell transplant (ASCT) (42%), and anti-GD2 antibody treatment (58%).
|howSupplied=DANYELZA (naxitamab-gqgk) injection is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow solution for intravenous infusion supplied as a carton containing one 40mg/10 mL (4 mg/mL) singledose vial.
|storage=Store DANYELZA vial refrigerated at 2°C to 8°C (36°F to 46°F) in the outer carton to protect from light until time of use.
|fdaPatientInfo=Advise the patient and caregiver to read the FDA-approved patient labeling:

'''Serious Infusion-Related Reactions''':
Advise patients and caregivers that DANYELZA can cause serious infusion-related reactions and anaphylaxis and to immediately report any signs or symptoms, such as facial or lip swelling, urticaria, or difficulty breathing, that occur during or following the infusion

'''Neurotoxicity''':
Advise patients and caregivers that DANYELZA can cause neurotoxicity, including severe pain, peripheral neuropathy, neurological disorders of the eye, prolonged urinary retention, transverse myelitis, and reverse posterior leukoencephalopathy syndrome. Advise patients to contact their healthcare provider for any new or worsening neurological symptoms

'''Myocarditis''':
Advise patients and caregivers that myocarditis has been seen in patients taking DANYELZA and to report any signs or symptoms, such as chest pain, shortness of breath or abnormal heart rhythms during treatment with DANYELZA

'''Hypertension''':
Advise patients and caregivers that DANYELZA can cause hypertension and to immediately report signs or symptoms of hypertension

'''Orthostatic Hypotension'''
Advise patients and caregivers that DANYELZA can cause severe low blood pressure when standing after sitting or lying down. Advise patients and caregivers to report any signs or symptoms, such as dizziness, lightheadedness or fainting during treatment with DANYELZA

'''Embryo-Fetal Toxicity '''
Advise females of reproductive potential, including pregnant women, of the potential risk to the fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy and to use effective contraception during treatment with and for 2 months after the last dose of DANYELZA

'''Lactation'''
Advise women not to breastfeed during treatment with DANYELZA and for 2 months after the last dose
|alcohol=Alcohol-Naxitamab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=Danyelza
}}

Naxitamab

2025-04-27T18:01:07Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=naxitamab |aOrAn=a |drugClass=IgG1 monoclonal antibody directed against GD2 disialogangliosides |indicationType=treatment |indication=of pediatric patients 1 year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response, or stable disease to prior therapy. |hasBlackBox..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=naxitamab
|aOrAn=a
|drugClass=IgG1 monoclonal antibody directed against GD2 disialogangliosides
|indicationType=treatment
|indication=of pediatric patients 1 year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response, or stable disease to prior therapy.
|hasBlackBoxWarning=Yes
|adverseReactions='''Serious Infusion-Related Reactions'''
'''Neurotoxicity'''
'''Myocarditis'''
'''Hypertension'''
'''Orthostatic Hypotension '''
|blackBoxWarningTitle='''SERIOUS INFUSION-RELATED REACTIONS and NEUROTOXICITY'''
|blackBoxWarningBody=''Serious Infusion-Related Reactions:'' (*DANYELZA can cause serious infusion reactions, including cardiac arrest, anaphylaxis, hypotension, bronchospasm, and stridor. Infusion reactions of any Grade occurred in 94-100% of patients. Severe infusion reactions occurred in 32-68% and serious infusion reactions occurred in 4 - 18% of patients in DANYELZA clinical studies
*Premedicate prior to each DANYELZA infusion as recommended and monitor patients for at least 2 hours following completion of each infusion. Reduce the rate, interrupt infusion, or permanently discontinue DANYELZA based on severity)
''Neurotoxicity:'' (*DANYELZA can cause severe neurotoxicity, including severe neuropathic pain, transverse myelitis and reversible posterior leukoencephalopathy syndrome (RPLS). Pain of any Grade occurred in 94-100% of patients in DANYELZA clinical studies
*Premedicate to treat neuropathic pain as recommended. Permanently discontinue DANYELZA based on the adverse reaction and severity)
|fdaLIADAdult=DANYELZA is indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), for the treatment of pediatric patients 1 year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response, or stable disease to prior therapy.
This indication is approved under accelerated approval based on overall response rate and duration of response.
Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

'''Recommended Dosage''':
The recommended dosage of DANYELZA is 3 mg/kg/day (up to 150 mg/day) on Days 1, 3, and 5 of each treatment cycle, administered as an intravenous infusion after dilution in combination with GM-CSF subcutaneously. Treatment cycles are repeated every 4 weeks until complete response or partial response, followed by 5 additional cycles every 4 weeks. Subsequent cycles may be repeated every 8 weeks. Discontinue DANYELZA and GM-CSF for disease progression or unacceptable toxicity.

The recommended dosage regimen for each treatment cycle:
*Days -4 to 0: administer GM-CSF 250 µg/m2/day by subcutaneous injection, beginning 5 days prior to DANYELZA infusion.
*Days 1 to 5: administer GM-CSF 500 µg/m2/day by subcutaneous injection. Administer at least 1 hour prior to DANYELZA administration on Days 1, 3, and 5.
*Days, 1, 3, and 5: administer DANYELZA 3 mg/kg/day (up to 150 mg/day) by intravenous infusion.

'''Missed Dose''':
If a DANYELZA dose is missed, administer the missed dose the following week by Day 10. Administer GM-CSF 500 µg /m2/day on the first day of the DANYELZA infusion, and on the day before and on the day of the second and third infusion, respectively (i.e. a total of 5 days with 500 µg /m2/day).
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Naxitamab in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Naxitamab in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Naxitamab in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Naxitamab in pediatric patients.
|contraindications=DANYELZA is contraindicated in patients with a history of severe hypersensitivity reaction to naxitamab-gqgk. Reactions have included anaphylaxis
|warnings='''Serious Infusion-Related Reactions''':
DANYELZA can cause serious infusion reactions requiring urgent intervention including fluid resuscitation, administration of bronchodilators and corticosteroids, intensive care unit admission, infusion rate reduction or interruption of DANYELZA infusion. Infusion-related reactions included hypotension, bronchospasm, hypoxia, and stridor

Serious infusion-related reactions occurred in 4% of patients in Study 201 and in 18% of patients in Study 12-230. Infusion-related reactions of any Grade occurred in 100% of patients in Study 201 and 94% of patients in Study 12-230. Hypotension of any grade occurred in 100% of patients in Study 201 and 89% of patients in Study 12-230.
In Study 201, 68% of patients experienced Grade 3 or 4 infusion reactions; and in Study 12-230, 32% of patients experienced Grade 3 or 4 infusion reactions. Anaphylaxis occurred in 12% of patients and 2 patients (8%) permanently discontinued DANYELZA due to anaphylaxis in Study 201. One patient in Study 12-230 (1.4%) experienced a Grade 4 cardiac arrest 1.5 hours following completion of DANYELZA infusion.

In Study 201, infusion reactions generally occurred within 24 hours of completing a DANYELZA infusion, most often within 30 minutes of initiation. Infusion reactions were most frequent during the first infusion of DANYELZA in each cycle. Eighty percent of patients required reduction in infusion rate and 80% of patients had an infusion interrupted for at least one infusion-related reaction.

Caution is advised in patients with pre-existing cardiac disease, as this may exacerbate the risk of severe hypotension.

Premedicate with an antihistamine, acetaminophen, an H2 antagonist and corticosteroid as recommended.
Monitor patients closely for signs and symptoms of infusion reactions during and for at least 2 hours following completion of each DANYELZA infusion in a setting where cardiopulmonary resuscitation medication and equipment are available.

Reduce the rate, interrupt infusion, or permanently discontinue DANYELZA based on severity and institute appropriate medical management as needed.

'''Neurotoxicity''':
DANYELZA can cause severe neurotoxicity, including severe neuropathic pain, transverse myelitis, and reversible posterior leukoencephalopathy syndrome.

''Pain''
Pain, including abdominal pain, bone pain, neck pain, and extremity pain, occurred in 100% of patients in Study 201 and 94% of patients in Study 12-230. Grade 3 pain occurred in 72% of patients in Study 201. One patient in Study 201 (4%) required interruption of an infusion due to pain. Pain typically began during the infusion of DANYELZA and lasted a median of less than one day in Study 201 (range less than one day and up to 62 days)
Premedicate with drugs that treat neuropathic pain (e.g., gabapentin) and oral opioids. Administer intravenous opioids as needed for breakthrough pain. Permanently discontinue DANYELZA based on severity

''Transverse Myelitis'':
Transverse myelitis has occurred with DANYELZA. Permanently discontinue DANYELZA in patients who develop transverse myelitis

''Reversible Posterior Leukoencephalopathy Syndrome (RPLS)''
Reversible posterior leukoencephalopathy syndrome (RPLS) (also known as posterior reversible encephalopathy syndrome or PRES) occurred in 2 (2.8%) patients in Study 12-230. Events occurred 2 and 7 days following completion of the first cycle of DANYELZA. Monitor blood pressure during and following DANYELZA infusion and assess for neurologic symptoms. Permanently discontinue DANYELZA in case of symptomatic RPLS.

''Peripheral Neuropathy''
Peripheral neuropathy, including peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, and neuralgia, occurred in 32% of patients in Study 201 and in 25% of patients in Study 12-230. Most signs and symptoms of neuropathy began on the day of the infusion and neuropathy lasted a median of 5.5 days (range 0 to 22 days) in Study 201 and 0 days (range 0 to 22 days) in Study 12-230

''Neurological Disorders of the Eye''
Neurological disorders of the eye including unequal pupils, blurred vision, accommodation disorder, mydriasis, visual impairment, and photophobia occurred in 24% of patients in Study 201 and 19% of patients in Study 12-230. Neurological disorders of the eye lasted a median of 17 days (range 0 to 84 days) in Study 201 with two patients (8%) experiencing an event that had not resolved at the time of data cutoff, and a median of 1 day (range less than one day to 21 days) in Study 12-230. Permanently discontinue DANYELZA based on severity

''Prolonged Urinary Retention''
Urinary retention occurred in 1 (4%) patient in Study 201 and in 3 patients (4%) in Study 12-230. All events in both studies occurred on the day of an infusion of DANYELZA and lasted between 0 and 24 days. Permanently discontinue DANYELZA in patients with urinary retention that does not resolve following discontinuation of opioids

'''Myocarditis''':
Myocarditis has occurred in adolescent patients receiving DANYELZA in clinical trials and expanded access programs. Myocarditis occurred within days of receiving DANYELZA requiring drug interruption. Monitor for signs and symptoms of myocarditis during treatment with DANYELZA. Withhold, reduce the dose, or permanently discontinue DANYELZA based on severity

'''Hypertension''':
Hypertension occurred in 44% of patients in Study 201 and 28% of patients in Study 12-230 who received DANYELZA. Grade 3 or 4 hypertension occurred in 4% of patients in Study 201 and 7% of patients in Study 12- 230. Four patients (6%) in Study 12-230 permanently discontinued DANYELZA due to hypertension. In both studies, most events occurred on the day of DANYELZA infusion and occurred up to 9 days following an infusion of DANYELZA.

Do not initiate DANYELZA in patients with uncontrolled hypertension. Monitor blood pressure during infusion, and at least daily on Days 1 to 8 of each cycle of DANYELZA and evaluate for complications of hypertension including RPLS. Interrupt DANYELZA infusion and resume at a reduced rate, or permanently discontinue DANYELZA based on the severity

'''Orthostatic Hypotension''':
Orthostatic hypotension has occurred in patients receiving DANYELZA in clinical trials and expanded access programs. Severe orthostatic hypotension, including cases requiring hospitalization, have occurred. Cases occurred within hours to 6 days of DANYELZA infusions in any cycle.

In patients with symptoms of orthostatic hypotension, monitor postural blood pressure prior to initiating treatment with DANYELZA and as clinically indicated with subsequent dosing. Withhold, reduce dose, or permanently discontinue DANYELZA based on severity.

'''Embryo-Fetal Toxicity''':
Based on its mechanism of action, DANYELZA may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential, including pregnant women, of the potential risk to a fetus. Advise females of reproductive potential to use effective contraceptive during treatment with DANYELZA and for two months after the last dose.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of DANYELZA in combination with GM-CSF was evaluated in patients with refractory or relapsed highrisk neuroblastoma in bone or bone marrow who had demonstrated a partial response, minor response, or stable disease following initial or subsequent therapy, and in patients who were in second complete remission, from two open-label, single arm studies, Study 201 (n=25) and Study 12-230 (n=72). Patients received DANYELZA 9 mg/kg/cycle administered as three separate intravenous infusions of 3 mg/kg (Day 1, 3 and 5) in the first week of each cycle. Patients also received GM-CSF 250 μg/m2/day subcutaneously on Days -4 to 0 and GM-CSF 500 μg/m2/day subcutaneously on Days 1 to 5

The most common adverse reactions in Studies 201 and 12-230 (≥25% in either study) were infusion-related reaction, pain, tachycardia, vomiting, cough, nausea, diarrhea, decreased appetite, hypertension, fatigue, erythema multiforme, peripheral neuropathy, urticaria, pyrexia, headache, injection site reaction, edema, anxiety, localized edema and irritability. The most common Grade 3 or 4 laboratory abnormalities (≥5% in either study) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased platelet count, decreased potassium, increased alanine aminotransferase, decreased glucose, decreased calcium, decreased albumin, decreased sodium and decreased phosphate.
|postmarketing=The following adverse reactions have been identified during expanded access and post-approval use of DANYELZA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
|useInLaborDelivery=Based on its mechanism of action, DANYELZA may cause fetal harm when administered to pregnant women. There are no available data on the use of DANYELZA in pregnant women and no animal reproduction studies have been conducted with DANYELZA. IgG1 monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. Advise pregnant women of potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
|useInNursing=There are no data on the presence of naxitamab-gqgk in human milk or its effects on the breastfed child, or on milk production, however, human IgG is present in human milk. Because of the potential for serious adverse reactions in a breastfed child from DANYELZA, advise women not to breastfeed during treatment and for 2 months after the last dose of DANYELZA.
|useInPed=The safety and effectiveness of DANYELZA, in combination with GM-CSF for the treatment of relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response or stable disease following prior therapy, have been established in pediatric patients 1 year of age and older.

Safety and effectiveness have not been established in pediatric patients younger than 1 year of age.
|useInGeri=Neuroblastoma is largely a disease of pediatric and young adult patients. Clinical studies of DANYELZA in combination with GM-CSF did not include patients 65 years of age and older.
|useInReproPotential=DANYELZA may cause fetal harm when administered to a pregnant woman
''Pregnancy Testing''
Verify pregnancy status in females of reproductive potential prior to initiating DANYELZA.

''Contraception''
FEMALES
Advise females of reproductive potential to use effective contraception during treatment and for 2 months after the last dose of DANYELZA.
|administration=*Administer DANYELZA as a diluted intravenous infusion as recommended. Do not administer DANYELZA as an intravenous push or bolus
*For the first infusion (Cycle 1, Day 1), administer DANYELZA intravenously over 60 minutes.
For subsequent infusions, administer DANYELZA intravenously over 30 to 60 minutes, as tolerated.
*Observe patients for a minimum of 2 hours following each infusion.
|monitoring=Premedicate with an antihistamine, acetaminophen, an H2 antagonist and corticosteroid as recommended.
Monitor patients closely for signs and symptoms of infusion reactions during and for at least 2 hours following completion of each DANYELZA infusion in a setting where cardiopulmonary resuscitation medication and equipment are available.

Reduce the rate, interrupt infusion, or permanently discontinue DANYELZA based on severity and institute appropriate medical management as needed.
|mechAction=Naxitamab-gqgk binds to the glycolipid GD2. GD2 is a disialoganglioside that is overexpressed on neuroblastoma cells and other cells of neuroectodermal origin, including the central nervous system and peripheral nerves. In vitro, naxitamab-gqgk was able to bind to cell surface GD2 and induce complement dependent cytotoxicity (CDC) and antibody dependent cell-mediated cytotoxicity (ADCC).
|PD=The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of naxitamab-gqgk have not been fully characterized.
|PK=The geometric mean (CV%) maximum plasma concentration (Cmax) of naxitamab-gqgk was 57.4 μg/mL (49%) following DANYELZA 3 mg/kg intravenous infusion over 30 minutes.

'''Elimination''':
The mean terminal half-life of naxitamab-gqgk was 8.2 days.

'''Metabolism''':
Naxitamab-gqgk is expected to be metabolized into small peptides by catabolic pathways.

'''Specific Populations''':
Population pharmacokinetic analyses suggest that age (range: 1 to 34 years), sex and race have no clinically important effect on the clearance (CL) of naxitamab-gqgk. The naxitamab-gqgk systemic exposure (AUC) at 150 mg/day (450 mg per cycle) for patients with body weight over 50 kg is not expected to differ clinically from that of the naxitamabgqgk exposures at 3 mg/kg/day (9 mg/kg per cycle) for patients with body weight of 30 - 50 kg.
|nonClinToxic='''Carcinogenesis, Mutagenesis, Impairment of Fertility''':
No animal studies have been conducted to evaluate the carcinogenic or mutagenic potential of naxitamab-gqgk.

Dedicated studies evaluating the effects of naxitamab-gqgk on fertility in animals have not been conducted.

'''Animal Toxicology and/or Pharmacology''':
Non-clinical studies suggest that naxitamab-gqgk-induced neuropathic pain is mediated by binding of the antibody to the GD2 antigen located on the surface of peripheral nerve fibers and myelin and subsequent induction of immunemediated cytotoxic activity.

In a nude rat model, slight-moderate hyperplasia and erosion of the glandular mucosa of the stomach occurred, occasionally accompanied by diffuse inflammation. Complete recovery of all histopathological findings in the stomachs of male rats was observed; however, only partial recovery was observed in the stomachs of female rats during the four week off-drug period.
|clinicalStudies=The efficacy of DANYELZA in combination with GM-CSF was evaluated in two open-label, single arm trials in patients with high-risk neuroblastoma with refractory or relapsed disease in the bone or bone marrow, Study 201 and Study 12-230.

'''Study 201''':
The efficacy of DANYELZA in combination with GM-CSF was evaluated in Study 201 (NCT03363373), a multicenter open-label, single arm trial, in a subpopulation of patients who had refractory or relapsed high-risk neuroblastoma in the bone or bone marrow and demonstrated a partial response, minor response, or stable disease to prior therapy. Patients with progressive disease were excluded. All patients received at least one systemic therapy to treat disease outside of the bone or bone marrow prior to enrollment. Patients received DANYELZA 9 mg/kg/cycle administered as three separate intravenous infusions of 3 mg/kg on Days 1, 3 and 5 of each cycle. Patients received GM-CSF subcutaneously at 250 μg/m2/day on Days -4 to 0 and at 500 μg/m2/day on Days 1 to 5. Preplanned radiation to the primary site was allowed.

The major efficacy outcome measure was overall response rate (ORR) according to the revised International Neuroblastoma Response Criteria (INRC), as determined by independent pathology and imaging review and confirmed by at least one subsequent assessment. An additional efficacy outcome measure was duration of response (DOR).

Of the 22 patients included in the efficacy analysis, 64% had refractory disease and 36% had relapsed disease; the median age was 5 years (range 3 to 10 years), 59% were male; 45% were White, 50% were Asian and 5% were Black. MYCN amplification was present in 14% of patients and 86% of patients were International Neuroblastoma Staging System (INSS) stage 4 at time of diagnosis. Disease sites included 59% in the bone only, 9% in bone marrow only, and 32% in both. Prior therapies included surgery (91%), chemotherapy (95%), radiation (36%), autologous stem cell transplant (ASCT) (18%), and anti-GD2 antibody treatment (18%).

'''Study 12-230'''
The efficacy of DANYELZA in combination with GM-CSF was evaluated in Study 12-230 (NCT01757626), a single center, open-label, single arm trial, in a subpopulation of patients who had relapsed or refractory high-risk neuroblastoma in bone or bone marrow and demonstrated a partial response, minor response, or stable disease to prior therapy. Patients with progressive disease were excluded. All patients received at least one systemic therapy to treat disease outside of the bone or bone marrow prior to enrollment. Patients were required to have received at least one dose of DANYELZA at a dose of 3 mg/kg or greater per infusion and have evaluable disease at baseline according to independent review per the revised INRC.

Patients received DANYELZA 9 mg/kg/cycle administered as three separate intravenous infusions of 3 mg/kg (on Days 1, 3 and 5) in the first week of each cycle. Patients received GM-CSF subcutaneously at 250 μg/m2/day on Days -4 to 0 and at 500 μg/m2/day on Days 1 to 5. Radiation to non-target bony lesions and soft tissue lesions was permitted at the investigator's discretion; assessment of response excluded sites that received radiation. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), as determined by independent pathology and imaging review according to the revised INRC and confirmed by at least one subsequent assessment.

Of the 38 patients included in the efficacy analysis, 55% had relapsed neuroblastoma and 45% had refractory disease; 50% were male, the median age was 5 years (range 2 to 23 years), 74% were White, 8% Asian and 5% were Black, 5% Native American/American Indian/Alaska Native, 3% other races and 5% was not available. MYCN-amplification was present in 16% of patients and most patients were International Neuroblastoma Staging System (INSS) stage 4 (95%). Fifty percent (50%) of patients had disease involvement in the bone only, 11% only in bone marrow, and 39% in both. Prior therapies included surgery (100%), chemotherapy (100%), radiation (47%), autologous stem cell transplant (ASCT) (42%), and anti-GD2 antibody treatment (58%).
|howSupplied=DANYELZA (naxitamab-gqgk) injection is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellow solution for intravenous infusion supplied as a carton containing one 40mg/10 mL (4 mg/mL) singledose vial.
|storage=Store DANYELZA vial refrigerated at 2°C to 8°C (36°F to 46°F) in the outer carton to protect from light until time of use.
|fdaPatientInfo=Advise the patient and caregiver to read the FDA-approved patient labeling:

'''Serious Infusion-Related Reactions''':
Advise patients and caregivers that DANYELZA can cause serious infusion-related reactions and anaphylaxis and to immediately report any signs or symptoms, such as facial or lip swelling, urticaria, or difficulty breathing, that occur during or following the infusion

'''Neurotoxicity''':
Advise patients and caregivers that DANYELZA can cause neurotoxicity, including severe pain, peripheral neuropathy, neurological disorders of the eye, prolonged urinary retention, transverse myelitis, and reverse posterior leukoencephalopathy syndrome. Advise patients to contact their healthcare provider for any new or worsening neurological symptoms

'''Myocarditis''':
Advise patients and caregivers that myocarditis has been seen in patients taking DANYELZA and to report any signs or symptoms, such as chest pain, shortness of breath or abnormal heart rhythms during treatment with DANYELZA

'''Hypertension''':
Advise patients and caregivers that DANYELZA can cause hypertension and to immediately report signs or symptoms of hypertension

'''Orthostatic Hypotension'''
Advise patients and caregivers that DANYELZA can cause severe low blood pressure when standing after sitting or lying down. Advise patients and caregivers to report any signs or symptoms, such as dizziness, lightheadedness or fainting during treatment with DANYELZA

'''Embryo-Fetal Toxicity '''
Advise females of reproductive potential, including pregnant women, of the potential risk to the fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy and to use effective contraception during treatment with and for 2 months after the last dose of DANYELZA

'''Lactation'''
Advise women not to breastfeed during treatment with DANYELZA and for 2 months after the last dose
|alcohol=Alcohol-Naxitamab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=Danyelza
}}

Berotralstat

2025-04-27T17:25:16Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=berotralstat |aOrAn=a |drugClass=plasma kallikrein inhibitor |indicationType=prophylaxis |indication=to prevent attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years of age and older. |adverseReactions=QT Prolongation |blackBoxWarningTitle='''TITLE''' |blackBoxWarningBody=''Condition Name:</..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=berotralstat
|aOrAn=a
|drugClass=plasma kallikrein inhibitor
|indicationType=prophylaxis
|indication=to prevent attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years of age and older.
|adverseReactions=QT Prolongation
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=ORLADEYO® is indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years of age and older.

'''Limitations of Use:''':
The safety and effectiveness of ORLADEYO for the treatment of acute HAE attacks have not been established. ORLADEYO should not be used for treatment of acute HAE attacks. Additional doses or doses of ORLADEYO higher than 150 mg once daily are not recommended due to the potential for QT prolongation

'''Recommended Dosage''':
The recommended dosage of ORLADEYO is one 150 mg capsule taken orally once daily with food.

'''Recommended Dosage in Patients with Hepatic Impairment''':
No dosage adjustment of ORLADEYO is recommended for patients with mild hepatic impairment (Child-Pugh Class A)

In patients with moderate or severe hepatic impairment (Child-Pugh B or C), the recommended dosage of ORLADEYO is one 110 mg capsule taken orally once daily with food

'''Dosage Adjustment in Patients with Persistent GI Reactions''':
Gastrointestinal (GI) reactions may occur in patients receiving ORLADEYO. If GI events persist, a reduced dose of 110 mg once daily with food may be considered.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Berotralstat in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Berotralstat in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Berotralstat in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Berotralstat in pediatric patients.
|contraindications=None
|warnings=''' Risk of QT Prolongation with Higher-Than-Recommended Dosages'''
ORLADEYO should not be used for treatment of acute attacks of HAE. Additional doses or doses of ORLADEYO higher than 150 mg once daily are not recommended. An increase in QT was observed at dosages higher than the recommended 150 mg once daily dosage and was concentration dependent
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of ORLADEYO is primarily based on 24-week (Part 1) data from a 3-part, double-blind, parallel-group, placebo-controlled study (Trial 1) in 120 patients with Type I or II HAE randomized and dosed with either ORLADEYO 110 mg, 150 mg, or placebo, once daily with food. After Week 24, patients who continued in the study received active treatment through 48 weeks.

In Trial 1, a total of 81 patients aged 12 years and older with HAE received at least one dose of ORLADEYO in Part 1. Overall, 66% of patients were female and 93% of patients were Caucasian with a mean age of 41.6 years. The proportion of patients who discontinued study drug prematurely due to adverse reactions was 7% and 3% for patients treated with 110 mg and 150 mg ORLADEYO, respectively, and 3% for placebo-treated patients. No deaths occurred in the trial.

The safety profile of ORLADEYO was generally similar across all subgroups of patients, including analysis by age, sex, and geographic region.

Gastrointestinal reactions, including abdominal pain, vomiting, and diarrhea occurred more frequently in patients receiving ORLADEYO 150 mg versus ORLADEYO 110 mg or placebo. These reactions generally occurred early after initiation of treatment with ORLADEYO, became less frequent with time, and typically self-resolved. No patients in the ORLADEYO 150 mg dose group and 1 patient in the ORLADEYO 110 mg dose group discontinued treatment due to a gastrointestinal adverse reaction.

''Less Common Adverse Reactions'':
Other adverse reactions that occurred in Part 1 of Trial 1 with an incidence between 5% and <10% at a higher incidence in ORLADEYO-treated patients compared to placebo included headache (9% versus 5%), fatigue (6% versus 3%), and flatulence (6% versus 3%).

A maculopapular drug rash was reported in less than 1% of patients treated with ORLADEYO. The rash resolved, including in subjects who continued dosing.

Safety data are also available from 227 patients enrolled in an ongoing, open-label, long-term safety study (Trial 2) who received ORLADEYO 110 mg (N=100) or 150 mg (N=127) once daily with food and are consistent with the 24-week controlled safety data.

'''Laboratory Abnormalities''':
''Transaminase elevations'':
In Part 1 of Trial 1, a single 150 mg ORLADEYO-treated patient discontinued treatment due to asymptomatic elevated transaminases (ALT >8× the upper limit of normal [ULN] and AST >3× ULN). Total bilirubin was normal. No subject receiving 110 mg or placebo developed transaminase levels >3× ULN. In addition to this patient, 2 ORLADEYO-treated patients developed laboratory-related hepatic adverse events compared to 1 placebo-treated patient. No patient reported serious adverse reactions of elevated transaminases.
|postmarketing=The following adverse reactions have been identified during postapproval use of ORLADEYO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal Disorders: nausea
|drugInteractions=This section describes clinically relevant drug interactions with ORLADEYO. Drug interaction studies are described elsewhere in the labeling

'''Potential for Other Drugs to Affect ORLADEYO'''
''P-gp Inducers''
Berotralstat is a substrate of P-gp and BCRP. P-gp inducers (e.g., rifampin, St. John's wort) may decrease berotralstat plasma concentration, leading to reduced efficacy of ORLADEYO. The use of P-gp inducers is not recommended with ORLADEYO.

'''Potential for ORLADEYO to Affect Other Drugs'''
''CYP2D6 and CYP3A4 Substrates''
ORLADEYO at a dose of 150 mg is a moderate inhibitor of CYP2D6 and CYP3A4. For concomitant medications with a narrow therapeutic index that are predominantly metabolized by CYP2D6 (e.g., thioridazine, pimozide) or CYP3A4 (e.g., cyclosporine, fentanyl), appropriate monitoring and dose titration is recommended

''Desogestrel'':
In a drug interaction study conducted in healthy women of childbearing potential (N=22), co-administration of ORLADEYO at a dose of 150 mg at steady state with a single dose of 0.15 mg/0.03 mg desogestrel/ethinyl estradiol resulted in increased exposure to etonogestrel, the active metabolite of desogestrel. If ORLADEYO is co-administered with desogestrel, any potential risk of concurrent use of desogestrel should be weighed against benefit

'''P-gp Substrates''':
ORLADEYO at a dose of 300 mg is a P-gp inhibitor. Appropriate monitoring and dose titration is recommended for P-gp substrates (e.g., digoxin) when co-administering with ORLADEYO
|useInLaborDelivery=There are insufficient data in pregnant women available to inform drug-related risks with ORLADEYO use in pregnancy. Based on animal reproduction studies, no evidence of structural alterations was observed when berotralstat was administered orally to pregnant rats and rabbits during organogenesis at doses up to approximately 10 and 2 times, respectively, the maximum recommended human daily dose (MRHDD) in adults on an AUC basis.
The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
''Animal Data''
In animal reproduction studies, oral administration of berotralstat to pregnant rats and rabbits during the period of organogenesis did not cause fetal structural alterations. The berotralstat dose in rats and rabbits was up to approximately 10 and 2 times, respectively, the MRHDD in adults (on an AUC basis at maternal doses of 75 and 100 mg/kg/day, respectively). In a pre- and postnatal development study in rats, oral administration of berotralstat to pregnant rats during the period of organogenesis and until delivery at doses up to 45 mg/kg/day (approximately 2 times of the MRHDD on a mg/m2 basis) did not cause fetal structural alterations either. Berotralstat concentrations in the fetal blood were approximately 5-11% of the maternal blood.
|useInNursing=There are no data on the presence of berotralstat in human milk, its effects on the breastfed infant, or its effects on milk production. However, when a drug is present in animal milk, it is likely that the drug will be present in human milk. Low levels of berotralstat were detected in the plasma of rat pups when dams were dosed with the drug orally during the lactation period. The berotralstat concentration in the pup plasma was approximately 2% of the maternal plasma

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ORLADEYO and any potential adverse effects on the breastfed infant from ORLADEYO or from the underlying maternal condition.
In the pre- and post-natal development study in rats, berotralstat was administered to dams during the pregnancy and lactation periods at doses up to 45 mg/kg/day (approximately 2 times of the MRHDD on a mg/m2 basis). Berotralstat was detected in the plasma of pups during the lactation period. The berotralstat concentration in the pup plasma was approximately 2% of the maternal plasma. Both dams and pups at 45 mg/kg/day showed statistically significant decreases in body weight gain (p<0.05). No treatment-related effects were observed at 25 mg/kg/day (approximately equal to the MRHDD on a mg/m2 basis).
|useInPed=The safety and effectiveness of ORLADEYO for prophylaxis to prevent attacks of hereditary angioedema have been established in pediatric patients aged 12 and older. Use of ORLADEYO in this population is supported by evidence from an adequate and well-controlled study (Trial 1) that included adults and a total of 6 adolescent patients aged 12 to <18 years of age. The safety profile and attack rate on study were similar to those observed in adults. An additional 10 adolescent patients aged 12 to <18 years were enrolled in the open-label study. The safety and effectiveness of ORLADEYO in pediatric patients <12 years of age have not been established.
|useInGeri=The safety and effectiveness of ORLADEYO were evaluated in a subgroup of patients (N=9) aged ≥65 years in Trial 1. Results of the subgroup analysis by age were consistent with overall study results. The safety profile from an additional 5 elderly patients aged ≥65 years enrolled in the open-label, long-term safety study (Trial 2) was consistent with data from Trial 1
|useInRenalImpair=No dosage adjustment of ORLADEYO is recommended for patients with mild, moderate, or severe renal impairment.
ORLADEYO has not been studied in patients with End-Stage Renal Disease (CLCR <15 mL/min or eGFR <15 mL/min/1.73 m2 or patients requiring hemodialysis), and therefore is not recommended for use in these patient populations
|useInHepaticImpair=No dosage adjustment of ORLADEYO is recommended for patients with mild hepatic impairment (Child-Pugh Class A).

In patients with moderate or severe hepatic impairment (Child-Pugh B or C), the recommended dose of ORLADEYO is 110 mg once daily with food
|administration='''Recommended Dosage''':
The recommended dosage of ORLADEYO is one 150 mg capsule taken orally once daily with food.

'''Recommended Dosage in Patients with Hepatic Impairment''':
No dosage adjustment of ORLADEYO is recommended for patients with mild hepatic impairment (Child-Pugh Class A)

In patients with moderate or severe hepatic impairment (Child-Pugh B or C), the recommended dosage of ORLADEYO is one 110 mg capsule taken orally once daily with food

'''Dosage Adjustment in Patients with Persistent GI Reactions''':
Gastrointestinal (GI) reactions may occur in patients receiving ORLADEYO. If GI events persist, a reduced dose of 110 mg once daily with food may be considered.
|monitoring=ORLADEYO at a dose of 150 mg is a moderate inhibitor of CYP2D6 and CYP3A4. For concomitant medications with a narrow therapeutic index that are predominantly metabolized by CYP2D6 (e.g., thioridazine, pimozide) or CYP3A4 (e.g., cyclosporine, fentanyl), appropriate monitoring and dose titration is recommended

'''P-gp Substrates'''
ORLADEYO at a dose of 300 mg is a P-gp inhibitor. Appropriate monitoring and dose titration is recommended for P-gp substrates (e.g., digoxin) when co-administering with ORLADEYO
|mechAction=Berotralstat is a plasma kallikrein inhibitor that binds to plasma kallikrein and inhibits its proteolytic activity. Plasma kallikrein is a protease that cleaves high-molecular-weight kininogen (HMWK) to generate cleaved HMWK (cHMWK) and bradykinin, a potent vasodilator that increases vascular permeability resulting in swelling and pain associated with HAE. In patients with HAE due to C1-inhibitor (C1-INH) deficiency or dysfunction, normal regulation of plasma kallikrein activity is not present, which leads to uncontrolled increases in plasma kallikrein activity and results in angioedema attacks. Berotralstat decreases plasma kallikrein activity to control excess bradykinin generation in patients with HAE.
|PD=Concentration-dependent inhibition of plasma kallikrein, measured as a reduction from baseline of specific enzyme activity, was demonstrated after oral administration of ORLADEYO once daily in patients with HAE.

'''Cardiac Electrophysiology'''
At the recommended dose of 150 mg once daily, ORLADEYO does not prolong the QT interval to any clinically relevant extent. At 3 times the recommended dose, the mean (upper 90% confidence interval) increase in QTcF was 15.9 msec (23.5 msec). The observed increase in QTcF was concentration-dependent.
|PK=Following oral administration of berotralstat 150 mg once daily, the steady-state Cmax and area under the curve over the dosing interval (AUCtau) are 158 ng/mL (range: 110 to 234 ng/mL) and 2770 ng*hr/mL (range: 1880 to 3790 ng*hr/mL), respectively. Following oral administration of berotralstat 110 mg once daily, the steady-state Cmax and AUCtau are 97.8 ng/mL (range: 63 to 235 ng/mL) and 1600 ng*hr/mL (range: 950 to 4170 ng*hr/mL), respectively.

Berotralstat exposure (Cmax and AUC) increases greater than proportionally with dose and steady state is reached by days 6 to 12. After once-daily administration, exposure of berotralstat at steady state is approximately 5 times that after a single dose.

The pharmacokinetics of berotralstat are similar between healthy adult subjects and in patients with HAE.

'''Absorption'''
The median time to maximum plasma concentration (Tmax) of berotralstat when administered with food is 5 hours (range: 1 to 8 hours)

''Effect of Food''
No differences in the Cmax and AUC of berotralstat were observed following administration with a high-fat meal, however the median Tmax was delayed by 3 hours, from 2 hours (fasted) to 5 hours (fed).

'''Distribution'''
Plasma protein binding is approximately 99%. After a single dose of radiolabeled berotralstat 300 mg, the blood to plasma ratio was approximately 0.92.

'''Elimination'''
The median elimination half-life of berotralstat was approximately 93 hours (range: 39 to 152 hours).

''Metabolism''
Berotralstat is metabolized by CYP2D6 and by CYP3A4 with low turnover in vitro. After a single oral radiolabeled berotralstat 300 mg dose, berotralstat represented 34% of the total plasma radioactivity, with 8 metabolites, each accounting for between 1.8 and 7.8% of the total radioactivity.

''Excretion''
After a single oral radiolabeled berotralstat 300 mg dose, approximately 9% was excreted in urine (3.4% unchanged; range: 1.8 to 4.7%) and 79% was excreted in feces.

'''Specific Populations'''
Body weight, age, gender, and race did not have a clinically meaningful influence on the systemic exposure of berotralstat.

''Geriatric Patients''
Based on the population pharmacokinetic analyses that included elderly patients (≥65 to 74 years, N=25), age does not have a clinically meaningful impact on the systemic exposure of berotralstat

''Pediatric Patients''
Based on population pharmacokinetic analyses that included pediatric patients 12 to <18 years of age, exposure at steady state following oral administration of berotralstat 150 mg once daily was approximately 20% higher compared to adults. The higher exposure in adolescents is not considered to be clinically meaningful.

''Patients with Renal Impairment''
The pharmacokinetics of a single 200 mg oral dose of berotralstat were studied in subjects with severe renal impairment (CLCR less than 30 mL/min). When compared to a concurrent cohort with normal renal function (CLCR greater than 90 mL/min), no clinically relevant differences were observed; Cmax was increased by 47%, while AUC0-last was increased by 14%

The pharmacokinetics of berotralstat has not been studied in patients with End-Stage Renal Disease (CLCR less than 15 mL/min or eGFR less than 15 mL/min/1.73 m2 or patients requiring hemodialysis)

''Patients with Hepatic Impairment''
The pharmacokinetics of a single 150 mg oral dose of berotralstat were studied in subjects with mild, moderate, and severe hepatic function (Child-Pugh Class A, B, and C, respectively). The pharmacokinetics of berotralstat were unchanged in subjects with mild hepatic impairment compared to subjects with normal hepatic function. In subjects with moderate hepatic impairment, Cmax was increased by 77%, while AUC0-inf was increased by 78%. In subjects with severe hepatic impairment, Cmax was increased by 27%, while AUC0-last was decreased by 5%. The median half-life of berotralstat was increased by 37% and 22% in patients with moderate and severe hepatic impairment, respectively, in comparison to healthy subjects. The percent of unbound berotralstat increased 2-fold from a mean of 1.2% in healthy subjects to a mean of 2.4% in subjects with severe hepatic impairment.

'''Drug Interaction Studies'''
''Effect of Other Drugs on the Pharmacokinetics of ORLADEYO''
Berotralstat is a P-gp and BCRP substrate. Cyclosporine, a P-gp and BCRP inhibitor, decreased berotralstat 150 mg Cmax by 7%, while AUC0-last and AUC0-inf increased by 27% and 24%, respectively.

''Effect of ORLADEYO on the Pharmacokinetics of Other Drugs''
Berotralstat 150 mg once daily is a moderate inhibitor of CYP2D6 and CYP3A4, and a weak inhibitor of CYP2C9 and CYP2C19.

Berotralstat at a 300 mg dose is an inhibitor of P-gp and is not an inhibitor of BCRP (rosuvastatin exposure was decreased by approximately 20%).

Co-administration of berotralstat 150 mg once daily with 0.15 mg/0.03 mg desogestrel/ethinyl estradiol led to a 2.6-fold increase in the AUC0-last of etonogestrel, the active metabolite of desogestrel
|nonClinToxic='''Carcinogenesis'''
Carcinogenicity of berotralstat was evaluated in a 2-year study in Wistar rats and a 26-week study in Tg.rasH2 transgenic mice. The berotralstat doses (oral gavage) were up to 20 and 50 mg/kg/day in rats and mice (approximately 5 and 10 times the MRHDD on a plasma AUC basis, respectively). No evidence of tumorigenicity was observed in either species.

'''Mutagenesis'''
Berotralstat tested negative in the in vitro bacterial reverse mutation assay (Ames test), the in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and the in vivo rat micronucleus assay.

'''Impairment of Fertility'''
In a fertility study in rats, berotralstat at oral doses up to 45 mg/kg/day (approximately 2 times the MRHDD on a mg/m2 basis) showed no effect on fertility in males or females.
|clinicalStudies='''Trial 1 (NCT3485911)'''
The efficacy of ORLADEYO for the prevention of angioedema attacks in patients 12 years of age and older with Type I or II HAE was demonstrated in Part 1 of a multicenter, randomized, double-blind, placebo-controlled, parallel-group study (Trial 1).

The study included 120 adult and adolescent patients who experienced at least two investigator-confirmed attacks within the first 8 weeks of the run-in period and took at least one dose of study treatment. Patients were randomized into 1 of 3 parallel treatment arms, stratified by baseline attack rate, in a 1:1:1 ratio (berotralstat 110 mg, berotralstat 150 mg, or placebo by oral administration once daily, with food) for the 24-week treatment period (Part 1).

Patients discontinued other prophylactic HAE medications prior to entering the study; however, all patients were allowed to use rescue medications for treatment of breakthrough HAE attacks.

A history of laryngeal angioedema attacks was reported in 74% of patients and 75% reported prior use of long-term prophylaxis. The median attack rate during the prospective run-in period (baseline attack rate) was 2.9/month. Seventy percent of patients enrolled had a baseline attack rate of ≥2 attacks/month.

ORLADEYO 150 mg and 110 mg produced statistically significant reductions in the rate of HAE attacks compared to placebo for the primary endpoint in the Intent-to-Treat (ITT) population as shown in Table 2. The percent reductions in HAE attack rate were greater with ORLADEYO 150 mg and 110 mg relative to placebo, regardless of attack rate during the run-in period.
|howSupplied=ORLADEYO (berotralstat) capsules:
*150 mg: a white opaque body with a black imprint "150" and a light blue opaque cap with a black imprint "BCX".
* 110 mg: light blue opaque capsules with a white imprint "110" on body and a white imprint "BCX" on cap.
*A 28-day supply of ORLADEYO is provided in a carton containing four child-resistant shellpaks, each containing a 7-capsule blister card. NDC 72769-101-01 (150 mg) and NDC 72769-102-01 (110 mg).
*Each carton contains a tamper-evident seal.
*Do not use if tamper-evident seal is broken or missing.
|storage=Store at 20°C to 25°C (68°F to 77°F). Excursions permitted between 15°C and 30°C (59°F to 86°F)
|fdaPatientInfo='''Drug Interactions''':
Advise patients that ORLADEYO may interact with other drugs and advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products.

'''Not for Acute Treatment of HAE Attacks'''
Advise patients to take their usual rescue medication to treat an acute attack of HAE. Inform patients that the safety and effectiveness of ORLADEYO has not been established as an acute treatment for HAE attacks. Advise patients that they should not take daily doses higher than 150 mg once daily or additional doses of ORLADEYO to treat an acute attack of HAE due to risk of QT prolongation
|alcohol=Alcohol-Berotralstat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=Orladeyo
}}

Tirbanibulin

2025-04-27T17:05:43Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=tirbanibulin |aOrAn=a |drugClass=non-ATP competitive Src kinase inhibitor and tubulin polymerization inhibitor. |indicationType=treatment |indication=of actinic keratosis on the face or scalp |adverseReactions=*Application site pruritus *Application site paina |blackBoxWarningTitle='''TITLE''' |blackBoxWarningBody=''..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=tirbanibulin
|aOrAn=a
|drugClass=non-ATP competitive Src kinase inhibitor and tubulin polymerization inhibitor.
|indicationType=treatment
|indication=of actinic keratosis on the face or scalp
|adverseReactions=*Application site pruritus
*Application site paina
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=KLISYRI is indicated for the topical field treatment of actinic keratosis on the face or scalp.
For topical use only; not for oral or ophthalmic use.

Apply KLISYRI evenly to cover up to 100 cm2 treatment field on the face or balding scalp once daily for 5 consecutive days using 1 unit-dose packet per application.

Wash hands immediately with soap and water after application.

Avoid washing and touching the treated area for approximately 8 hours after application of KLISYRI. Following this time, the area may be washed with a mild soap.

Avoid transfer of KLISYRI to the periocular area
Avoid application near and around the mouth and lips.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Tirbanibulin in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Tirbanibulin in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Tirbanibulin in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Tirbanibulin in pediatric patients.
|contraindications=None
|warnings='''Ophthalmic Adverse Reactions''':
KLISYRI may cause eye irritation.

Avoid transfer of the drug into the eyes and to the periocular area during and after application. Wash hands immediately after application. If accidental exposure occurs, instruct patient to flush eyes with water and seek medical care as soon as possible.

'''Local Skin Reactions''':
Local skin reactions, including severe reactions (erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation and erosion/ulceration) in the treated area can occur after topical application of KLISYRI. Occlusion after topical application of KLISYRI is more likely to result in irritation. Avoid use until skin is healed from any previous drug, procedure, or surgical treatment.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Two double-blind, vehicle-controlled clinical trials were conducted in 702 adult subjects with actinic keratosis on the face or scalp. Subjects were randomized 1:1 to KLISYRI or vehicle. Subjects enrolled in the trials had 4 to 8 clinically typical, visible, and discrete AK lesions in a contiguous area of 25 cm2 on the face or scalp. Subjects’ average age was 70 years (range 45 to 96 years) and they were predominantly White (99%), male (87%), with Fitzpatrick skin types I or II (72%) and actinic keratosis on the face (68%) or scalp (32%). Treatment groups were comparable across all demographics and baseline characteristics, including AK lesion count and distribution on the face or scalp.

In the controlled trials, local skin reactions (LSRs) were collected independent of adverse events. Local skin reactions including erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, erosions/ulcerations were assessed by the investigators using a grading scale of 0 = absent, 1 = mild (slightly, barely perceptible), 2 = moderate (distinct presence), and 3 = severe (marked, intense).
|useInLaborDelivery=There are no available data with KLISYRI use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

In animal reproduction studies, oral administration of tirbanibulin to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal deaths and malformations at a systemic exposure that was at least 19 times the exposure associated with the maximum recommended human dose (MRHD). Oral administration of tirbanibulin to pregnant rabbits during the period of organogenesis resulted in reduced mean fetal weight and size at a systemic exposure that was 41 times the exposure associated with the MRHD. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

''Animal Data''
Tirbanibulin induced fetal deaths and external, visceral, and skeletal malformations when administered orally to pregnant rats during the period of organogenesis at doses greater than or equal to 1.25 mg/kg/day, which resulted in systemic exposures at least 19 times the exposure associated with the MRHD on an Area Under the Curve (AUC) comparison basis. Tirbanibulin had no apparent effects on fetal development in rats at a dose of 0.5 mg/kg/day, which resulted in systemic exposures 5 times the exposure associated with the MRHD.

Tirbanibulin reduced mean fetal weight and size (crown-rump length) when administered orally to pregnant rabbits during the period of organogenesis at a dose of 3 mg/kg/day, which resulted in a systemic exposure 41 times the exposure associated with the MRHD on an AUC comparison basis. Tirbanibulin had no apparent effects on fetal development in rabbits at a dose of 1 mg/kg/day, which resulted in systemic exposures 14 times the exposure associated with the MRHD.

Tirbanibulin was assessed for effects on peri- and post-natal development of rats in a study that involved oral administration to pregnant rats during the period of organogenesis through lactation at dosages up to 1.25 mg/kg/day. These dosages resulted in systemic exposures up to 19 times the exposure associated with the MRHD on an AUC comparison basis. No adverse effects on maternal function or developmental, neurobehavioral, or reproductive performance of offspring were observed.
|useInNursing=There are no data on lactational transfer of KLISYRI to human or animal milk. The effects of KLISYRI on the breastfed infant, or its effects on milk production, are unknown.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for KLISYRI and any potential adverse effects on the breastfed child from tirbanibulin or from the underlying maternal condition.
|useInPed=The safety and effectiveness of KLISYRI for actinic keratosis in subjects less than 18 years of age have not been established. Actinic keratosis is not a condition generally seen within the pediatric population.
|useInGeri=Of the 353 subjects with AK treated with KLISYRI in the 2 controlled Phase 3 trials, 246 (70%) were 65 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
|administration=Apply KLISYRI evenly to cover up to 100 cm2 treatment field on the face or balding scalp once daily for 5 consecutive days using 1 unit-dose packet per application.

Wash hands immediately with soap and water after application.

Avoid washing and touching the treated area for approximately 8 hours after application of KLISYRI. Following this time, the area may be washed with a mild soap.

Avoid transfer of KLISYRI to the periocular area
Avoid application near and around the mouth and lips.
|mechAction=Tirbanibulin is a microtubule inhibitor. The mechanism of action of KLISYRI for the topical treatment of actinic keratosis is unknown
|PD=The pharmacodynamics of tirbanibulin in the treatment of actinic keratosis is unknown.
|PK='''Absorption''':
Following topical treatment of a mean daily dose of 348 mg (range: 224 to 435 mg) of KLISYRI to a 100 cm2 contiguous area of the face or balding scalp, once daily for 5 consecutive days. On Day 5, systemic exposure to tirbanibulin had a mean±SD maximum plasma concentration (Cmax) of 1.32±0.74 ng/mL and 0.71±0.31 ng/mL, and a mean±SD area under the plasma concentration from time zero to 24 hours (AUC24) of 19.6±8.1 h∗ng/mL and 11.7±4.4 h∗ng/mL, in subjects who received the face and scalp topical treatment, respectively. The median time to reach Cmax (Tmax) was ~6 hours.

'''Distribution''':
Plasma protein binding of tirbanibulin is 88% and is independent of concentrations in the range of 0.01 to 10 µg/mL.

'''Elimination''':
''Metabolism'':

Following topical treatment with KLISYRI to adult subjects with actinic keratosis, the plasma concentrations of KX2-5036, KX2-5163, and KX2-5180, three pharmacologically inactive metabolites, were detectable with the highest plasma concentrations of 0.36 ng/mL, 0.42 ng/mL, and 1.70 ng/mL, respectively.

The in vitro study indicated that incubation of 1 or 10 µM tirbanibulin with human hepatocytes generated KX2-5036, KX2-5162 and other unidentified metabolites.

In vitro, tirbanibulin is mainly metabolized by CYP3A4, and to a lesser extent, CYP2C8.

''Excretion'':
Excretion of tirbanibulin has not been fully characterized in humans.

'''Drug Interactions'''
''Clinical Studies'':
No clinical studies evaluating the drug interaction potential of KLISYRI have been conducted.

''In Vitro Studies''
CYP Enzymes: Tirbanibulin and the metabolite KX2-5036 directly or time-dependently inhibited CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 with an IC50 value of >17 µM. Tirbanibulin up to 1 µM (431.5 ng/mL) and the metabolite KX2-5036 up to 3 µM (1024 ng/mL) did not induce CYP 1A2, 2B6, or 3A4. The metabolite KX2-5180 was neither an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4 with an IC50 value of > 225 nM (85 ng/mL) nor an inducer of CYP1A2, 2B6, and 3A4 at a concentration of 225 nM (85 ng/mL). These findings suggest that KLISYRI has no clinically meaningful effect on the PK of drugs metabolized by CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4.

Drug Transporters: Neither tirbanibulin nor the metabolite KX2-5036 was a substrate of MDR1, BCRP, BSEP, MRP2, MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1 or OCT2. The metabolite KX2-5180 was a substrate of BCRP, but not a substrate for other transporters. Tirbanibulin and the metabolites of KX2-5036 and KX2-5180 inhibited MDR1, BCRP, MRP2, BSEP, MATE1, MATE2-K, OAT1, OTA3, OATP1B1, OATP1B3, OCT1 and/or OCT2 with an IC5050 value of >1 µM. The results suggest that KLISYRI has no clinically meaningful effect on the PK of drugs mediated by MDR1, BCRP, MRP2, BSEP, MATE1, MATE2-K, OAT1, OTA3, OATP1B1, OATP1B3, OCT1 and OCT2.
|nonClinToxic=No studies have been performed to evaluate the potential of tirbanibulin to induce carcinogenesis.

Tirbanibulin was negative in an in vitro bacterial reverse mutation (Ames) assay. Tirbanibulin was positive in an in vitro chromosomal aberration assay with Chinese hamster ovary (CHO) cells, an in vitro mouse lymphoma assay with L5178/TK+/- cells, and an in vivo micronucleus assay in rats.

Tirbanibulin was assessed for effects on fertility or reproductive function in rats. Reproductive performance of rats was unaffected by oral doses of tirbanibulin up to 4 mg/kg/day (24 times the MRHD on an AUC comparison basis) in males and 1 mg/kg/day (15 times the MRHD on an AUC comparison basis) in females. However, oral administration of 4 mg/kg/day of tirbanibulin to male rats adversely affected spermatogenesis, including reduced sperm count and motility, and increased observations of morphologically abnormal sperm. No effects on sperm were observed in males treated at 2 mg/kg/day (12 times the MRHD on an AUC comparison basis).
|clinicalStudies='''Actinic Keratosis of the Face or Scalp'''
Two double-blind, vehicle-controlled clinical trials (NCT03285477 and NCT03285490) were conducted with 702 adult subjects with actinic keratosis on the face or scalp. Subjects were randomized 1:1 to KLISYRI or vehicle. Subjects enrolled had 4 to 8 clinically typical, visible, and discrete AK lesions in a contiguous area of 25 cm2 on the face or scalp. Subjects had an average age of 70 years (range 45 to 96 years), were predominantly White (99%), male (87%), with Fitzpatrick skin types I or II (72%) and actinic keratosis on the face (68%) or scalp (32%). Treatment groups were comparable across all demographics and baseline characteristics, including AK lesion count and distribution on the face or scalp.

Subjects received 5 consecutive days of once daily treatment with either KLISYRI (353) or vehicle control (349) to the treatment field. Subjects with complete (100%) clearance of AK lesions in the treatment area at Day 57 returned to the clinic for recurrence assessment every 3 months for a total of 12 months post-Day 57.

The primary efficacy endpoint was complete (100%) clearance of AK lesions in the treatment area, defined as the proportion of subjects at Day 57 with no clinically visible AK lesions in the treatment area and the secondary endpoint was partial (≥75%) clearance of AK lesions in the treatment area. Results from both trials are presented below.
|howSupplied=KLISYRI is a white to off-white ointment and is supplied in unit-dose packets containing either 250 mg or 350 mg of tirbanibulin ointment 1%. Discard each unit-dose packet after use.

NDC 16110-391-05 (5 unit-dose packets each containing 250 mg of ointment)
NDC 16110-391-55 (5 unit-dose packets each containing 350 mg of ointment)
|storage=Store at 20°C-25°C (68°F-77°F), excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Do not refrigerate or freeze.
|fdaPatientInfo='''Ophthalmic Adverse Reactions'''
Advise patients that KLISYRI is not for ophthalmic use. Advise patients to avoid application around the eyes, and transfer of the drug into the eyes and to the periocular area. If accidental exposure occurs, advise patients to flush eyes with water and seek medical care

'''Local Skin Reactions''':
Inform patients that treatment with KLISYRI may lead to local skin reactions

'''Important Administration Instructions''':
Advise patients that KLISYRI is for topical use only. Advise patients to avoid application near and around the eyes, mouth and lips.

Instruct patients to:
*Wash hands well after applying KLISYRI to avoid transfer of the drug into the eyes and to the periocular area after application.
* Avoid washing and touching the treated area for 8 hours after treatment. Following this time, patients may wash the area with a mild soap and water
*Avoid inadvertent transfer of KLISYRI to other areas, or to another person.
|alcohol=Alcohol-Tirbanibulin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=Klisyri
}}

Margetuximab

2025-04-27T16:14:10Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=margetuximab |aOrAn=a |drugClass=HER2/neu receptor antagonist |indicationType=treatment |indication=of adult patients with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease |hasBlackBoxWarning=Yes |adverseReactions='''Left Ventricular Dysfunction''' '''Embryo-Fetal Toxicity''' '''Infusio..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=margetuximab
|aOrAn=a
|drugClass=HER2/neu receptor antagonist
|indicationType=treatment
|indication=of adult patients with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease
|hasBlackBoxWarning=Yes
|adverseReactions='''Left Ventricular Dysfunction'''
'''Embryo-Fetal Toxicity'''
'''Infusion-Related Reactions'''
|blackBoxWarningTitle='''LEFT VENTRICULAR DYSFUNCTION AND EMBRYO-FETAL TOXICITY'''
|blackBoxWarningBody=''Left Ventricular Dysfunction::'' (MARGENZA may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate cardiac function prior to and during treatment. Discontinue MARGENZA treatment for a confirmed clinically significant decrease in left ventricular function)

''Embryo-Fetal Toxicity:'' (Exposure to MARGENZA during pregnancy can cause embryo-fetal harm. Advise patients of the risk and need for effective contraception)
|fdaLIADAdult=MARGENZA is indicated, in combination with chemotherapy, for the treatment of adult patients with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease

''' Recommended Doses and Schedules''':
The recommended dose of MARGENZA is 15 mg/kg, administered as an intravenous infusion every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

Administer MARGENZA as an intravenous infusion at 15 mg/kg over 120 minutes for the initial dose, then over a minimum of 30 minutes every 3 weeks for all subsequent doses.

On days when both MARGENZA and chemotherapy are to be administered, MARGENZA may be administered immediately after chemotherapy completion.

Refer to the respective Prescribing Information for each therapeutic agent administered in combination with MARGENZA for the recommended dosage information, as appropriate.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Margetuximab in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Margetuximab in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Margetuximab in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Margetuximab in pediatric patients.
|contraindications=None
|warnings='''Left Ventricular Dysfunction''':
Left ventricular cardiac dysfunction can occur with MARGENZA. In SOPHIA, left ventricular dysfunction occurred in 1.9% of patients treated with MARGENZA. MARGENZA has not been studied in patients with a pretreatment LVEF value of < 50%, a prior history of myocardial infarction or unstable angina within 6 months, or congestive heart failure NYHA class II-IV.

Withhold MARGENZA for ≥ 16% absolute decrease in LVEF from pretreatment values or LVEF value below institutional limits of normal (or 50% if no limits are available) and ≥ 10% absolute decrease in LVEF from pretreatment values. Permanently discontinue MARGENZA if LVEF decline persists for greater than 8 weeks, or if dosing is interrupted on greater than 3 occasions due to LVEF decline

''Cardiac Monitoring'':
Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended:
*Baseline LVEF measurement within 4 weeks prior to initiation of MARGENZA
*LVEF measurements (MUGA/echocardiogram) every 3 months during and upon completion of MARGENZA
*Repeat LVEF measurement at 4-week intervals if MARGENZA is withheld for significant left ventricular cardiac dysfunction

'''Embryo-Fetal Toxicity''':
Based on findings in animals and mechanism of action, MARGENZA can cause fetal harm when administered to a pregnant woman. There are no available data on the use of MARGENZA in pregnant women to inform the drug-associated risk. In postmarketing reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities and neonatal death. In an animal reproduction study, intravenous administration of margetuximab-cmkb to pregnant cynomolgus monkeys once every 3 weeks starting at gestational day (GD) 20 until delivery resulted in oligohydramnios and delayed infant kidney development. Animal exposures were ≥ 3 times the human exposures at the recommended dose, based on Cmax.

Verify pregnancy status of females of reproductive potential prior to initiation of MARGENZA. Advise pregnant women and females of reproductive potential that exposure to MARGENZA during pregnancy or within 4 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 4 months following the last dose of MARGENZA

'''Infusion-Related Reactions''':
MARGENZA can cause infusion-related reactions (IRRs).ymptoms may include fever, chills, arthralgia, cough, dizziness, fatigue, nausea, vomiting, headache, diaphoresis, tachycardia, hypotension, pruritus, rash, urticaria, and dyspnea.

In SOPHIA, IRRs were reported by 13% of patients on MARGENZA plus chemotherapy. Most of the IRRs occur during Cycle 1. Grade 3 IRRs were reported in 1.5% of MARGENZA-treated patients. All IRRs resolved within 24 hours, irrespective of severity. In SOPHIA, IRRs leading to interruption of treatment occurred in 9% of patients treated with MARGENZA and chemotherapy. One patient (0.4%) on MARGENZA discontinued treatment due to IRR.

An infusion substudy in 88 patients in SOPHIA evaluated MARGENZA administered over 120 minutes for the initial dose, then 30 minutes from Cycle 2 forward. IRRs were ≤ Grade 2 and most occurred during the first (120 minutes) administration of MARGENZA. From Cycle 2 onward, one patient (1.1%) had an IRR (Grade 1).

Monitor patients for IRRs during MARGENZA administration and as clinically indicated after completion of infusion. Have medications and emergency equipment to treat IRRs available for immediate use. Monitor patients carefully until resolution of signs and symptoms.

In patients who experience mild or moderate IRRs, consider premedications, including antihistamines, corticosteroids, and antipyretics. Decrease the rate of infusion for mild or moderate IRRs. Interrupt MARGENZA infusion in patients experiencing dyspnea or clinically significant hypotension and intervene with medical therapy which may include epinephrine, corticosteroids, diphenhydramine, bronchodilators and oxygen. Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanently discontinue MARGENZA in all patients with severe or life-threatening IRRs.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice.
The safety of MARGENZA was evaluated in HER2-positive breast cancer patients who received two or more prior anti-HER2 regimens in SOPHIA.
Patients were randomized (1:1) to receive either MARGENZA 15 mg/kg every 3 weeks plus chemotherapy or trastuzumab plus chemotherapy. Among patients who received MARGENZA, 40% were exposed for 6 months or longer and 11% were exposed for greater than one year.

Serious adverse reactions occurred in 16% of patients who received MARGENZA. Serious adverse reactions in > 1% of patients included febrile neutropenia (1.5%), neutropenia/neutrophil count decrease (1.5%) and infusion related reactions (1.1%). Fatal adverse reactions occurred in 1.1% of patients who received MARGENZA, including viral pneumonia (0.8%) and aspiration pneumonia (0.4%).

Permanent discontinuation due to an adverse reaction occurred in 3% of patients who received MARGENZA. Adverse reactions which resulted in permanent discontinuation in > 1% of patients who received MARGENZA included left ventricular dysfunction and infusion-related reactions.

Dosage interruptions due to an adverse reaction occurred in 11% of patients who received MARGENZA. Adverse reactions which required dosage interruption in > 5% of patients who received MARGENZA included infusion-related reactions.
|drugInteractions='''Anthracyclines''':
Patients who receive anthracyclines less than 4 months after stopping MARGENZA may be at increased risk of cardiac dysfunction. While this interaction has not been studied with MARGENZA, clinical data from other HER2-directed antibodies warrants consideration. Avoid anthracycline-based therapy for up to 4 months after stopping MARGENZA. If concomitant use is unavoidable, closely monitor patient's cardiac function.
|useInLaborDelivery=Based on findings in animals and mechanism of action, MARGENZA can cause fetal harm when administered to a pregnant woman. There are no available data on use of MARGENZA in pregnant women to inform the drug-associated risk. In postmarketing reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. In an animal reproduction study, intravenous administration of margetuximab-cmkb to pregnant cynomolgus monkeys once every 3 weeks, starting at gestational day (GD) 20 until delivery, resulted in oligohydramnios and delayed infant kidney development. Animal exposures were ≥ 3 times the human exposures at the recommended dose, based on Cmax. Advise patients of potential risks to a fetus. There are clinical considerations if MARGENZA is used during pregnancy or within 4 months prior to conception. Estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 - 4% and 15 - 20%, respectively.
Monitor women who received MARGENZA during pregnancy or within 4 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care.
|useInNursing=There is no information regarding presence of MARGENZA in human milk, effects on the breastfed child, or effects on milk production. Published data suggest human IgG is present in human milk but does not enter neonatal or infant circulation in substantial amounts. Consider developmental and health benefits of breastfeeding along with the mother's clinical need for MARGENZA treatment and any potential adverse effects on the breastfed child from MARGENZA or from the underlying maternal condition. This consideration should also take into account the MARGENZA washout period of 4 months
|useInPed=Safety and effectiveness of MARGENZA have not been established in pediatric patients.
|useInGeri=Of the 266 patients treated with MARGENZA 20% were 65 years of age or older and 4% were 75 years or older. No overall differences in efficacy were observed between patients ≥ 65 years of age compared to younger patients. There was a higher incidence of Grade ≥ 3 adverse reactions observed in patients age 65 years or older (56%) compared to younger patients (47%), as well as adverse reactions associated with potential cardiotoxicity (35% vs 18%).
|useInReproPotential='''Contraception''':
''Females''
Advise females of reproductive potential to use effective contraception during treatment and for 4 months following the last dose of MARGENZA

'''Pregnancy Testing''':
Verify pregnancy status of females of reproductive potential prior to initiation of MARGENZA.
|administration=*Administer diluted infusion solution intravenously over 120 minutes for the initial dose, then over a minimum of 30 minutes every 3 weeks for all subsequent doses. Administer through an intravenous line containing a sterile, non-pyrogenic, low-protein binding polyethersulfone (PES) 0.2 micron in-line or add-on filter.

*Do not co-administer other drugs through the same infusion line.
|monitoring=''Cardiac Monitoring'':
Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan. The following schedule is recommended:
*Baseline LVEF measurement within 4 weeks prior to initiation of MARGENZA
*LVEF measurements (MUGA/echocardiogram) every 3 months during and upon completion of MARGENZA
*Repeat LVEF measurement at 4-week intervals if MARGENZA is withheld for significant left ventricular cardiac dysfunction

'''Embryo-Fetal Toxicity''':
Based on findings in animals and mechanism of action, MARGENZA can cause fetal harm when administered to a pregnant woman. There are no available data on the use of MARGENZA in pregnant women to inform the drug-associated risk. In postmarketing reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities and neonatal death. In an animal reproduction study, intravenous administration of margetuximab-cmkb to pregnant cynomolgus monkeys once every 3 weeks starting at gestational day (GD) 20 until delivery resulted in oligohydramnios and delayed infant kidney development. Animal exposures were ≥ 3 times the human exposures at the recommended dose, based on Cmax.

Verify pregnancy status of females of reproductive potential prior to initiation of MARGENZA. Advise pregnant women and females of reproductive potential that exposure to MARGENZA during pregnancy or within 4 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 4 months following the last dose of MARGENZA

Monitor patients for IRRs during MARGENZA administration and as clinically indicated after completion of infusion. Have medications and emergency equipment to treat IRRs available for immediate use. Monitor patients carefully until resolution of signs and symptoms.

Monitor women who received MARGENZA during pregnancy or within 4 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care.
|mechAction=Margetuximab-cmkb binds to the extracellular domain of the human epidermal growth factor receptor 2 protein (HER2). Upon binding to HER2-expressing tumor cells, margetuximab-cmkb inhibits tumor cell proliferation, reduces shedding of the HER2 extracellular domain and mediates antibody-dependent cellular cytotoxicity (ADCC).

In vitro, the modified Fc region of margetuximab-cmkb increases binding to activating Fc receptor FCGR3A (CD16A) and decreases binding to inhibitory Fc receptor FCGR2B (CD32B). These changes lead to greater in vitro ADCC and NK cell activation.
|PD=The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of margetuximab-cmkb have not been fully characterized.
|PK=Following the approved recommended dosage, the steady-state geometric mean (%CV) Cmax of margetuximab-cmkb is 466 (20%) µg/mL and AUC0-21d is 4120 (21%) µg.day/mL in patients with HER2-positive relapsed or refractory advanced breast cancer. Margetuximab-cmkb undergoes both linear and nonlinear elimination. After a single dose, margetuximab-cmkb Cmax and AUC0-21d increase in an approximately dose proportional manner from 10 to 18 mg/kg (0.67 to 1.2 times the approved recommended dose). At the approved recommended dosage, time to steady-state was 2 months, and accumulation ratio was 1.65 based on AUC0-21d. No clinically significant differences in margetuximab-cmkb exposure were observed when infusion time was reduced from 120 minutes to 30 minutes.

'''Distribution''':
Margetuximab-cmkb geometric mean (%CV) steady-state volume of distribution is 5.47 L (22%).

'''Elimination''':
The geometric mean (%CV) terminal half-life of margetuximab-cmkb is 19.2 days (28%) and clearance is 0.22 L/day (24%). Four months after margetuximab-cmkb discontinuation, concentrations decrease to approximately 3% of the steady-state trough serum concentration.

'''Metabolism''':
Margetuximab-cmkb is expected to be metabolized into small peptides by catabolic pathways.

'''Specific Populations''':
No clinically significant differences in margetuximab-cmkb PK were observed based on age (29 to 83 years), sex, race (Caucasian, Black, Asian), mild to moderate (CLcr 30 to 89 mL/min estimated using the Cockcroft-Gault equation) renal impairment, mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 ULN and any AST), HER2 expression level (0 to 3 by IHC), tumor burden (2 – 317 mm), ECOG score (0 to 2), albumin (24 to 50 g/L), FCGR3A (CD16A), FCGR2A (CD32A) and FCGR2B (CD32B) genotype, number of metastatic sites (≤ 2 or > 2), number of prior therapy lines (≤ 2 or > 2) or concurrent chemotherapies (capecitabine, gemcitabine, eribulin and vinorelbine).

The effect of severe renal impairment (CLcr 15 to 29 mL/min), end-stage renal disease with or without hemodialysis, and moderate (total bilirubin > 1.5 to ≤ 3 ULN and any AST) or severe hepatic impairment (total bilirubin >3 ULN and any AST) on margetuximab-cmkb PK is unknown.
|nonClinToxic=Studies have not been performed to evaluate carcinogenic or mutagenic potential of margetuximab-cmkb.

Animal fertility studies have not been conducted with margetuximab-cmkb. In repeat-dose toxicity studies of up to 13-week duration, margetuximab-cmkb had no effect on male and female reproductive organs in sexually mature cynomolgus monkeys.
|clinicalStudies='''Metastatic Breast Cancer''':
The efficacy of MARGENZA plus chemotherapy was evaluated in SOPHIA (NCT02492711), a randomized, multicenter, open-label trial of 536 patients with IHC 3+ or ISH-amplified HER2+ metastatic breast cancer who had received prior treatment with other anti-HER2 therapies. Patients were randomized (1:1) to MARGENZA plus chemotherapy or trastuzumab plus chemotherapy. Randomization was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), number of lines of therapy in the metastatic setting (≤ 2, > 2), and number of metastatic sites (≤ 2, > 2). Patients were required to have progressed on or after the most recent line of therapy. Prior radiotherapy and hormonal therapy were allowed. Patients received MARGENZA intravenously at a dose of 15 mg/kg every 3 weeks administered over 120 minutes for the initial administration and then over 30 to 120 minutes thereafter. Trastuzumab was given intravenously at an initial dose of 8 mg/kg over 90 minutes, followed by 6 mg/kg over 30 minutes every 3 weeks thereafter. Patients were treated with MARGENZA or trastuzumab in combination with chemotherapy until disease progression or unacceptable toxicity.

Major efficacy outcome measures were progression-free survival (PFS) by blinded independent central (BICR) review and overall survival (OS) of MARGENZA plus chemotherapy, compared with trastuzumab plus chemotherapy. Additional efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) assessed by BICR.

The median age was 56 years (range: 27-86); 78% of patients were < 65 years. The majority of patients were female (99.4%), and the majority were White (80%). Patients had an ECOG performance status of 0 (58%) or 1 (42%) at baseline. Forty seven percent had visceral disease, 57% had bone metastases, and 13% had brain metastases. Sixty percent were hormone receptor positive. The median number of prior lines of therapy in the locally advanced/metastatic setting was 2 (range: 1-4). All study patients had previously received trastuzumab, all but 1 patient had previously received pertuzumab, and 91% had previously received ado-trastuzumab emtansine.
|howSupplied=MARGENZA (margetuximab-cmkb) injection is a clear to slightly opalescent, colorless to pale yellow or pale brown solution in a single-dose vial supplied
|storage=Store vials refrigerated at 2°C to 8°C (36°F to 46°F) in original carton to protect from light until time of use.

Do not freeze. Do not shake.
|fdaPatientInfo='''Left Ventricular Dysfunction''':
Advise patients to contact a health care professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness

'''Embryo-Fetal Toxicity''':
Advise pregnant women and females of reproductive potential that exposure to MARGENZA during pregnancy or within 4 months prior to conception can result in fetal harm. Advise female patients to contact their healthcare provider with a known or suspected pregnancy

Advise females of reproductive potential to use effective contraception during treatment with MARGENZA and for 4 months following the last dose
|alcohol=Alcohol-Margetuximab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=Margenza
}}

Relugolix

2025-04-27T15:54:56Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=relugolix |aOrAn=a |drugClass=gonadotropin-releasing hormone (GnRH) receptor antagonist |indicationType=treatment |indication=of adult patients with advanced prostate cancer. |adverseReactions=QT/QTc Interval Prolongation |blackBoxWarningTitle='''TITLE''' |blackBoxWarningBody=''Condition Name:'' (Content) |fdaL..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=relugolix
|aOrAn=a
|drugClass=gonadotropin-releasing hormone (GnRH) receptor antagonist
|indicationType=treatment
|indication=of adult patients with advanced prostate cancer.
|adverseReactions=QT/QTc Interval Prolongation
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=ORGOVYX is indicated for the treatment of adult patients with advanced prostate cancer.

'''Recommended Dosage''':
Initiate treatment of ORGOVYX with a loading dose of 360 mg on the first day and continue treatment with a 120 mg dose taken orally once daily at approximately the same time each day.ORGOVYX can be taken with or without food. Instruct patients to swallow tablets whole and not to crush or chew tablets.Advise patients to take a missed dose of ORGOVYX as soon as they remember. If the dose was missed by more than 12 hours, patients should not take the missed dose and resume with the next scheduled dose.If treatment with ORGOVYX is interrupted for greater than 7 days, restart ORGOVYX with a loading dose of 360 mg on the first day, and continue with a dose of 120 mg once daily.In patients treated with GnRH receptor agonists and antagonists for prostate cancer, treatment is usually continued upon development of nonmetastatic or metastatic castration-resistant prostate cancer.

'''Dose Modification for Use with P-gp Inhibitors''':
Avoid co-administration of ORGOVYX with oral P-gp inhibitors. If co-administration is unavoidable, take ORGOVYX first and separate dosing by at least 6 hours. Treatment with ORGOVYX may be interrupted for up to two weeks if a short course of treatment with a P-gp inhibitor is required.

'''Dose Modification for Use with Combined P-gp and Strong CYP3A Inducers''':
Avoid co-administration of ORGOVYX with combined P-gp and strong CYP3A inducers. If co-administration is unavoidable, increase the ORGOVYX dose to 240 mg once daily. After discontinuation of the combined P-gp and strong CYP3A inducer, resume the recommended ORGOVYX dose of 120 mg once daily

Tablets: 120 mg, light red, almond-shaped, film-coated, and debossed with “R” on one side and “120” on the other side.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Relugolix in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Relugolix in adult patients.
|fdaLIADPed=None
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Relugolix in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Relugolix in pediatric patients.
|contraindications=ORGOVYX is contraindicated in patients with severe hypersensitivity to relugolix or to any of the product components.
|warnings='''QT/QTc Interval Prolongation''':
Androgen deprivation therapy, such as ORGOVYX may prolong the QT/QTc interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, or frequent electrolyte abnormalities and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes

'''Hypersensitivity Reactions''':
ORGOVYX is contraindicated in patients with severe hypersensitivity to relugolix or any of the product components.Hypersensitivity reactions, including pharyngeal edema and other serious cases of angioedema, have been reported in postmarketing in patients treated with ORGOVYX.
Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue ORGOVYX and promptly seek medical care. Discontinue ORGOVYX for severe hypersensitivity reactions and manage as clinically indicated.

'''Embryo-Fetal Toxicity''':
The safety and efficacy of ORGOVYX have not been established in females. Based on findings in animals and mechanism of action, ORGOVYX can cause fetal harm and loss of pregnancy when administered to a pregnant female. In an animal reproduction study, oral administration of relugolix to pregnant rabbits during the period of organogenesis caused embryo-fetal lethality at maternal exposures that were 0.3 times the human exposure at the recommended dose of 120 mg daily based on area under the curve (AUC). Advise males with female partners of reproductive potential to use effective contraception during treatment and for 2 weeks after the last dose of ORGOVYX.

'''Laboratory Testing''':
Therapy with ORGOVYX results in suppression of the pituitary gonadal system. Results of diagnostic tests of the pituitary gonadotropic and gonadal functions conducted during and after ORGOVYX may be affected. The therapeutic effect of ORGOVYX should be monitored by measuring serum concentrations of prostate specific antigen (PSA) periodically. If PSA increases, serum concentrations of testosterone should be measured.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of ORGOVYX was evaluated in HERO, a randomized (2:1), open-label, clinical study in patients with advanced prostate cancer.atients received orally administered ORGOVYX as a loading dose of 360 mg on the first day followed by 120 mg taken orally once daily (n = 622) or received leuprolide acetate administered by depot injection at doses of 22.5 mg (n = 264) or 11.25 mg (n = 44) per local guidelines every 12 weeks (n = 308). Leuprolide acetate 11.25 mg is a dosage regimen that is not recommended for this indication in the US. Among patients who received ORGOVYX, 91% were exposed for at least 48 weeks. Ninety-nine (16%) patients received concomitant radiotherapy and 17 (3%) patients received concomitant enzalutamide with ORGOVYX.

Serious adverse reactions occurred in 12% of patients receiving ORGOVYX. Serious adverse reactions in ≥ 0.5% of patients included myocardial infarction (0.8%), acute kidney injury (0.6%), arrhythmia (0.6%), hemorrhage (0.6%), and urinary tract infection (0.5%). Fatal adverse reactions occurred in 0.8% of patients receiving ORGOVYX including metastatic lung cancer (0.3%), myocardial infarction (0.3%), and acute kidney injury (0.2%). Fatal and non-fatal myocardial infarction and stroke were reported in 2.7% of patients receiving ORGOVYX.

Permanent discontinuation of ORGOVYX due to an adverse reaction occurred in 3.5% of patients. Adverse reactions which resulted in permanent discontinuation of ORGOVYX in ≥ 0.3 % of patients included atrioventricular block (0.3%), cardiac failure (0.3%), hemorrhage (0.3%), increased transaminases (0.3%), abdominal pain (0.3%), and pneumonia (0.3%).

Dosage interruptions of ORGOVYX due to an adverse reaction occurred in 2.7% of patients. Adverse reactions which required dosage interruption in ≥ 0.3% of patients included fracture (0.3%).

The most common adverse reactions (≥ 10%) and laboratory abnormalities (≥ 15%), were hot flush (54%), glucose increased (44%), triglycerides increased (35%), musculoskeletal pain (30%), hemoglobin decreased (28%), alanine aminotransferase increased (ALT) (27%), fatigue (26%), aspartate aminotransferase increased (AST) (18%), constipation (12%), and diarrhea (12%).
|postmarketing=The following adverse reactions have been identified during post-approval use of ORGOVYX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: hypersensitivity, including angioedema and urticaria.
|drugInteractions='''Effect of Other Drugs on ORGOVYX''':
*P-gp Inhibitors:
Relugolix is a P-gp substrate. Co-administration of ORGOVYX with an oral P-gp inhibitor increases relugolix exposure which may increase the risk of adverse reactions associated with ORGOVYX.

Avoid co-administration of ORGOVYX with oral P-gp inhibitors.If co-administration with an oral P-gP inhibitor cannot be avoided, take ORGOVYX first and wait at least 6 hours before taking the P-gp inhibitor. Closely monitor patients for increased adverse reactions. If an oral P-gp inhibitor will only be administered for up to 2 weeks, ORGOVYX may be interrupted while the P-gp inhibitor is being administered. Resume ORGOVYX after the P-gp is discontinued. If ORGOVYX is interrupted for more than 7 days, resume ORGOVYX at 360 mg on the first day, followed by 120 mg once daily.

*Combined P-gp and Strong CYP3A Inducers:
Co-administration of ORGOVYX with a combined P-gp and strong CYP3A inducer decreases relugolix exposure, which may reduce the effects of ORGOVYX.Avoid co-administration of ORGOVYX with combined P-gp and strong CYP3A inducers.

If co-administration cannot be avoided, increase the ORGOVYX dose. After discontinuation of the combined P-gp and strong CYP3A inducer, resume ORGOVYX once daily at the same dose
|useInLaborDelivery=The safety and efficacy of ORGOVYX have not been established in females.

Based on findings in animals and mechanism of action, ORGOVYX can cause fetal harm and loss of pregnancy when administered to a pregnant female. There are no human data on the use of ORGOVYX in pregnant females to inform the drug-associated risk. In an animal reproduction study, oral administration of relugolix to pregnant rabbits during organogenesis caused embryo-fetal lethality at maternal exposures that were 0.3 times the human exposure at the recommended dose of 120 mg daily based on AUC. Advise patients of the potential risk to the fetus.In an embryo-fetal development study, oral administration of relugolix to pregnant rabbits during the period of organogenesis resulted in abortion, total litter loss, or decreased number of live fetuses at a dose of 9 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose of 120 mg daily based on AUC).
|useInNursing=The safety and efficacy of ORGOVYX at the recommended dose of 120 mg daily have not been established in females. There are no data on the presence of relugolix in human milk, the effects on the breastfed child, or the effects on milk production. Relugolix and/or its metabolites were present in milk of lactating rats. In lactating rats administered a single oral dose of 30 mg/kg radiolabeled relugolix on post-partum day 14, relugolix and/or its metabolites were present in milk at concentrations up to 10-fold higher than in plasma at 2 hours post-dose.
|useInPed=The safety and efficacy of ORGOVYX in pediatric patients have not been established.
|useInGeri=Of the 622 patients who received ORGOVYX in the HERO study, 81% were 65 years of age or older, while 35% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. There was no clinically relevant impact of age on the pharmacokinetics of ORGOVYX or testosterone response based on population pharmacokinetic and pharmacokinetic/pharmacodynamic analyses in men 45 to 91 years of age.
|useInReproPotential='''Contraception''':
MALES
Based on findings in animals and mechanism of action, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 2 weeks after the last dose of ORGOVYX

'''Infertility''':
MALES
Based on findings in animals and mechanism of action, ORGOVYX may impair fertility in males of reproductive potential
|administration=Initiate treatment of ORGOVYX with a loading dose of 360 mg on the first day and continue treatment with a 120 mg dose taken orally once daily at approximately the same time each day.
ORGOVYX can be taken with or without food. Instruct patients to swallow tablets whole and not to crush or chew tablets.

Advise patients to take a missed dose of ORGOVYX as soon as they remember. If the dose was missed by more than 12 hours, patients should not take the missed dose and resume with the next scheduled dose.

If treatment with ORGOVYX is interrupted for greater than 7 days, restart ORGOVYX with a loading dose of 360 mg on the first day, and continue with a dose of 120 mg once daily.

In patients treated with GnRH receptor agonists and antagonists for prostate cancer, treatment is usually continued upon development of nonmetastatic or metastatic castration-resistant prostate cancer.
'''Dose Modification for Use with P-gp Inhibitors''':
Avoid co-administration of ORGOVYX with oral P-gp inhibitors. If co-administration is unavoidable, take ORGOVYX first and separate dosing by at least 6 hours. Treatment with ORGOVYX may be interrupted for up to two weeks if a short course of treatment with a P-gp inhibitor is required.

'''Dose Modification for Use with Combined P-gp and Strong CYP3A Inducers''':
Avoid co-administration of ORGOVYX with combined P-gp and strong CYP3A inducers. If co-administration is unavoidable, increase the ORGOVYX dose to 240 mg once daily. After discontinuation of the combined P-gp and strong CYP3A inducer, resume the recommended ORGOVYX dose of 120 mg once daily
|monitoring=Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, or frequent electrolyte abnormalities and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes.
|mechAction=Relugolix is a nonpeptide GnRH receptor antagonist that competitively binds to pituitary GnRH receptors, thereby, reducing the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and consequently testosterone.
|PD='''Pituitary and Gonadal Hormones''':
Relugolix reduced LH, FSH and testosterone concentrations after oral administration of the recommended loading dose of 360 mg and a 120 mg dose once daily.

Out of 622 patients, 56% had testosterone concentrations at castrate levels (< 50 ng/dL) by the first sampling timepoint at Day 4, and 97% maintained castrate levels of testosterone through 48 weeks. In a substudy of 137 patients who did not receive subsequent androgen deprivation therapy for at least 90 days after discontinuation of relugolix, the cumulative incidence rate of achieving testosterone concentrations above the lower limit of the normal range (> 280 ng/dL) or baseline at 90 days was 55%

'''Cardiac Electrophysiology''':
In a randomized, double-blind, placebo- and positive-controlled (open-label moxifloxacin), parallel-group thorough QT/QTc study, no increase in mean QTc interval > 10 ms was identified after administration of a single 60 mg or 360 mg (0.2 or 1 times the recommended loading dose, respectively) relugolix dose.
|PK=After administration of single doses ranging from 60 mg to 360 mg (0.17 to 1 times the recommended loading dose), the area under concentration-time curve from time zero to infinity (AUC0-inf) and the maximum observed plasma concentration (Cmax) of relugolix increased approximately proportionally with dose. After administration of multiple doses of relugolix once daily, the AUCtau of relugolix increased approximately proportionally with dose while the Cmax increase was greater than dose proportional for doses from 20 mg to 180 mg (0.17 to 1.5 times the recommended dosage). After administration of a single 360 mg loading dose in patients, the mean (± standard deviation [± SD]) of AUC0-24 and Cmax of relugolix were 985 (± 742) ng.hr/mL and 215 (± 184) ng/mL, respectively. After administration of a 120 mg dose once daily in patients, the mean (± SD) of AUC0-24 and Cmax of relugolix at steady-state were 407 (± 168) ng.hr/mL and 70 (± 65) ng/mL, respectively. The accumulation of relugolix upon once daily administration is approximately 2-fold.

'''Absorption''':
Relugolix is a substrate for intestinal P-gp. The mean (CV%) absolute bioavailability of relugolix is 12% (62%). The median (range) Tmax of relugolix is 2.25 hours (0.5 to 5.0 hours).

*Effect of Food:
No clinically meaningful differences in the pharmacokinetics of relugolix were observed following consumption of a high-calorie, high-fat meal (approximately 800 to 1000 calories with 500, 220, and 124 from fat, carbohydrate, and protein, respectively).

*Distribution:
Plasma protein binding of relugolix is 68 to 71%, primarily to albumin and to a lesser extent to α1-acid glycoprotein. The mean blood-to-plasma ratio is 0.78.

*Elimination:
The mean effective half-life of relugolix is 25 hours and the mean (CV%) terminal elimination half-life is 60.8 (11%) hours. The mean (CV%) total clearance of relugolix is 29.4 (15%) L/h and the renal clearance is 8 L/h.

*Metabolism:
Relugolix is metabolized primarily by CYP3A and to a lesser extent by CYP2C8 in vitro.

*Excretion:
After oral administration of a single 80 mg radiolabeled dose of relugolix, approximately 81% of the radioactivity was recovered in feces with 4.2% as unchanged and 4.1% in urine with 2.2% as unchanged.

*Specific Populations:
No clinically meaningful differences in the pharmacokinetics of relugolix were observed based on age (45 to 91 years), race/ethnicity (Asian [19%], White [71%], Black/African American [6%]), body weight (41 to 193 kg), mild to severe renal impairment (creatinine clearance [CLcr] 15 to 89 mL/min, as estimated by the Cockcroft-Gault equation), or mild to moderate hepatic impairment (Child-Pugh A or B). The effect of end-stage renal disease with or without hemodialysis or severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of relugolix has not been evaluated.

Combined P-gp and Moderate CYP3A Inhibitors: Co-administration with erythromycin (P-gp and moderate CYP3A inhibitor) increased the AUC and Cmax of relugolix by 3.5- and 2.9-fold respectively.

Combined P-gp and Strong CYP3A Inducers: Co-administration of relugolix with rifampin (P-gp and strong CYP3A inducer) decreased the AUC and Cmax of relugolix by 55% and 23%, respectively.

Other Drugs: No clinically significant differences in the pharmacokinetics of relugolix were observed when co-administered with voriconazole (strong CYP3A inhibitor), atorvastatin, enzalutamide, or acid-reducing agents. No clinically significant differences in the pharmacokinetics of midazolam (sensitive CYP3A substrate) or rosuvastatin (BCRP substrate), or dabigatran etexilate (P-gp substrate) were observed upon co-administration with relugolix.

Cytochrome P450 (CYP) Enzymes: Relugolix is a substrate of CYP3A and CYP2C8. Relugolix is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Relugolix is an inducer of CYP3A and CYP2B6, but not an inducer of CYP1A2.

Transporter Systems: Relugolix is a substrate of P-gp, but not a substrate of BCRP. Relugolix is an inhibitor of BCRP and P-gp, but not an inhibitor of OATP1B1, OATP1B3, OATP2B1, OAT1, OAT3, OCT2, MATE1, MATE2-K, or BSEP.
|nonClinToxic='''Carcinogenesis, Mutagenesis, Impairment of Fertility''':
Two-year carcinogenicity studies were conducted in mice at oral relugolix doses up to 100 mg/kg/day and in rats at doses up to 600 mg/kg/day. Relugolix was not carcinogenic in mice or rats at exposures up to approximately 75 or 224 times, respectively, the human exposure at the recommended dose of 120 mg daily based on AUC.

Relugolix was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro chromosomal aberration assay in Chinese hamster lung cells or the in vivo rat bone marrow micronucleus assay.

In human GnRH-receptor knock-in male mice, oral administration of relugolix decreased prostate and seminal vesicle weights at doses ≥ 3 mg/kg twice daily for 28 days. The effects of relugolix were reversible, except for testis weight, which did not fully recover within 28 days after drug withdrawal. In a 39-week repeat-dose toxicity study in monkeys, there were no significant effects on male reproductive organs at oral relugolix doses up to 50 mg/kg/day (approximately 53 times the human exposure at the recommended dose of 120 mg daily based on AUC).

'''Animal Toxicology and/or Pharmacology''':
Phospholipidosis (intracellular phospholipid accumulation) was observed in multiple organs and tissues (e.g., liver, pancreas, spleen, kidney, lymph nodes, lung, bone marrow, gastrointestinal tract or testes) after repeated oral administration of relugolix in rats and monkeys. In a rat 26-week toxicity study, phospholipidosis was observed at doses ≥ 100 mg/kg (approximately 18 times the human exposure at the recommended dose based on AUC). In a monkey 39-week toxicity study, this effect was observed at doses ≥ 1.5 mg/kg (approximately 0.6 times the human exposure at the recommended dose based on AUC) and demonstrated evidence of reversibility after cessation of treatment. The significance of this finding in humans is unknown.
|clinicalStudies='''HERO Study''':
The safety and efficacy of ORGOVYX was evaluated in HERO (NCT03085095), a randomized, open label study in men with advanced prostate cancer requiring at least 1 year of androgen deprivation therapy and defined as biochemical (PSA) or clinical relapse following local primary intervention, newly diagnosed castration-sensitive metastatic disease, or advanced localized disease.
|howSupplied=The 120 mg tablets are film-coated, light red, almond shaped, and debossed with “R” on one side and “120” on the other side and are supplied in two configurations, bottles and blister packs. Each bottle (NDC 72974-120-01) contains 30 tablets and a desiccant and is closed with a child resistant induction seal cap. The blister cards contain nine tablets packaged in a carton (NDC 72974-120-02). Each ORGOVYX tablet contains 120 mg of relugolix.
|storage=*Store ORGOVYX at room temperature. Do not store above 30°C (86°F).
* Dispense to patients in original container only.
*For bottles, keep container tightly closed after first opening.
*Keep out of reach of children.
|fdaPatientInfo='''QT/QTc Interval Prolongation''':
*Advise patients that androgen deprivation therapy treatment with ORGOVYX may prolong the QT interval. Inform patients of the signs and symptoms of QT prolongation. Advise patients to contact their healthcare provider immediately for signs or symptoms of QT prolongation

'''Hypersensitivity''':
*Inform patients that if they have experienced severe hypersensitivity with relugolix or to any of the product components, ORGOVYX is contraindicated
*Inform patients that ORGOVYX can cause severe hypersensitivity reactions that include angioedema
*Advise patients who experience hypersensitivity symptoms to discontinue ORGOVYX and promptly contact their healthcare provider.

'''Androgen Deprivation''':
*Inform patients about adverse reactions related to androgen deprivation therapy with ORGOVYX, including hot flashes, flushing of the skin, increased weight, decreased sex drive, and difficulties with erectile function

'''Embryo-Fetal Toxicity''':
*Inform patients that ORGOVYX can be harmful to a developing fetus and can cause loss of pregnancy.
*Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 2 weeks after the last dose of ORGOVYX

'''Infertility''':
* Inform patients that ORGOVYX may cause infertility

'''Drug Disposal''':
*Advise patients to dispose of unused medication via a take-back option if available. Otherwise, advise to follow FDA instructions for disposing medication in the household trash, www.fda.gov/drugdisposal and NOT to flush down the toilet.
|alcohol=Alcohol-Relugolix interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=Orgovyx
}}

Ansuvimab-zykl

2025-04-27T14:56:04Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=Ebanga |aOrAn=a |drugClass=ebolavirus (EBOV) glycoprotein 1 (GP1)-directed recombinant, human Immunoglobulin G1 (IgG1) monoclonal antibody. |indicationType=treatment |indication=of infection caused by Orthoebolavirus zairense(formerly Zaire ebolavirus) in adult and pediatric patients, including neonates born to a mother who is RT-PCR positive for Orthoebolavirus zairense infection..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=Ebanga
|aOrAn=a
|drugClass=ebolavirus (EBOV) glycoprotein 1 (GP1)-directed recombinant, human Immunoglobulin G1 (IgG1) monoclonal antibody.
|indicationType=treatment
|indication=of infection caused by Orthoebolavirus zairense(formerly Zaire ebolavirus) in adult and pediatric patients, including neonates born to a mother who is RT-PCR positive for Orthoebolavirus zairense infection
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult='''Recommended Dosage for Adult and Pediatric Patients''':
The recommended dosage of EBANGA is 50 mg/kg administered as a single intravenous (IV) infusion over 60 minutes. EBANGA must be reconstituted with Sterile Water for Injection, USP then further diluted in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP prior to IV infusion

'''Preparation, Administration, and Storage Instructions''':
EBANGA must be prepared and administered under the supervision of a health care professional.

EBANGA must be prepared and administered under the supervision of a health care professional.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Ansuvimab-zykl in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Ansuvimab-zykl in adult patients.
|fdaLIADPed=The recommended dosage of EBANGA is 50 mg/kg administered as a single intravenous (IV) infusion over 60 minutes. EBANGA must be reconstituted with Sterile Water for Injection, USP then further diluted in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP prior to IV infusion.

'''Preparation, Administration, and Storage Instructions''':
EBANGA must be prepared and administered under the supervision of a health care professional.

EBANGA must be prepared and administered under the supervision of a health care professional.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Ansuvimab-zykl in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Ansuvimab-zykl in pediatric patients.
|contraindications=None.
|warnings='''Hypersensitivity Reactions Including Infusion-Associated Events''':
Hypersensitivity reactions including infusion-associated events have been reported with EBANGA. These may include acute, life-threatening reactions during and after the infusion. Monitor all patients for signs and symptoms including, but not limited to, hypotension, chills and elevation of fever, during and following EBANGA infusion. In the case of severe or life-threatening hypersensitivity reactions, discontinue the administration of EBANGA immediately and administer appropriate emergency care.

Infusion could not be completed in 1% of participants who received EBANGA due to infusion-associated adverse events. The rate of infusion of EBANGA may be slowed or interrupted if the patient develops any signs of infusion-associated events or other adverse events
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice.

Overall, 424 adult and pediatric participants with Orthoebolavirus zairense infection received EBANGA in one clinical trial and as part of an expanded access program during the 2018 Orthoebolavirus zairense outbreak in the Democratic Republic of Congo (DRC).

In the PALM trial, the safety of EBANGA was evaluated in a multi-center, open-label, randomized controlled trial, in which 173 participants (119 adults and 54 pediatric participants) with confirmed Orthoebolavirus zairense infection received EBANGA as a single 50 mg/kg IV infusion and 168 participants received an investigational control.

All participants received optimized standard of care treatment (oSOC). The median age of the study population that received EBANGA was 26 years (range: 1 day to 85 years) and 55% were female.

During the same outbreak, 251 participants (173 adults and 78 pediatric participants) with laboratory- confirmed Orthoebolavirus zairense infection received EBANGA under an expanded access program, 57% of whom were female. Ages ranged from 6 days to 80 years, with a median age of 25 years.
|drugInteractions='''Vaccine Interactions''':
No vaccine-therapeutic interaction studies have been performed in human participants using EBANGA. However, because of the potential for EBANGA to inhibit replication of a live vaccine virus indicated for prevention of Orthoebolavirus zairense infection and possibly reduce the efficacy of the vaccine, avoid the concurrent administration of a live vaccine during treatment with EBANGA. The interval between administration of EBANGA therapy and live vaccination should be in accordance with current vaccination guidelines. The efficacy of EBANGA among participants who reported receipt of a recombinant live vaccine prior to their enrollment in the PALM trial was similar to participants who did not report receiving a vaccine prior to enrollment.
|useInLaborDelivery=Orthoebolavirus zairense infection is life-threatening for both the mother and fetus and treatment should not be withheld due to pregnancy.
Available data from the PALM trial in which pregnant women with Orthoebolavirus zairense infection were treated with EBANGA demonstrate the high rate of maternal and fetal/neonatal morbidity consistent with published literature regarding the risk associated with underlying maternal Orthoebolavirus zairense infection. These data are insufficient to evaluate for a drug associated risk of major birth defects, miscarriage, or adverse maternal/fetal outcome.

Animal reproduction studies with ansuvimab-zykl have not been conducted. Monoclonal antibodies, such as EBANGA, are transported across the placenta; therefore, EBANGA has the potential to be transferred from the mother to the developing fetus.

Disease-associated maternal and/or embryo/fetal risk

Maternal, fetal and neonatal outcomes are poor among pregnant women infected with Orthoebolavirus zairense. The majority of such pregnancies result in maternal death with miscarriage, stillbirth, or neonatal death. Treatment should not be withheld due to pregnancy.
|useInNursing=The Centers for Disease Control and Prevention recommend that mothers with confirmed Orthoebolavirus zairense not breastfeed their infants to reduce the risk of postnatal transmission of Orthoebolavirus zairense infection.

There are no data on the presence of ansuvimab-zykl in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to ansuvimab-zykl are unknown.
|useInPed=The safety and effectiveness of EBANGA for the treatment of infection caused by Orthoebolavirus zairense have been established in pediatric patients from birth to less than 18 years of age. Use of EBANGA for this indication is supported by evidence from a multi-center, open label, randomized controlled trial of EBANGA in adults and pediatric participants that included 54 pediatric participants birth to less than 18 years of age, including neonates born to a mother who is RT-PCR positive for Orthoebolavirus zairense infection. Of the total number of participants administered EBANGA in the PALM trial, pediatric participants (1 day to 17 years) accounted for 31% (n=54) of the study population in the PALM trial. The 28-day mortality and safety in adult and pediatric participants treated with EBANGA were similar.
An additional 78 (31%) pediatric participants from birth to less than 18 years of age received EBANGA in an expanded access program.
|useInGeri=Clinical trials of EBANGA did not include sufficient numbers of participants aged 65 and over to determine whether the safety profile of EBANGA is different in this population compared to younger participants. Of the total number of participants administered EBANGA in the PALM trial, 6 participants (3%) were 65 years or older. The limited clinical experience has not identified differences in responses between the elderly and younger participants.
|administration=*Aseptically reconstitute and further dilute EBANGA prior to IV infusion. Do not administer as an IV push or bolus.
*More than one vial may be needed for a full dose. Calculate the dose (mg) based on the patient’s actual weight in kg and the number of EBANGA vials required
*Prior to reconstitution, allow EBANGA vial(s) to reach ambient temperature (15°C to 27°C [59°F to 81°F]) for approximately 20 minutes. If for any reason reconstitution cannot proceed immediately upon reaching ambient temperature, vials that have NOT been reconstituted may be kept at ambient temperature, protected from light, for no more than 24 hours.
*Immediately upon reaching ambient temperature, use a sterile 10 mL syringe and an 18-gauge needle to withdraw 7.7 mL of Sterile Water for Injection, USP. Insert the needle tip into the EBANGA vial. Holding horizontally, angle the needle down at an approximate 45° angle, above the lyophilized powder, which has a cake-like appearance. Slowly inject the diluent along the wall of the vial and without any air to avoid foaming and bubbles.
*Gently swirl (do NOT shake) for approximately 10 seconds; then set the vial down to rest for at least 10 seconds. Repeat until the cake is dissolved. This may take up to 20 minutes.
*Upon reconstitution, one vial delivers 8 mL of solution that is clear to slightly opalescent and colorless to slightly yellow containing 50 mg/mL of ansuvimab-zykl. Do NOT administer and discard the vial if the reconstituted solution is discolored or contains visible particles.
*Dilute the EBANGA solution immediately upon reconstitution. If needed, the reconstituted solution may be stored refrigerated at 2°C to 8°C (36°F to 46°F), protected from light, for up to 4 hours. This 4-hour window includes time required for further dilution and EBANGA solution should be infused immediately upon further dilution.

'''Dilution Instructions''':

Following reconstitution, EBANGA must be further diluted prior to IV infusion.
Use an 18-20 gauge, 1-1.5" needle with an appropriately sized syringe up to 60 mL to perform the dilution steps.

Prepare the EBANGA IV dosing solution using an appropriately sized syringe up to 60 mL.
*For patients weighing ≥ 2 kg, prepare the diluent using either a latex-free, di-ethylhexylphthalate (DEHP)-free 0.9% Sodium Chloride Injection USP infusion bag, or latex-free, DEHP-free 5% Dextrose Injection USP infusion bag. For patients weighing 0.5 to < 2 kg use a pump-compatible syringe
*For adult and pediatric patients, either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP can be used as the diluent.
*The total volume of the infusion solution to be administered is based on the patient’s body weight

*For patients weighing 0.5 to < 2 kg:
- Use a 10 mL syringe compatible with the IV infusion pump.
- Fill the 10 mL syringe with the appropriate amount of diluent
- Add the calculated volume of EBANGA to the 10 mL syringe
- Mix the diluted solution by gentle inversion (3 to 5 times) until admixed. Do not shake.

*For patients weighing ≥ 2 kg:
- Select a diluent solution infusion bag size of appropriate fill volume based on the patient's body weight
- Withdraw and discard from the bag a volume of diluent solution that will leave remaining in the bag the appropriate volume based on the patient's weight
- Gently invert the IV bag 5 to 10 times until the diluted solution is admixed. Do NOT shake.

*Infuse the EBANGA solution immediately upon dilution. If needed, the diluted infusion solution may be stored refrigerated at 2°C to 8°C (36°F to 46°F), for up to 4 hours. Do not freeze the diluted solution. If refrigerated, allow approximately 20 minutes for the diluted solution to come to ambient temperature prior to use. These time limits include reconstitution time.

*Prepare a medical label including patient weight in kg, date, and time of reconstitution.
|monitoring=Monitor all patients for signs and symptoms including, but not limited to, hypotension, chills and elevation of fever, during and following EBANGA infusion. In the case of severe or life-threatening hypersensitivity reactions, discontinue the administration of EBANGA immediately and administer appropriate emergency care
|IVCompat=*Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not administer if discolored or if the vial contains visible particles.
*Do not mix with or administer as an infusion with other medicinal products.
*Prepare the IV infusion line with 1.2 micron in-line filter extension set.
*Administer the IV infusion solution over 60 minutes.
*At the end of the infusion, if a syringe pump was used, then remove the syringe and flush the line with 2 to 5 mL of diluent, but not to exceed the total infusion volume. If an infusion bag was used, replace the empty bag and flush the line by infusing at least 25 mL of the diluent, to ensure complete product administration.
|mechAction=Ansuvimab-zykl is a recombinant human monoclonal antibody with antiviral activity against Orthoebolavirus zairense
|PD=Ansuvimab-zykl exposure-response relationship and the time course of pharmacodynamic response is unknown.
|PK=Limited data from 18 healthy participants 22 to 56 years of age suggests that the pharmacokinetic profile of ansuvimab-zykl is consistent with the profile of other IgG1 monoclonal antibodies. Pharmacokinetic data are not available for Orthoebolavirus zairense infected patients.
|nonClinToxic=Carcinogenicity, genotoxicity and fertility studies have not been conducted with ansuvimab-zykl.
|clinicalStudies=The efficacy of EBANGA has been evaluated in 174 participants with confirmed Orthoebolavirus zairense infection in the PALM trial, a multi-center, open-label, randomized, controlled trial (NCT03719586). The trial was conducted in the North Kivu and Ituri provinces in the Democratic Republic of Congo, where an outbreak began in August 2018, and enrolled 681 participants of all ages, including pregnant women, with documented Orthoebolavirus zairense infection and symptoms of any duration who were receiving oSOC. Eligible participants had a positive reverse transcriptase-polymerase chain reaction (RT-PCR) for the nucleoprotein (NP) gene of Orthoebolavirus zairense and had not received other investigational treatments (with the exception of experimental vaccines) within the previous 30 days. Neonates ≤7 days of age were eligible if the mother had documented infection. Neonates born to a mother who had cleared Orthoebolavirus zairense following a course of her assigned investigational medication were also eligible to be enrolled at investigator discretion regarding the likelihood that the neonate was infected. Participants were randomized to receive EBANGA 50 mg/kg IV as a single infusion, an investigational control 50 mg/kg IV every third day, for a total of 3 doses, or other investigational drugs. Randomization was stratified by reverse transcription-PCR cycle threshold calculated using NP targets (CtNP ≤22.0 vs ˃22.0; corresponding to high and low viral load, respectively) and Ebola Treatment Unit (ETU) site. All participants received oSOC consisting, at a minimum, of IV fluids, daily clinical laboratory testing, correction of hypoglycemia and electrolyte imbalances, and broad-spectrum antibiotics and antimalarials, as indicated.
|howSupplied=EBANGA (ansuvimab-zykl) for injection is supplied as a sterile, preservative-free, off-white to white lyophilized powder in a single-dose vial (NDC 71655-578-01) for reconstitution and further dilution.

One primary carton (NDC 71655-578-02) contains thirty-six 400 mg vials packaged in a box containing either one primary carton (NDC 71655-578-03), four primary cartons (NDC 71655-578-04), or eight primary cartons (NDC 71655-578-08).
|storage=Prior to reconstitution, allow EBANGA vial(s) to reach ambient temperature (15°C to 27°C [59°F to 81°F]) for approximately 20 minutes. If for any reason reconstitution cannot proceed immediately upon reaching ambient temperature, vials that have NOT been reconstituted may be kept at ambient temperature, protected from light, for no more than 24 hours.

Store refrigerated at 2ºC to 8ºC (36ºF to 46ºF) in the original carton to protect from light. Do not freeze. Do not shake.

Prior to reconstitution, allow EBANGA vial(s) to reach ambient temperature (15°C to 27°C [59°F to 81°F]) for approximately 20 minutes. If for any reason reconstitution cannot proceed immediately upon reaching ambient temperature, vials that have NOT been reconstituted may be kept at ambient temperature, protected from light, for no more than 24 hours.

After reconstitution, if storage is needed, the entire storage time for the reconstituted solution in the vial and the diluted solution in the IV bag should be protected from light and limited to 4 hours refrigerated at 2°C to 8°C (36°F to 46°F)
|fdaPatientInfo=Inform patients that hypersensitivity reactions including infusion-associated events have been reported during and post-infusion with EBANGA and to immediately report if they experience any symptoms of systemic hypersensitivity reactions.

Instruct patients with Orthoebolavirus zairense not to breastfeed because of the risk of passing Orthoebolavirus zairense to the baby
|alcohol=Alcohol-Ansuvimab-zykl interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=Ebanga
}}

Vibegron

2025-04-27T14:21:21Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=Gemtesa |aOrAn=a |drugClass=selective beta-3 adrenergic receptor |indicationType=treatment |indication=of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency in adults. treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency in adult males on pharmacological therapy for benig..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=Gemtesa
|aOrAn=a
|drugClass=selective beta-3 adrenergic receptor
|indicationType=treatment
|indication=of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency in adults.

treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency in adult males on pharmacological therapy for benign prostatic hyperplasia (BPH).
|adverseReactions=Urinary retention
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult='''Overactive Bladder in Adults''':
GEMTESA® is indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency in adults.

''' Overactive Bladder in Adult Males with Benign Prostatic Hyperplasia (BPH)''':
GEMTESA is indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency in adult males on pharmacological therapy for benign prostatic hyperplasia (BPH).

'''Recommended Dosage''' :
The recommended dosage of GEMTESA is one 75 mg tablet orally, once daily with or without food. Swallow GEMTESA tablets whole with a glass of water.

In adults, GEMTESA tablets also may be crushed, mixed with a tablespoon (approximately 15 mL) of applesauce and taken immediately with a glass of water
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Vibegron in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Vibegron in adult patients.
|fdaLIADPed=The safety and effectiveness of GEMTESA in pediatric patients have not been established.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Vibegron in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Vibegron in pediatric patients.
|contraindications=GEMTESA is contraindicated in patients with known hypersensitivity to vibegron or any components of GEMTESA. Hypersensitivity reactions, such as angioedema, have occurred
|warnings=*Urinary Retention:
Urinary retention has been reported in patients taking GEMTESA. The risk of urinary retention may be increased in patients with bladder outlet obstruction and also in patients taking muscarinic antagonist medications for the treatment of OAB. Monitor patients for signs and symptoms of urinary retention, particularly in patients with bladder outlet obstruction or patients taking muscarinic antagonist medications for the treatment of OAB. Discontinue GEMTESA in patients who develop urinary retention

*Angioedema:
Angioedema of the face and/or larynx has been reported with GEMTESA. Angioedema has been reported to occur hours after the first dose or after multiple doses. Angioedema, associated with upper airway swelling, may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, immediately discontinue GEMTESA and provide appropriate therapy and/or measures necessary to ensure a patent airway. GEMTESA is contraindicated in patients with known hypersensitivity to vibegron or any component of GEMTESA
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

*Overactive Bladder in Adults:
The safety of GEMTESA was evaluated in a 12-week, double-blind, placebo- and active-controlled study (Study 3003) in patients with OAB.

A total of 545 patients received GEMTESA. The majority of the patients were White (78%) and female (85%) with a mean age of 60 years (range 18 to 93 years).

Other adverse reactions reported in <2% of patients treated with GEMTESA included:

Gastrointestinal disorders: dry mouth, constipation

Investigations: residual urine volume increased

Renal and urinary disorders: urinary retention

Vascular disorders: hot flush

GEMTESA was also evaluated for long-term safety in an extension study (Study 3004) in 505 patients who completed the 12-week study (Study 3003). Of the 273 patients who received GEMTESA 75 mg once daily in the extension study, 181 patients were treated for a total of one year.

Adverse reactions reported in ≥2% of patients treated with GEMTESA 75 mg for up to 52 weeks in the long-term extension study, and not already listed above, were urinary tract infection (6.6%) and bronchitis (2.9%)

* Overactive Bladder in Adult Males with BPH
The safety of GEMTESA was evaluated in a 24-week double-blind, randomized, placebo-controlled study (Study 3005) in male patients with OAB on pharmacological therapy for BPH. A total of 553 patients received GEMTESA
|postmarketing=The following adverse reactions have been identified during post-approval use of vibegron. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse events have been reported in association with vibegron use in worldwide postmarketing experience:

Urologic disorders: urinary retention

Skin and subcutaneous tissue disorders: angioedema of the face and larynx; hypersensitivity reactions, including urticaria, pruritus, rash and drug eruption; eczema

Gastrointestinal disorders: constipation
|drugInteractions=Concomitant use of GEMTESA increases digoxin maximal concentrations (Cmax) and systemic exposure as assessed by area under the concentration-time curve (AUC). Serum digoxin concentrations should be monitored before initiating and during therapy with GEMTESA and used for titration of the digoxin dose to obtain the desired clinical effect. Continue monitoring digoxin concentrations upon discontinuation of GEMTESA and adjust digoxin dose as needed.
|useInLaborDelivery=There are no available data on GEMTESA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

In animal studies, no effects on embryo-fetal development were observed following administration of vibegron during the period of organogenesis at exposures approximately 275-fold and 285-fold greater than clinical exposure at the recommended daily dose of GEMTESA, in rats and rabbits, respectively. Delayed fetal skeletal ossification was observed in rabbits at approximately 898-fold clinical exposure, in the presence of maternal toxicity. In rats treated with vibegron during pregnancy and lactation, no effects on offspring were observed at 89-fold clinical exposure. Developmental toxicity was observed in offspring at approximately 458-fold clinical exposure, in the presence of maternal toxicity. No effects on offspring were observed at 89-fold clinical exposure.
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies carry some risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

In an embryo-fetal developmental toxicity study, pregnant rats were treated with daily oral doses of 0, 30, 100, 300, or 1000 mg/kg/day vibegron during the period of organogenesis (Days 6 to 20 of gestation). These doses were associated with systemic exposures (AUC) 0-, 9-, 89-, 275-, and 1867-fold higher, respectively, than in humans treated with the recommended daily dose of GEMTESA. No embryo-fetal developmental toxicity was observed at doses up to 300 mg/kg/day. Treatment with the high dose of 1000 mg/kg/day was discontinued due to maternal toxicity.

In an embryo-fetal developmental toxicity study, pregnant rabbits were treated with daily oral doses of 0, 30, 100, or 300 mg/kg/day vibegron during the period of organogenesis (Days 7 to 20 of gestation). These doses were associated with systemic exposures (AUC) 0-, 86-, 285-, and 898-fold higher, respectively, than in humans treated with the recommended daily dose of GEMTESA. No embryo-fetal developmental toxicity was observed at doses of vibegron up to 100 mg/kg/day. Maternal toxicity (decreased food consumption), reduced fetal body weight, and an increased incidence of delayed skeletal ossification, were observed at 300 mg/kg/day.

In a pre- and post-natal developmental toxicity study, pregnant or lactating rats were treated with daily oral doses of 0, 30, 100, or 500 mg/kg/day vibegron from day 6 of gestation through day 20 of lactation. These doses were associated with estimated systemic exposures (AUC) 0-, 9-, 89-, and 458-fold higher, respectively, than in humans treated with the recommended daily dose of GEMTESA. No developmental toxicity was observed in F1 offspring at doses up to 100 mg/kg/day. Maternal toxicity was observed during lactation (decreased body weight gain) at doses ≥100 mg/kg/day and during gestation (decreased body weight gain and food consumption) at 500 mg/kg/day. Developmental toxicity was observed in F1 offspring (increased stillborn index, lethality, reduced viability and weaning indices, decreased body weight and body weight gains, low physical development differentiation indices, and effects on sensory function and reflexes) at 500 mg/kg/day.
|useInNursing=There are no data on the presence of vibegron in human milk, the effects of the drug on the breastfed infant, or the effects on milk production. When a single oral dose of radiolabeled vibegron was administered to postnatal nursing rats, radioactivity was observed in milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for GEMTESA and any potential adverse effects on the breastfed infant from GEMTESA or from the underlying maternal condition.

In a lactational transfer study, lactating rats were treated with a single oral dose of 10 mg/kg radiolabeled [3H] vibegron on postpartum day 10. Levels of radioactivity were determined in milk and plasma collected at 1, 4, 12, and 24 after dosing. The Cmax of total radioactivity in milk and plasma were observed at 9 and 2 hours after dosing, respectively, with a maximum milk-to-plasma concentration ratio of 2.2 observed at 12 hours after dosing. Vibegron elimination from milk showed a similar trend as that from plasma. The radioactivity concentration in milk at 24 hours after administration was approximately 25% of the Cmax.
|useInPed=The safety and effectiveness of GEMTESA in pediatric patients have not been established.
|useInGeri=Of 526 patients who received GEMTESA in the clinical studies for OAB with symptoms of urge urinary incontinence, urgency, and urinary frequency, 242 (46%) were 65 years of age or older, and 75 (14%) were 75 years of age or older. No overall differences in safety or effectiveness of GEMTESA have been observed between patients 65 years of age and older and younger adult patients.Of the total number of GEMTESA-treated patients in clinical studies for OAB with symptoms of urge urinary incontinence, urgency, and urinary frequency in adult males on pharmacological therapy for benign prostatic hyperplasia (BPH), 347 (63%) were 65 years of age and older, while 100 (18%) were 75 years of age and older. No overall differences in safety of GEMTESA have been observed between patients 65 years of age and older and younger adult patients.
|useInRenalImpair=No dosage adjustment for GEMTESA is recommended for patients with mild, moderate, or severe renal impairment (eGFR 15 to <90 mL/min/1.73 m2). GEMTESA has not been studied in patients with eGFR <15 mL/min/1.73 m2 (with or without hemodialysis) and is not recommended in these patients
|useInHepaticImpair=No dosage adjustment for GEMTESA is recommended for patients with mild to moderate hepatic impairment (Child-Pugh A and B). GEMTESA has not been studied in patients with severe hepatic impairment (Child-Pugh C) and is not recommended in this patient population.
|administration=The recommended dosage of GEMTESA is one 75 mg tablet orally, once daily with or without food. Swallow GEMTESA tablets whole with a glass of water.

In adults, GEMTESA tablets also may be crushed, mixed with a tablespoon (approximately 15 mL) of applesauce and taken immediately with a glass of wate
|monitoring=Monitor patients for signs and symptoms of urinary retention, particularly in patients with bladder outlet obstruction or patients taking muscarinic antagonist medications for the treatment of OAB.
|overdose=There is no experience with inadvertent GEMTESA overdosage. In case of suspected overdose, treatment should be symptomatic and supportive.
|mechAction=Vibegron is a selective human beta-3 adrenergic receptor agonist. Activation of the beta-3 adrenergic receptor increases bladder capacity by relaxing the detrusor smooth muscle during bladder filling.
|PD=Vibegron's exposure-response relationship and the time course of pharmacodynamic response are not fully characterized.

* Blood Pressure:
In a 4-week, randomized, placebo-controlled, ambulatory blood pressure study in OAB patients (n=200), daily treatment with GEMTESA 75 mg was not associated with clinically significant changes in blood pressure. Subjects enrolled in this study had a mean age of 59 years and 75% were female. Thirty-five percent of subjects had pre-existing hypertension at baseline and 29% of all subjects were taking at least 1 concomitant antihypertensive medication.

*Cardiac Electrophysiology:
GEMTESA does not prolong the QT interval to any clinically relevant extent at a single dose 5.3 times the approved recommended dose.
|PK=Mean vibegron Cmax and AUC increased in a greater than dose-proportional manner up to 600 mg (8 times the approved recommended dosage). Steady state concentrations are achieved within 7 days of once daily dosing. The mean accumulation ratio (Rac) was 1.7 for Cmax and 2.4 for AUC0-24hr.

*Absorption:
Median vibegron Tmax is approximately 1 to 3 hours.

Oral administration of a 75 mg vibegron tablet crushed and mixed with 15 mL of applesauce resulted in no clinically relevant changes in vibegron pharmacokinetics when compared to administration of an intact 75 mg vibegron tablet.

*Distribution:
The mean apparent volume of distribution is 6304 liters. Human plasma protein binding of vibegron is approximately 50%. The average blood-to-plasma concentration ratio is 0.9.

*Elimination:
Vibegron has an effective half-life of 30.8 hours across all populations.

*Metabolism:
Metabolism plays a minor role in the elimination of vibegron. CYP3A4 is the predominant enzyme responsible for in vitro metabolism.

*Excretion:
Following a radiolabeled dose, approximately 59% of the dose (54% as unchanged) was recovered in feces and 20% (19% as unchanged) in urine.

*Specific Populations:
No clinically significant differences in the pharmacokinetics of vibegron were observed based on age (18 to 93 years), sex, race/ethnicity (Japanese vs. non-Japanese), mild (eGFR 60 to <90 mL/min/1.73 m2), moderate (eGFR 30 to <60 mL/min/1.73 m2), and severe (eGFR 15 to <30 mL/min/1.73 m2) renal impairment, or moderate (Child-Pugh B) hepatic impairment. The effect of more severe renal impairment (eGFR <15 mL/min/1.73 m2) with or without hemodialysis or severe (Child-Pugh C) hepatic impairment on vibegron pharmacokinetics was not studied.
|nonClinToxic=*Carcinogenesis:
No carcinogenicity was observed in long-term studies conducted in mice and rats treated with daily oral doses of vibegron for approximately 2 years. In the mouse carcinogenicity study, CD-1 mice were treated with daily oral doses of vibegron up to 90 mg/kg/day in males and up to 150 mg/kg/day in females, corresponding to estimated systemic exposures (AUC) 21- and 55-fold higher, respectively, than in humans treated with the recommended daily dose of GEMTESA. In the rat carcinogenicity study, Sprague Dawley rats were treated with daily oral doses of vibegron up to 30 mg/kg/day in males and up to 180 mg/kg/day in females, corresponding to systemic exposures (AUC) 18- and 117-fold higher, respectively, than in humans treated with the recommended daily dose of GEMTESA.

*Mutagenesis:
Vibegron was not mutagenic in in vitro microbial reverse mutation assays, showed no evidence of genotoxic activity in an in vitro human peripheral blood lymphocyte chromosomal aberration assay, and did not increase the frequency of micronucleated polychromatic erythrocytes in an in vivo rat bone marrow micronucleus assay.

*Impairment of Fertility:
In fertility/general reproductive toxicity studies conducted in rats, females were treated with daily oral doses of 0, 30, 100, 300, or 1000 mg/kg/day vibegron and males were treated with daily oral doses of 0, 10, 30, or 300 mg/kg/day vibegron. No effects on fertility were observed in female or male rats at doses up to 300 mg/kg/day, associated with systemic exposure (AUC) at least 274-fold higher than in humans treated with the recommended daily dose of GEMTESA. General toxicity, decreased fecundity, and decreased fertility were observed in female rats at 1000 mg/kg/day, associated with estimated systemic exposure 1867-fold higher than in humans treated with the recommended daily dose of GEMTESA.
|clinicalStudies=*Overactive Bladder in Adults:
The efficacy of GEMTESA was evaluated in a 12-week, double-blind, randomized, placebo-controlled, and active-controlled trial (Study 3003, NCT03492281) in patients with OAB (urge urinary incontinence, urgency, and urinary frequency). Patients were randomized 5:5:4 to receive either GEMTESA 75 mg, placebo, or active control orally, once daily for 12 weeks. For study entry, patients had to have symptoms of OAB for at least 3 months with an average of 8 or more micturitions per day and at least 1 urge urinary incontinence (UUI) per day, or an average of 8 or more micturitions per day and an average of at least 3 urgency episodes per day. Urge urinary incontinence was defined as leakage of urine of any amount because the patient felt an urge or need to urinate immediately. The study population included OAB medication-naïve patients as well as patients who had received prior therapy with OAB medications.

The co-primary endpoints were change from baseline in average daily number of micturitions and average daily number of UUI episodes at week 12. Additional endpoints included change from baseline in average daily number of “need to urinate immediately” (urgency) episodes and average volume voided per micturition.

A total of 1,515 patients received at least one daily dose of placebo (n=540), GEMTESA 75 mg (n=545), or an active control treatment (n=430). The majority of patients were White (78%) and female (85%) with a mean age of 60 (range 18 to 93) years.
|howSupplied=GEMTESA 75 mg tablets are light green, oval, film-coated tablets, debossed with V75 on one side and no debossing on the other side.

GEMTESA is marketed in two packaging configurations:

Thirty (30) tablets in a HDPE bottle with a child-resistant cap, NDC 73336-075-30

Ninety (90) tablets in a HDPE bottle with a child-resistant cap, NDC 73336-075-90
|storage=Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F)
|fdaPatientInfo=*Urinary Retention:
Inform patients that GEMTESA has been associated with urinary retention. Inform patients that the risk of urinary retention may be increased in patients taking muscarinic antagonist medications for the treatment of OAB. Instruct patients to contact their healthcare provider if they experience symptoms consistent with urinary retention while taking GEMTESA

*Angioedema:
Inform patients that GEMTESA may cause angioedema. Advise patients to immediately discontinue GEMTESA and seek medical attention if angioedema associated with upper airway swelling occurs as this may be life-threatening.

*Administration Instructions:
Advise patients that GEMTESA tablets can be swallowed whole with a glass of water or may be crushed, mixed with a tablespoon of applesauce and taken immediately with a glass of water
|alcohol=Alcohol-Vibegron interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=Gemtesa
}}

Givinostat Hydrochloride

2025-04-10T11:53:57Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=givinostat |aOrAn=an |drugClass=inhibits class I and class II histone deacetylases (HDACs) and several pro-inflammatory cytokines |indicationType=treatment |indication=of Duchenne muscular dystrophy (DMD) in patients 6 years of age and older. |adverseReactions=*Hematological Changes *Increased Triglycerides *Gastrointestinal Disturbances *QTc Prolongation |blackBoxWarningTitle='..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=givinostat
|aOrAn=an
|drugClass=inhibits class I and class II histone deacetylases (HDACs) and several pro-inflammatory cytokines
|indicationType=treatment
|indication=of Duchenne muscular dystrophy (DMD) in patients 6 years of age and older.
|adverseReactions=*Hematological Changes
*Increased Triglycerides
*Gastrointestinal Disturbances
*QTc Prolongation
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=DUVYZAT is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 6 years of age and older.
Obtain and evaluate baseline platelet counts and triglycerides prior to initiation of DUVYZAT
Do not initiate DUVYZAT in patients with a platelet count less than 150 x 109/L. Monitor platelet counts and triglycerides as recommended during treatment to determine if dosage modifications are needed
In addition, in patients with underlying cardiac disease or taking concomitant medications that cause QT prolongation, obtain ECGs when initiating treatment with DUVYZAT, during concomitant use, and as clinically indicated
The recommended dosage of DUVYZAT is based on body weight and administered orally twice daily with food
*Platelet count <150 x 109/L verified in two assessments one week apart
or
*Moderate or severe diarrhea
or
*Fasting triglycerides >300 mg/dL verified by two assessments one week apart
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Givinostat Hydrochloride in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Givinostat Hydrochloride in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Givinostat Hydrochloride in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Givinostat Hydrochloride in pediatric patients.
|contraindications=None.
|warnings=*Hematological Changes:
DUVYZAT can cause dose-related thrombocytopenia and other signs of myelosuppression, including decreased hemoglobin and neutropenia.

In Study 1 thrombocytopenia occurred in 33% of patients treated with DUVYZAT compared to no patients on placebo. The maximum decrease in platelets occurred within the first 2 months of therapy and remained low throughout the course of therapy. In a few patients, thrombocytopenia was associated with bleeding events including epistaxis, hematoma or contusions. Low platelet counts resulted in DUVYZAT dose reduction in 28% of patients. Patients with baseline platelet counts below the lower limit of normal were excluded from the study.

Decreased hemoglobin and decreased neutrophils were also observed in patients treated with DUVYZAT compared to placebo.
Monitor blood counts every 2 weeks for the first 2 months of treatment, then monthly for the first 3 months, and every 3 months thereafter. Modify the dosage of DUVYZAT for confirmed thrombocytopenia
Treatment should be permanently discontinued if the abnormalities worsen despite dose modification. If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible, and hold dosing until platelet count is confirmed.

*Increased Triglycerides
DUVYZAT can cause elevations in triglycerides. In Study 1 hypertriglyceridemia occurred in 23% of patients treated with DUVYZAT (one of whom had familial hypertriglyceridemia) compared to 7% of patients on placebo. High triglycerides (i.e., levels greater than 300 mg/dL) resulted in discontinuation and led to dosage modification in 2% and 8%, respectively, of patients treated with DUVYZAT.Monitor triglycerides at 1 month, 3 months, 6 months, and then every 6 months thereafter. Modify the dosage if fasting triglycerides are verified > 300 mg/dLTreatment with DUVYZAT should be discontinued if triglycerides remain elevated despite adequate dietary intervention and dosage adjustment.
*Gastrointestinal Disturbances:
Gastrointestinal disturbances, including diarrhea, nausea/vomiting, and abdominal pain were common adverse reactions in DUVYZAT clinical trials in DMD. In Study 1, diarrhea was reported in 37% of patients treated with DUVYZAT (with 1 severe case reported) compared to 20% of patients on placebo. Diarrhea usually occurred within the first few weeks of initiation of treatment with DUVYZAT.

Vomiting and nausea, sometimes severe and usually occurring within the first 2 months of treatment, occurred in 32% of patients treated with DUVYZAT compared to 18% of patients on placebo. Abdominal pain occurred in 34% of patients treated with DUVYZAT compared to 25% of patients on placebo. One case of abdominal pain was serious.
Antiemetics or antidiarrheal medications may be considered during treatment with DUVYZAT. Fluid and electrolytes should be replaced as needed to prevent dehydration
Modify the dosage of DUVYZAT in patients with moderate or severe diarrhea, and treatment should be discontinued if significant symptoms persist

*QTc Prolongation:
Avoid use of DUVYZAT in patients who are at an increased risk for ventricular arrhythmias (including torsades de pointes), such as those with congenital long QT syndrome, coronary artery disease, electrolyte disturbance concomitant use of other medicinal products known to cause QT prolongation Obtain ECGs prior to initiating treatment with DUVYZAT in patients with underlying cardiac disease or in patients who are taking concomitant medications that cause QT prolongation
|clinicalTrials=*Hematological Changes
*Increased Triglycerides
*Gastrointestinal Disturbances
*QTc Prolongation
|drugInteractions=*Effect of DUVYZAT on Other Drugs:
Givinostat is a weak intestinal CYP3A4 inhibitor. Closely monitor when DUVYZAT is used in combination with orally administered CYP3A4 sensitive substrates for which a small change in substrate plasma concentration may lead to serious toxicities.

*OCT2 Sensitive Substrates:
Givinostat is a weak inhibitor of the renal uptake transporter OCT2 Closely monitor when DUVYZAT is used in combination with drugs known as a sensitive substrate of the OCT2 transporter for which a small change in substrate plasma concentration may lead to serious toxicities.

*Effect of Other Drugs on DUVYZAT:
Avoid concomitant use of DUVYZAT with other product(s) with a known potential to prolong the QTc interval. If concomitant use cannot be avoided, obtain ECGs when initiating, during concomitant use, and as clinically indicated Withhold DUVYZAT if the QTc interval is > 500 ms or the change from baseline is > 60 ms Concomitant use of DUVYZAT with other products that prolong the QTc interval may result in a greater increase in the QTc interval and adverse reactions associated with QTc interval prolongation, including Torsade de pointes, other serious arrythmias, and sudden death
|useInPregnancyAUS=DUVYZAT is indicated for the treatment of DMD, which is a disease of predominantly young male patients. Therefore, there are no adequate data available to assess the use of DUVYZAT in pregnant women. In animal studies, oral administration of givinostat during organogenesis resulted in decreased fetal body weight and increased structural variations; oral administration during pregnancy and lactation resulted in increased embryofetal and offspring mortality and neurobehavioral changes in the offspring. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
|useInNursing=There are no human or animal data to assess the effect of DUVYZAT or its metabolites on milk production, the presence of givinostat in milk, or the effects on the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for DUVYZAT and any potential adverse effects on the breastfed infant from DUVYZAT or from the underlying maternal condition.
|useInPed=The safety and effectiveness of DUVYZAT in children aged 6 years and older have been established
|useInGeri=DMD is largely a disease of children and young adults; therefore, there is no experience with DUVYZAT in geriatric DMD patients.
|useInHepaticImpair=A dedicated clinical study was not conducted to evaluate the pharmacokinetics of DUVYZAT in subjects with hepatic impairment, and no recommendation for dosage adjustment can be made for patients with hepatic impairment. Because DUVYZAT is eliminated mainly through hepatic metabolism, hepatic impairment is expected to increase the exposure of givinostat
|useInReproPotential=No human data are available on the effect of DUVYZAT on reproductive potential.

Animal studies indicate possible adverse effects on reproduction
|administration=DUVYZAT is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 6 years of age and older.
Obtain and evaluate baseline platelet counts and triglycerides prior to initiation of DUVYZAT
Do not initiate DUVYZAT in patients with a platelet count less than 150 x 109/L. Monitor platelet counts and triglycerides as recommended during treatment to determine if dosage modifications are needed
In addition, in patients with underlying cardiac disease or taking concomitant medications that cause QT prolongation, obtain ECGs when initiating treatment with DUVYZAT, during concomitant use, and as clinically indicated
The recommended dosage of DUVYZAT is based on body weight and administered orally twice daily with food
*Platelet count <150 x 109/L verified in two assessments one week apart
or
*Moderate or severe diarrhea
or
*Fasting triglycerides >300 mg/dL verified by two assessments one week apart
|mechAction=DUVYZAT is a histone deacetylase inhibitor. The precise mechanism by which DUVYZAT exerts its effect in patients with DMD is unknown.
|PD=*Muscle Fat Fraction as Assessed by MR Spectroscopy: The percentage of fat fraction present in the vastus lateralis muscles (VLM) of the thigh was measured in Study 1
using magnetic resonance spectroscopy. At 18 months, for the patients with VLM fat fraction baseline in the range of >5% to ≤30%, a mean increase (absolute difference from baseline levels) of VLM fat fraction was 7.48% in the DUVYZAT-treated patients compared to a 10.89% increase in patients who received placebo.

*Cardiac Electrophysiology:
The largest mean increase in QTc interval of 13.6 ms (upper confidence interval of 17.1 ms) occurred 5 hours after administration of givinostat 265.8 mg to healthy subjects (approximately 5 times the 53.2 mg dose recommended for DMD patients weighing 60 kg or more).
02
|PK=Givinostat exhibits linear kinetics with the studied dose range. Systemic exposure to givinostat was dose-proportional across the therapeutic dose range. Steady-state concentrations are achieved within 5 to 7 days after twice daily dosing. An accumulation of less than 2-fold was observed for givinostat after twice daily administration.
|nonClinToxic=Carcinogenesis

Studies to assess the carcinogenic potential of givinostat have not been conducted.

Mutagenesis

Givinostat was positive in a bacterial reverse mutation (Ames) assay, and negative in an in vitro mammalian cell (mouse lymphoma) mutation assay, an in vitro chromosomal aberration assay in mammalian (human lymphocytes) cells, and an in vivo gene mutation assay (with Pig-a endpoints) in Big Blue transgenic rats.

Impairment of Fertility

Oral administration of givinostat (0, 40, 80, or 160 mg/kg) prior to and throughout mating in male and female rats and continuing to gestation day 7 in females, resulted in no adverse effects on fertility. However, there was an increase in corpora lutea at the mid and high doses and increased pre- and postimplantation loss at all doses. A no-effect dose for adverse effects on early embryonic development was not identified; plasma exposures (AUC) at the lowest dose tested were lower than that in humans at the maximum recommended human dose of 53.2 mg twice daily.
|clinicalStudies=The effectiveness of DUVYZAT for the treatment of Duchenne muscular dystrophy (DMD) was evaluated in a randomized, double-blind, placebo-controlled 18-month study (Study 1; NCT02851797). A total of 179 patients were randomized 2:1 to receive either DUVYZAT (n = 118) or placebo (n = 61). A weight-based dose regimen was appliedThe study included male patients 6 years of age and older with a confirmed diagnosis of DMD who were ambulatory and on a stable dosage of corticosteroids. At baseline, patients had a mean age of 9.8 years, 90% were White, 3% were Asian, 3% were Black.

The primary endpoint was the change from baseline to Month 18 in 4-stair climb (4SC) time for DUVYZAT compared to placebo. The 4SC is a measure of muscle function that tests the time it takes to climb 4 stairs. A secondary efficacy endpoint was change from baseline to Month 18 in physical function as assessed by the North Star Ambulatory Assessment (NSAA).

The primary analysis population was based on a prespecified range of baseline muscle fat fraction as determined by MR spectroscopy. Patients treated with DUVYZAT showed statistically significant less decline in the 4-stair climb compared to placebo Patients treated with givinostat experienced less worsening on the NSAA compared to placebo, which was nominally significant but not statistically significant based on the prespecified multiplicity adjustment.
|howSupplied=DUVYZAT (givinostat) oral suspension is a white to off-white or faintly pink, peach-cream flavored suspension. It is supplied in an amber polyethylene terephthalate bottle closed with a high-density polyethylene child-resistant, screw cap with low-density polyethylene syringe adapter, containing 140 mL of oral suspension (NDC 11797-110-01). Each mL contains 8.86 mg of givinostat.
|storage=Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not freeze. Store upright.

Discard any unused DUVYZAT remaining after 60 days of first opening of the bottle.
|fdaPatientInfo=*Shake DUVYZAT oral suspension well before measuring out each dose.
*Administer using the provided graduated oral syringe to measure the appropriate volume of suspension corresponding to the prescribed dose for the patient.
*Take DUVYZAT with food.
*Discard any unused DUVYZAT oral suspension remaining after 60 days of first opening the bottle
|alcohol=Alcohol-Givinostat Hydrochloride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=DUVYZAT
}}

Sotatercept-csrk

2025-04-10T10:33:12Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName= Alara Ece Dagsali, M.D. |aOrAn=an |drugClass=activin signalling inhibitor |indicationType=treatment |indication=of adults with pulmonary arterial hypertension (PAH, World Health Organization [WHO] Group 1) to increase exercise capacity, improve WHO functional class (FC), and reduce the risk of clinical worsening events. |adverseReactions=*Erythrocytosis *Severe Thr..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=[[User: AED| Alara Ece Dagsali, M.D.]]
|aOrAn=an
|drugClass=activin signalling inhibitor
|indicationType=treatment
|indication=of adults with pulmonary arterial hypertension (PAH, World Health Organization [WHO] Group 1) to increase exercise capacity, improve WHO functional class (FC), and reduce the risk of clinical worsening events.
|adverseReactions=*Erythrocytosis
*Severe Thrombocytopenia
*Serious Bleeding
*Embryo-Fetal Toxicity
*Impaired Fertility
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=WINREVAIR™ is indicated for the treatment of adults with pulmonary arterial hypertension (PAH, World Health Organization [WHO] Group 1) to increase exercise capacity, improve WHO functional class (FC), and reduce the risk of clinical worsening events.

*Recommended Starting Dosage
WINREVAIR is administered once every 3 weeks by subcutaneous injection according to patient body weight. The starting dose of WINREVAIR is 0.3 mg/kg.

Obtain hemoglobin (Hgb) and platelet count prior to the first dose of WINREVAIR. Do not initiate treatment if platelet count is <50,000/mm3 (<50 x 109/L)

Injection volume should be rounded to the nearest 0.1 mL.

For example: (70 kg x 0.3 mg/kg) ÷ 50 mg/mL = 0.42 mL, rounds to 0.4 mL.

* Recommended Target Dosage
After verifying acceptable Hgb and platelet count, increase to the target dose of 0.7 mg/kg. Continue treatment at 0.7 mg/kg every 3 weeks unless dosage adjustments are required
Injection volume should be rounded to the nearest 0.1 mL.

For example: (70 kg x 0.7 mg/kg) ÷ 50 mg/mL = 0.98 mL, rounds to 1 mL
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Sotatercept-csrk in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Sotatercept-csrk in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Sotatercept-csrk in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Sotatercept-csrk in pediatric patients.
|contraindications=None
|warnings=*Erythrocytosis
WINREVAIR may increase hemoglobin. Severe erythrocytosis may increase the risk of thromboembolic events or hyperviscosity syndrome. In clinical studies, moderate elevations in Hgb (>2 g/dL above ULN) occurred in 15% of patients taking WINREVAIR while no elevations ≥4 g/dL above ULN were observed. Monitor Hgb before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter, to determine if dose adjustments are required

*Severe Thrombocytopenia
WINREVAIR may decrease platelet count. Severe thrombocytopenia may increase the risk of bleeding. In clinical studies, severe thrombocytopenia (platelet count <50,000/mm3 [<50 x 109/L]) occurred in 3% of patients taking WINREVAIR. Thrombocytopenia occurred more frequently in patients also receiving prostacyclin infusion.

Do not initiate treatment if platelet count is <50,000/mm3

Monitor platelets before each dose for the first 5 doses, or longer if values are unstable, and periodically thereafter to determine whether dose adjustments are required.

*Serious Bleeding
In clinical studies, serious bleeding (e.g., gastrointestinal, intracranial hemorrhage) was reported in 4% of patients taking WINREVAIR and 1% of patients taking placebo. Patients with serious bleeding were more likely to be on prostacyclin background therapy and/or antithrombotic agents, or have low platelet counts. Advise patients about signs and symptoms of blood loss. Evaluate and treat bleeding accordingly. Do not administer WINREVAIR if the patient is experiencing serious bleeding

*Embryo-Fetal Toxicity
Based on findings in animal reproduction studies, WINREVAIR may cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of WINREVAIR to pregnant rats and rabbits during organogenesis resulted in adverse developmental outcomes, including increased embryo-fetal mortality, alterations to growth, and structural variations at exposures 4-fold and 0.6-fold (based on area under the curve [AUC]) those occurring at the maximum recommended human dose (MRHD), respectively. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with WINREVAIR and for at least 4 months after the final dose

*Impaired Fertility
Based on findings in animals, WINREVAIR may impair female and male fertility. Advise patients on the potential effects on fertilit
|clinicalTrials=*Erythrocytosis
*Serious Bleeding
*Severe Thrombocytopenia
*Serious Bleeding
*Embryo-Fetal Toxicity
*Impaired Fertility
|useInPregnancyFDA=Based on findings in animal reproduction studies, WINREVAIR may cause fetal harm when administered to a pregnant woman. There are risks to the mother and the fetus associated with pulmonary arterial hypertension in pregnancy.
There are no available data on WINREVAIR use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

In animal reproduction studies, administration of WINREVAIR to pregnant rats and rabbits during the period of organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality, alterations to growth, and structural variations at exposures 4-fold and 0.6-fold (based on area under the curve [AUC]) above those occurring at the maximum recommended human dose (MRHD), respectively (see Data). Advise pregnant women of the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated population is not known. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
|useInNursing=There are no data on the presence of sotatercept-csrk in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with WINREVAIR, and for 4 months after the final dose.
|useInPed=The safety and effectiveness of WINREVAIR have not been established in patients less than 18 years of age
|useInGeri=A total of 81 patients ≥65 years of age participated in clinical studies for PAH, of which 52 (16%) were treated with WINREVAIR. No differences in efficacy of WINREVAIR were observed between the <65-year-old and ≥65-year-old subgroups.

With the exception of bleeding events (a collective group of adverse events of clinical interest), there were no differences in safety between the <65-year-old and ≥65-year-old subgroups. Bleeding events occurred more commonly in the older WINREVAIR subgroup, but with no imbalance between age subgroups for any specific bleeding event.

Clinical studies of WINREVAIR did not include sufficient numbers of patients aged 75 and older to determine whether they respond differently from younger patients.
|useInReproPotential=*WINREVAIR may cause fetal harm when administered to pregnant women
*Pregnancy testing is recommended for females of reproductive potential before starting WINREVAIR treatment.
*Contraception:
Advise female patients of reproductive potential to use effective contraception during treatment with WINREVAIR and for at least 4 months after the final dose if treatment is discontinued
*Infertility:
Based on findings in animals, sotatercept-csrk may impair female and male fertility
*In male rats, although adverse histologic changes in reproductive organs were not reversible after a 13-week period, functional fertility demonstrated reversibility.
|administration=WINREVAIR™ is indicated for the treatment of adults with pulmonary arterial hypertension (PAH, World Health Organization [WHO] Group 1) to increase exercise capacity, improve WHO functional class (FC), and reduce the risk of clinical worsening events.

*Recommended Starting Dosage
WINREVAIR is administered once every 3 weeks by subcutaneous injection according to patient body weight. The starting dose of WINREVAIR is 0.3 mg/kg.

Obtain hemoglobin (Hgb) and platelet count prior to the first dose of WINREVAIR. Do not initiate treatment if platelet count is <50,000/mm3 (<50 x 109/L)

Injection volume should be rounded to the nearest 0.1 mL.

For example: (70 kg x 0.3 mg/kg) ÷ 50 mg/mL = 0.42 mL, rounds to 0.4 mL.

* Recommended Target Dosage
After verifying acceptable Hgb and platelet count, increase to the target dose of 0.7 mg/kg. Continue treatment at 0.7 mg/kg every 3 weeks unless dosage adjustments are required
Injection volume should be rounded to the nearest 0.1 mL.

For example: (70 kg x 0.7 mg/kg) ÷ 50 mg/mL = 0.98 mL, rounds to 1 mL
|overdose=In healthy volunteers, WINREVAIR dosed at 1 mg/kg resulted in increases in Hgb associated with hypertension; both improved with phlebotomy. In the event of overdose, monitor closely for increases in Hgb and blood pressure, and provide supportive care as appropriate. WINREVAIR is not dialyzable.
|mechAction=Sotatercept-csrk, a recombinant activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein, is an activin signaling inhibitor that binds to activin A and other TGF- β superfamily ligands. As a result, sotatercept-csrk improves the balance between the pro-proliferative (ActRIIA/Smad2/3-mediated) and anti-proliferative (BMPRII/Smad1/5/8-mediated) signaling to modulate vascular proliferation. In rat models of PAH, a sotatercept-csrk analog reduced inflammation and inhibited proliferation of endothelial and smooth muscle cells in diseased vasculature. These cellular changes were associated with thinner vessel walls, partial reversal of right ventricular remodeling, and improved hemodynamics.
|PD=A statistically significantly greater decrease from baseline in PVR was observed in the WINREVAIR group compared to the placebo group in the Phase 3 STELLAR study. The median treatment difference in PVR between sotatercept-csrk and placebo was -235 dynes*sec/cm5 (95% CI: -288, -181; p<0.001). Sotatercept-csrk steady state exposure at 0.7 mg/kg dose was associated with near maximal reduction in PVR based on exposure-response analysis.

NT-proBNP:

A statistically significantly greater decrease from baseline in NT-proBNP was observed in the WINREVAIR group compared to the placebo group in the Phase 3 STELLAR study. The median treatment difference in NT-proBNP between the sotatercept-csrk and placebo was -442 pg/mL (95% CI: -574, -310; p<0.001).
|PK=Following subcutaneous administration of 0.7 mg/kg WINREVAIR every three weeks to PAH patients, the steady state geometric mean (%CV) area under the time concentration curve (AUC) is 172 mcg×d/mL (34.2%), and peak concentration (Cmax) is 9.7 mcg/mL (30%). Sotatercept-csrk AUC and Cmax increased proportionally with dose. Steady state is achieved after approximately 15 weeks following initiation of multiple dosing. The accumulation ratio of sotatercept-csrk AUC is approximately 2.2.
|nonClinToxic=No carcinogenicity or mutagenicity studies have been conducted with sotatercept-csrk.

In a fertility and early embryonic development study in female rats, sotatercept-csrk was administered SC once weekly at doses of 5, 15, and 50 mg/kg beginning 2 weeks prior to mating and through gestation day 7. At doses ≥15 mg/kg (≥9 fold the MRHD, based on estimated AUC), pregnancy rates were decreased and there were increases in preimplantation and postimplantation loss and reductions in live litter size. Increased estrous cycle duration occurred at 50 mg/kg only (21-fold the MRHD, based on estimated AUC).

In a fertility study in male rats, sotatercept-csrk was administered SC once weekly at doses of 0.3, 3, and 30 mg/kg for 13 weeks (beginning 10 weeks prior to mating). A subset of animals was examined after a 13-week recovery period. At ≥0.3 mg/kg (0.5-fold the MRHD, based on estimated AUC) there were non-reversible histologic changes in the efferent ducts, testes, and epididymides. Reversible decreases in functional fertility endpoints occurred at 30 mg/kg (20-fold the MRHD, based on estimated AUC).
|clinicalStudies=Pulmonary Arterial Hypertension:
The efficacy of WINREVAIR was evaluated in adult patients with PAH in the STELLAR trial (NCT04576988). STELLAR was a global, double-blind, placebo-controlled, multicenter, parallel-group clinical trial in which 323 patients with PAH (WHO Group 1 FC II or III) were randomized 1:1 to WINREVAIR (target dose 0.7 mg/kg) (n=163) or placebo (n=160) administered subcutaneously once every 3 weeks.

Participants were: 79% female; had a median age of 48 years (range: 18 to 82 years), and median body weight of 68 kg (range 38 to 141 kg); and 89% White/Caucasian, 2% Black/African American, 2% Asian, 0.3% American Indian or Alaska Native, 0.3% Native Hawaiian or Other Pacific Islander, 6% Missing/Other races. The most common PAH etiologies were idiopathic PAH (59%), heritable PAH (18%), and PAH associated with connective tissue diseases (CTD) (15%). STELLAR excluded patients with human immunodeficiency virus (HIV)-associated PAH, PAH associated with portal hypertension, schistosomiasis-associated PAH, and pulmonary veno occlusive disease. The mean time from PAH diagnosis to screening was 8.8 years. Most participants were receiving either three (61%) or two (35%) background drugs for PAH, and 40% were receiving prostacyclin infusions. Patients had a WHO FC II (49%) or III (51%) at baseline.

The primary efficacy endpoint was the change from baseline at Week 24 in 6-Minute Walk Distance (6 MWD). In the WINREVAIR group, the placebo-adjusted median increase in 6 MWD was 41 meters (95% CI: 28, 54; p<0.001). Figure 1 displays placebo-adjusted changes in 6 MWD at Week 24 in relevant subgroups.

hange from baseline in 6 MWD at Week 24 for subjects who died was imputed to -2000 meters to receive the worst rank. Change from baseline in 6 MWD at Week 24 for subjects who had missing data due to a non-fatal clinical worsening event was imputed to -1000 meters to receive the next-worst rank.

Treatment with WINREVAIR led to an improvement from baseline by at least 1 WHO FC at Week 24 in 29% of patients compared to 14% of patients treated with placebo (p<0.001).

Treatment with WINREVAIR resulted in an 84% reduction in the occurrence of death from any cause or PAH clinical worsening events compared to placebo.

,These outcomes were captured until the last patient completed the Week 24 visit (data up to the data cutoff; median duration of exposure 33.6 weeks)

These outcomes were captured until the last patient completed the Week 24 visit (data up to the data cutoff; median duration of exposure 33.6 weeks).
|howSupplied=WINREVAIR (sotatercept-csrk) for injection is a white to off-white lyophilized cake or powder appearance supplied in single-dose vials (45 mg or 60 mg) packaged in kits that contain one measuring syringe and one safety needle.
|storage=Store vials refrigerated at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze.

The kit should remain in the refrigerator until ready for use. The unused kit can be out of the refrigerator for (up to 25°C/77°F) up to 24 hours. For additional information on temperature excursions, call Merck Sharp & Dohme LLC at 1-800-672-6372.
|fdaPatientInfo=*Erythrocytosis:
Caution patients that WINREVAIR may raise Hgb to levels that increase their risk of thrombotic events. Inform patients that Hgb levels will be assessed before at least the first 5 doses and then periodically, as dosage may need to be adjusted

*Severe Thrombocytopenia:
Caution patients that WINREVAIR may cause platelet count to decrease, which if severe could cause bleeding. Inform patients that platelet count will be assessed before at least the first 5 doses and then periodically, as dosage may need to be adjusted

*Serious Bleeding:
Inform patients of the possibility of serious bleeding, which is more likely to occur if they have low platelet counts or while on prostacyclin background therapy and/or antithrombotic agents. Advise patients to notify their healthcare provider about signs and symptoms of bleeding

*Embryo-Fetal Toxicity:
Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception while receiving WINREVAIR and for at least 4 months after the final dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected during treatment with WINREVAIR

*Lactation:
Advise females not to breastfeed during treatment with WINREVAIR and for 4 months after the final dose

*Females and Males of Reproductive Potential:
Advise females and males of reproductive potential that WINREVAIR may impair fertility.

*Administration by Patient or Caregiver:
Review the IFU with the patient or caregiver step-by-step. Provide training to the patient or caregiver regarding proper preparation and administration of WINREVAIR and decide whether a patient or caregiver is capable of preparing and administering WINREVAIR independently

*Inform patients to call their healthcare provider for further instruction if they take more than or less than the correct dose. Advise them about signs/symptoms to monitor for and what to do if any of these signs/symptoms should occur. Advise them that additional laboratory tests may be required prior to the next scheduled dose to ensure that the next dose can be safely administered.

*Incorrect Dose or Missed Dose:
Instruct the patient that if they miss the prescribed dose of WINREVAIR, they should take it within 3 days and maintain the original schedule for the next dose. If not taken within 3 days, instruct them to call their healthcare provider for guidance.
|alcohol=Alcohol-Sotatercept-csrk interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=Winrevair
}}

Nogapendekin alfa inbakicept-pmln

2025-04-10T06:03:39Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=nogapendekin alfa inbakicept-pmln |aOrAn=an |drugClass=interleukin-15 (IL-15) receptor agonist |indicationType=treatment |indication=of adult patients with BCG-unresponsive nonmuscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors. |adverseReactions=The most common (≥15%) adverse reactions, were increased creatinine, dysuria, hematuri..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=nogapendekin alfa inbakicept-pmln
|aOrAn=an
|drugClass=interleukin-15 (IL-15) receptor agonist
|indicationType=treatment
|indication=of adult patients with BCG-unresponsive nonmuscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors.
|adverseReactions=The most common (≥15%) adverse reactions, were increased creatinine, dysuria, hematuria, urinary frequency, micturition urgency, urinary tract infection, increased potassium, musculoskeletal pain, chills and pyrexia.
|blackBoxWarningTitle='''TITLE'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=ANKTIVA in combination with Bacillus Calmette-Guérin (BCG) is indicated for the treatment of adult patients with BCG-unresponsive nonmuscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors.
''2.1 Recommended Dosage''
For Intravesical Use Only. Do NOT administer by subcutaneous or intravenous or intramuscular routes.
For induction: ANKTIVA is recommended at a dose of 400 mcg administered intravesically with BCG once a week for 6 weeks. A second induction course may be administered if complete response is not achieved at month 3.
For maintenance: After BCG and ANKTIVA induction therapy, ANKTIVA is recommended at a dose of 400 mcg administered intravesically with BCG once a week for 3 weeks at months 4, 7, 10, 13 and 19 (for a total of 15 doses). For patients with an ongoing complete response at month 25 and later, maintenance instillations with BCG may be administered once a week for 3 weeks at months 25, 31, and 37 for a maximum of 9 additional instillations.

The recommended duration of treatment is until disease persistence after second induction, disease recurrence or progression, unacceptable toxicity, or a maximum of 37 months.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Nogapendekin alfa inbakicept-pmln in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Nogapendekin alfa inbakicept-pmln in adult patients.
|fdaLIADPed=None
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Nogapendekin alfa inbakicept-pmln in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Nogapendekin alfa inbakicept-pmln in pediatric patients.
|contraindications=None
|warnings=Delaying cystectomy in patients with BCG-unresponsive CIS could lead to development of muscle invasive or metastatic bladder cancer, which can be lethal. The risk of developing muscle invasive or metastatic bladder cancer increases the longer cystectomy is delayed in the presence of persisting CIS.

Of the 77 evaluable patients with BCG-unresponsive CIS treated with ANKTIVA with BCG in QUILT-3.032, 10% (n = 8) progressed to muscle invasive (T2 or greater) bladder cancer, including 7 during the treatment period. Three patients had progression determined at the time of cystectomy. The median time between determination of persistent or recurrent CIS and progression to muscle-invasive disease was 107 days (range: 0 – 210).

If patients with CIS do not have a complete response to treatment after a second induction course of ANKTIVA with BCG, reconsider cystectomy.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of ANKTIVA with BCG was evaluated in Cohort A of QUILT-3.032, a single-arm, multicenter clinical study in 88 patients with BCG-unresponsive high-grade NMIBC with CIS with or without Ta/T1 papillary disease [see Clinical Studies ( 14)]. Patients received 400 mcg ANKTIVA with BCG weekly for 6 consecutive weeks during induction and then once a week for every 3 weeks at 4, 7, 10, 13, and 19 months for patients with no or low grade disease. Patients with persistent CIS or high grade Ta at 3 months were eligible to receive a second induction. Patients with ongoing CR at 25 months were eligible to receive additional instillations once a week every 3 weeks at months 25, 31, and 37. The median number of doses of ANKTIVA with BCG administered to patients was 12 (range 2 – 30) doses. The median duration of exposure to ANKTIVA with BCG was 7.1 months (range: 0.26 to 36.3 months).

Serious adverse reactions occurred in 16% of patients receiving ANKTIVA with BCG. Serious adverse reactions that occurred in ≥2% of patients who received ANKTIVA with BCG included hematuria (3.4%). A fatal adverse reaction of cardiac arrest occurred in 1 (1.1%) patient receiving ANKTIVA with BCG.

Permanent discontinuation of ANKTIVA with BCG due to adverse reactions occurred in 7% of patients. Adverse reactions (>2%) resulting in permanent discontinuation of ANKTIVA with BCG included musculoskeletal pain (2.3%).

Dosage interruptions due to adverse reactions occurred in 34% of patients receiving ANKTIVA with BCG. Adverse reactions (≥5%) that resulted in interruption of ANKTIVA with BCG were urinary tract infection (10%), dysuria (8%), hematuria (6%), and bladder irritation (6%).

Dosage reductions due to adverse reactions were not permitted for ANKTIVA; however, dose reduction of BCG was allowed for adverse reactions and occurred in 3.4% of patients including (>1%) urinary tract infection (2.3%), hematuria (1.1%), urinary frequency (1.1%), and bladder irritation (1.1%).

The most common (≥15%) adverse reactions, including laboratory test abnormalities, were increased creatinine, dysuria, hematuria, urinary frequency, micturition urgency, urinary tract infection, increased potassium, musculoskeletal pain, chills and pyrexia.
|postmarketing=None
|drugInteractions=None
|useInLaborDelivery=Systemic exposure of nogapendekin alfa inbakicept-pmln following intravesical administration of the approved dosage of ANKTIVA was below the limit of quantitation.
Based on its mechanism of action, ANKTIVA may cause fetal harm when administered to a pregnant woman if systemic exposure occurs
There are no available data on ANKTIVA use in pregnant women to inform a drug-associated risk. Animal reproductive and developmental toxicity studies have not been conducted with nogapendekin alfa inbakicept-pmln. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
|useInNursing=There are no data on the presence of nogapendekin alfa inbakicept-pmln in human milk, or the effects on the breastfed child, or on milk production. Systemic exposure of nogapendekin alfa inbakicept-pmln in patients receiving intravesical administration of the approved dosage of ANKTIVA was below the limit of quantitation
indicating any amount in the milk will be low. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ANKTIVA and any potential adverse effects on the breastfed child from ANKTIVA or from the underlying maternal condition.
|useInPed=Safety and effectiveness of ANKTIVA in pediatric patients have not been established.
|useInGeri=Of the total number of patients in clinical studies of ANKTIVA for BCG-unresponsive NMIBC, 84% were 65 years of age or older and 40% were 75 years or older. Clinical studies of ANKTIVA did not include sufficient numbers of younger adult patients to determine if patients 65 years of age and older respond differently than younger adult patients.
|administration=Preparation of Agent
See BCG Prescribing Information for information on preparation and handling of BCG.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution is clear to slightly opalescent and colorless to slightly yellow. Discard the vial if visible particles are observed.

Draw 0.4 mL of ANKTIVA into a small syringe and using aseptic technique add to the saline containing the BCG suspension that has been prepared following the instructions provided in the Prescribing Information for BCG. Mix the suspension gently. Using a 60-mL syringe connected to an appropriate size needle, withdraw the ANKTIVA BCG mixture to a final volume of 50 mL.

If the admixture of ANKTIVA in combination with BCG is not used immediately, store refrigerated at 2°C to 8°C (36°F to 46°F) and use within 2 hours. Unused solution of admixture should be discarded after 2 hours.

Treatment
The admixture of ANKTIVA in combination with BCG is instilled into the bladder via a catheter. After instillation is complete, the catheter is removed. The ANKTIVA in combination with BCG admixture is retained in the bladder for 2 hours and then voided. Patients unable to retain the suspension for 2 hours should be allowed to void sooner, if necessary. Do not repeat the dose if the patient voids before 2 hours.

See BCG Prescribing Information for information on retention in the bladder and patient positioning during bladder instillation.
|mechAction=Nogapendekin alfa inbakicept-pmln is an IL-15 receptor agonist. IL-15 signals through a heterotrimeric receptor that is composed of the common gamma chain (γc) subunit, the beta chain (βc) subunit, and the IL-15-specific alpha subunit, IL-15 receptor α. IL-15 is trans-presented by the IL-15 receptor α to the shared IL-2/IL-15 receptor (βc and γc) on the surface of CD4 +and CD8 +T cells and NK cells.

Binding of nogapendekin alfa inbakicept-pmln to its receptor results in proliferation and activation of NK, CD8 +, and memory T cells without proliferation of immuno-suppressive Treg cells. In vivo, intravesicular nogapendekin alfa inbakicept-pmln alone or in combination with BCG showed anti-tumor activity when compared to BCG alone, in a carcinogen-induced model of bladder cancer in immunocompetent rats.
|PD=The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of nogapendekin alfa inbakicept-pmln have not been fully characterized.
|PK=Systemic exposure of nogapendekin alfa inbakicept-pmln was less than 100 pg/mL following the approved recommended dosage in all patients. This was below the lower limit of quantitation in all patients.
|nonClinToxic=''13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility''
Carcinogenicity and genotoxicity studies have not been conducted with nogapendekin alfa inbakicept-pmln.

Fertility studies with nogapendekin alfa inbakicept-pmln have not been conducted.
|clinicalStudies=The efficacy of ANKTIVA was evaluated in QUILT-3.032 (NCT03022825), a single-arm, multicenter trial in 77 adults with BCG-unresponsive, high-risk, NMIBC with CIS with or without Ta/T1 papillary disease following transurethral resection.

BCG unresponsive high-risk NMIBC CIS was defined as persistent or recurrent CIS alone or with Ta/T1 disease within 12 months of completion of adequate BCG therapy. Adequate BCG therapy was defined as administration of at least 5 of 6 doses of an initial induction course plus either of at least 2 of 3 doses of maintenance therapy or at least 2 of 6 doses of a second induction course. Prior to treatment, all patients with Ta or T1 disease had undergone transurethral resection of bladder tumor (TURBT) to remove all resectable disease. Residual CIS not amenable to complete resection, fulguration, or cauterization was permitted. The trial excluded patients with history of or evidence of muscle invasive (i.e., T2, T3, T4), locally advanced, metastatic, and/or extra-vesical (i.e., urethra, ureter, or renal pelvis) bladder cancer.

Patients received 400 mcg ANKTIVA with BCG weekly for 6 consecutive weeks during the induction treatment period and then once a week every 3 weeks at 4, 7, 10, 13, and 19 months for patients with no or low grade disease. Patients with persistent CIS or high grade Ta disease at 3 months were eligible to receive a second induction course. Patients with ongoing CR at 25 months were eligible to receive additional instillations once a week every 3 weeks at months 25, 31, and 37. Assessment of tumor status was performed every 3 months for up to two years. Assessment for ongoing response beyond month 24 was per local community standards. Random or cystoscopy directed biopsies were required within the first 6 months after treatment initiation. The major efficacy outcome measures were complete response (CR) at any time (as defined by negative results for cystoscopy [with TURBT/biopsies as applicable] and urine cytology) and duration of response.

The median age of patients was 73 years (range, 50–91 years); 86% were male; race was White (90%), Black (6%), Asian (1%), American Indian or Alaska Native (1%), or Unknown (1%); and patients had baseline ECOG performance status of 0 (83%) or 1 (17%).

Tumor characteristics at study entry were CIS without Ta/T1 papillary disease (69%), CIS with Ta papillary disease (21%) or CIS with T1 +/- Ta papillary disease (10%). Baseline high-risk NMIBC disease status was 43% refractory and 57% relapsed. The median number of prior BCG doses received was 12 doses (range: 8–45 doses); 13% received partial-dose prior BCG. Baseline cystoscopy imaging modality was white light (57%), blue light or narrow band imaging (40%), and unknown (3%).

Efficacy results are summarized in Table 3. Thirty-one percent (n=24) of patients received a second induction course.
|howSupplied=ANKTIVA (nogapendekin alfa inbakicept-pmln) is clear to slightly opalescent and colorless to slightly yellow solution available in:

Carton containing 400 mcg/0.4 mL, single-dose vial (NDC 81481-803-01).
|storage=Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake.
|fdaPatientInfo=*Risk of Metastatic Bladder Cancer with Delayed Cystectomy: Inform patients that delaying cystectomy could lead to development of metastatic bladder cancer. Discuss the risk of metastatic bladder cancer and that the risk increases the longer cystectomy is delayed in the presence of persisting CIS

*Local Adverse Reactions Before and During Treatment: nform patients that irritable bladder symptoms may occur during instillation, and retention of ANKTIVA, and following voiding

*Inform patients that for the first 24 hours following administration, red-tinged urine may occur.

*Advise patients to immediately report prolonged irritable bladder symptoms or prolonged passage of red-colored urine to their healthcare provider.

*Instruct patients to maintain adequate hydration following ANKTIVA treatment.

*Administration:
Inform patients that the ANKTIVA in combination with BCG admixture should be retained in the bladder for 2 hours and then voided.Advise patients that if unable to retain the suspension for 2 hours they can void sooner if necessary.Instruct patients to void while seated to avoid splashing of urine.

*Embryo-Fetal Toxicity:Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.Advise females of reproductive potential to use effective contraception during treatment with ANKTIVA and for 1 week after the last dose.

See the BCG prescribing information, Information for Patients for additional patient counseling information.
|alcohol=Alcohol-Nogapendekin alfa inbakicept-pmln interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=ANKTIVA
}}

Vadadustat

2025-03-20T10:20:36Z

Alara E. Dagsali: Created page with "{{DrugProjectFormSinglePage |authorTag= Alara Ece Dagsali, M.D. |genericName=vadadustat |indicationType=treatment |indication=VAFSEO is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least three months. |hasBlackBoxWarning=Yes |adverseReactions=*VAFSEO increases the risk of thrombotic vascular events, including major adverse cardiovascular events (MACE) *Targeting a hemoglobin lev..."

{{DrugProjectFormSinglePage
|authorTag=[[User: AED| Alara Ece Dagsali, M.D.]]
|genericName=vadadustat
|indicationType=treatment
|indication=VAFSEO is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least three months.
|hasBlackBoxWarning=Yes
|adverseReactions=*VAFSEO increases the risk of thrombotic vascular events, including major adverse cardiovascular events (MACE)
*Targeting a hemoglobin level greater than 11 g/dL is expected to further increase the risk of death and arterial and venous thrombotic events, as occurs with erythropoietin stimulating agents (ESAs), which also increase erythropoietin levels
*No trial has identified a hemoglobin target level, dose of VAFSEO, or dosing strategy that does not increase these risks
*Use the lowest dose of VAFSEO sufficient to reduce the need for red blood cell transfusions
|blackBoxWarningTitle='''INCREASED RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, AND THROMBOSIS OF VASCULAR ACCESS'''
|blackBoxWarningBody=''Condition Name:'' (Content)
|fdaLIADAdult=VAFSEO is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least three months.

Adults Not Being Treated with an ESA:
The recommended starting dose is 300 mg orally once daily.

Adults Being Switched from an ESA:
When converting from an ESA to VAFSEO, the recommended starting dose is 300 mg orally once daily.

Taking into account the gradual rise in Hb with VAFSEO, red blood cell (RBC) transfusions or ESA treatment may be considered during the transition phase if Hb values fall below 9 g/dL or Hb response is considered not acceptable. Patients receiving RBC transfusions should continue VAFSEO treatment during the transfusion period. VAFSEO should be paused for those patients receiving temporary ESA rescue treatment and may be resumed when Hb levels are greater than or equal to 10 g/dL. Depending on the ESA used for rescue, the pause in VAFSEO treatment should be extended to:

*2 days after the last dose of epoetin
*7 days after the last dose of darbepoetin alfa
*14 days after the last dose of methoxy polyethylene glycol-epoetin beta.

Following ESA rescue, VAFSEO should be resumed at the prior dose or with a dose that is 150 mg greater than the prior dose, with subsequent titration according to the dose titration guidelines given below in this section.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Vadadustat in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Vadadustat in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of Vadadustat in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of Vadadustat in pediatric patients.
|contraindications=VAFSEO is contraindicated in patients:
*with a known hypersensitivity to VAFSEO or any of its components
*with uncontrolled hypertension
|warnings='''5.1 Increased Risk of Death, Myocardial Infarction (MI), Stroke, Venous Thromboembolism, and Thrombosis of Vascular Access'''

VAFSEO increases the risk of arterial and venous thrombotic events, that may be fatal, including myocardial infarction, stroke, venous thromboembolism and vascular access thrombosis
Patients with cardiovascular or cerebrovascular disease are at increased risk of these events. Avoid use in patients with a history of myocardial infarction, cerebrovascular event, or acute coronary syndrome within the 3 months prior to starting VAFSEO.

A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks. Targeting a hemoglobin level of greater than 11 g/dL is expected to further increase the risk of death and arterial and venous thrombotic events, as occurs with ESAs, which also increase erythropoietin levels.

No trial has identified a hemoglobin target level, dose of VAFSEO, or dosing strategy that does not increase these risks. Use the lowest dose of VAFSEO sufficient to reduce the need for red blood cell transfusions. Adherence to dosing and hemoglobin monitoring recommendations is important to avoid excessive erythropoiesis

Advise patients to seek immediate medical attention if they develop signs or symptoms of myocardial infarction, stroke, venous thromboembolism, or thrombosis of vascular access. Evaluate and manage promptly if these occur.

'''5.2 Hepatotoxicity'''

VAFSEO may cause hepatotoxicity. In clinical trials, hepatocellular injury attributed to VAFSEO was reported in less than 1% of patients, including one case of severe hepatocellular injury with jaundice. All events were asymptomatic and resolved after discontinuation of VAFSEO. The time to onset was generally within the first 3 months of treatment.

Elevated serum ALT, AST, and bilirubin were seen in 1.8%, 1.8% and 0.3% of CKD patients treated with VAFSEO, respectively.

Measure ALT, AST and bilirubin prior to the initiation of VAFSEO and monthly after initiation for the first 6 months and then monitor as clinically indicated

Discontinue VAFSEO if there is persistent ALT or AST greater than 3 times ULN or if ALT or AST elevations greater than 3 times upper limit of normal (ULN) are accompanied by a bilirubin increase greater than 2 times ULN.

VAFSEO is not recommended in patients with cirrhosis or active, acute liver disease.

'''5.3 Hypertension'''
VAFSEO is contraindicated in patients with uncontrolled hypertension. In the INNO2VATE-1 and INNO2VATE-2 clinical trials, worsening of hypertension was reported in 14% (9.4 per 100 person-years [PY]) of patients receiving VAFSEO and 17% (11.8 per 100 PY) of patients receiving darbepoetin alfa. Serious worsening of hypertension was reported in 2.7% (1.7 per 100 PY) of patients receiving VAFSEO and 3% (1.8 per 100 PY) of patients receiving darbepoetin alfa. Cases of hypertensive crisis including hypertensive encephalopathy and seizures have also been reported in patients receiving VAFSEO. Periodically monitor blood pressure and adjust or initiate anti-hypertensive therapy as needed

'''5.4 Seizures'''
Seizures have occurred in patients treated with VAFSEO. In the INNO2VATE-1 and INNO2VATE-2 clinical trials, seizures occurred in 1.6% (1.0 per 100 PY) of patients who received VAFSEO and 1.6% (1.0 per 100 PY) of patients who received darbepoetin alfa. Following initiation of VAFSEO, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms, or change in seizure frequency.

'''5.5 Gastrointestinal Erosion'''
In the INNO2VATE-1 and INNO2VATE-2 clinical trials, gastric or esophageal erosions occurred in 6.4% (4.0 per 100 PY) of patients receiving VAFSEO and 5.3% (3.3 per 100 PY) of darbepoetin alfa-treated patients. Serious gastrointestinal erosions, including gastrointestinal bleeding and the need for red blood cell transfusions were reported in 3.4% (2.1 per 100 PY) and 3.3% (2.0 per 100 PY) of those receiving VAFSEO and darbepoetin alfa, respectively. Consider this risk particularly in patients at increased risk for gastrointestinal erosions, such as those with a history of gastrointestinal erosion, peptic ulcer disease, use of concomitant medications that increase the risk of gastrointestinal erosion, and current tobacco smokers and alcohol drinkers.

Advise patients of the symptoms and signs of gastric and esophageal erosions and of gastrointestinal bleeding and to seek prompt medical care if these occur.

'''5.6 Serious Adverse Reactions in Patients with Anemia Due to Chronic Kidney Disease and Not on Dialysis'''
The safety of VAFSEO has not been established for the treatment of anemia due to CKD in adults not on dialysis and its use is not recommended in this setting [see Indications and Usage (1)].

In large clinical trials in adults with anemia of CKD who were not on dialysis (PRO2TECT-1 and PRO2TECT-2), an increased risk of mortality, stroke, myocardial infarction, serious acute kidney injury, serious hepatic injury, and serious gastrointestinal erosions was observed in patients treated with VAFSEO compared to darbepoetin alfa.

'''5.7 Malignancy'''
Because increased hypoxia inducible factor (HIF)-1 levels may be associated with unfavorable effects on cancer growth, VAFSEO has not been studied and is not recommended in patients with active malignancies. In the INNO2VATE-1 and INNO2VATE-2 clinical trials, malignancies were observed in 2.2% (1.3 per 100 PY) of patients treated with VAFSEO and 3.0% (1.8 per 100 PY) of patients treated with darbepoetin alfa. No evidence of increased carcinogenicity was observed in animal studies
|clinicalTrials=The following clinically significant adverse reactions are discussed elsewhere in the labeling:
*Increased risk of death, myocardial infarction, stroke and venous thromboembolism, and thrombosis of vascular access
*Hepatotoxicity
*Hypertension
*Seizures
*Gastrointestinal erosion
*Serious adverse reactions in patients with anemia due to chronic kidney disease and not on dialysis
|drugInteractions=*Co-administration with oral iron supplements, products containing iron, or phosphate binders decreases the exposure of vadadustat
*Co-administration with OAT1/OAT3 (Organic Anion Transporter) inhibitors may increase the area under the concentration curve (AUC) of vadadustat.
*Vadadustat may increase the exposure of BCRP substrates
*Vadadustat increases the maximal concentration (Cmax) and AUC of some statins when co-administered
*Vadadustat may increase the exposure of co-administered OAT3 substrates which may increase the risk of adverse reactions related to these substrates.
|useInPregnancyFDA=Risk Summary
Available data with VAFSEO use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with CKD (see Clinical Considerations). Vadadustat administration orally to pregnant rats and rabbits during the period of organogenesis was associated with reduced fetal weight at doses that caused maternal toxicity. In rat and rabbit studies, vadadustat was not teratogenic (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. VAFSEO should only be used during pregnancy if the benefit justifies the potential risk to the fetus.

Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk: CKD in pregnancy increases the risk for maternal hypertension, preeclampsia, miscarriage, stillbirth, preterm delivery, low birth weight infants, and polyhydramnios.

Data
Animal Data
Vadadustat decreased fetal weight and reduced fetal skeletal ossification in rats at a dose of 160 mg/kg/day (1.7 times the maximum recommended human dose [MRHD] based on AUC), which was associated with maternal toxicity defined by reduced body weight gain and food consumption.

Vadadustat was orally administered to pregnant rabbits at doses of 10, 25, or 50 mg/kg/day from gestation day 6 until gestation day 18 during the period of organogenesis. Vadadustat administration at 50 mg/kg/day resulted in maternal toxicity of reduced body weight gain, but no adverse effects on embryofetal development were observed at doses less than or equal to 50 mg/kg/day (1.5 times the MRHD based on AUC).

In a pre- and postnatal development study, pregnant rats were dosed orally with vadadustat 20, 40, or 80 mg/kg/day from implantation until weaning (gestation day 6 to lactation day 20) at 20, 40, or 80 mg/kg/day. There were decreased body weights of offspring at the dose of 80 mg/kg/day but no adverse effects were observed at doses less than or equal to 80 mg/kg/day (0.3 times the MRHD based on AUC) in dams.
|useInNursing=There are no data on the presence of vadadustat in human milk, the effects of vadadustat on the breastfed child, or the effects on milk production. Vadadustat is present in the milk of lactating rats (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Given the serious adverse reactions seen in adults treated with VAFSEO, such as thrombotic vascular events, advise patients not to breastfeed during treatment with VAFSEO, and for 2 days after the final dose.
|useInPed=The safety and effectiveness of VAFSEO in pediatric patients have not been established.
|useInGeri=There were 1330 patients 65 years of age and older in the pooled INNO2VATE-1 and INNO2VATE-2 clinical trials. Of the total number of VAFSEO-treated patients in these studies, 449 (23%) were 65 to 74 years of age, 194 (10%) were 75 to 84 years of age, and 24 (1%) were 85 years of age and older. No overall differences in safety or effectiveness were observed between patients 65 years of age and older and younger adult patients
|useInHepaticImpair=VAFSEO is not recommended in patients with cirrhosis or active, acute liver disease
|administration=Correct and exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding) before initiation of VAFSEO. Evaluate iron status in all patients before and during treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%. The majority of patients with CKD will require supplemental iron during the course of therapy.
|monitoring=Following initiation of therapy and after each dose adjustment, monitor hemoglobin (Hb) levels, every two weeks until stable, then monitor at least monthl
|mechAction=Vadadustat is a reversible inhibitor of HIF-prolyl-4-hydroxylases (PH)1, PH2, and PH3 (IC50 in the nM range). This activity results in the stabilization and nuclear accumulation of HIF-1α and HIF-2α transcription factors, and increased production of erythropoietin (EPO).
|PD=After a single dose of vadadustat 80 to 1200 mg (0.27 to 4 times the approved recommended starting dosage) in healthy male adults, a dose-dependent increase in EPO was observed.
|PK=Vadadustat AUC and observed peak concentration (Cmax) increased proportionally after single doses from 80 mg to 1200 mg (0.27 to 4 times the approved recommended starting dosage). Vadadustat is expected to reach steady state by day 3 following once daily dosing, with no significant accumulation.
|nonClinToxic=Vadadustat was not carcinogenic when administered orally at doses of 2, 7, and 20 mg/kg/day in a 6-month study in transgenic mice and at doses of 5, 15, and 50 mg/kg/day in a 2-year study in rats. The highest exposure to vadadustat in rats corresponds to 0.2 times the MRHD based on AUC.

Vadadustat was negative for mutagenicity in the in vitro bacterial reverse mutation assay. Vadadustat exhibited clastogenic activity in vitro but was negative in the in vivo chromosomal aberration assay in peripheral blood lymphocytes and comet assay in rats. Based on the weight of evidence, vadadustat is not considered genotoxic.

Fertility and early embryonic development toxicity studies were conducted in rats at dose levels of 40 to 120 mg/kg/day. Vadadustat did not impact fertility or reproduction in rats up to 80 mg/kg/day
|clinicalStudies=The efficacy and safety of VAFSEO given once daily for the treatment of anemia in adults with CKD on dialysis were demonstrated in two global, multi-center, randomized, active-controlled, non-inferiority, open-label trials in a total of 3923 patients with DD-CKD (INNO2VATE-1 and INNO2VATE-2). Patients in each trial were randomized 1:1 to receive VAFSEO with a starting dose of 300 mg once daily or darbepoetin alfa administered subcutaneously or intravenously as per the prescribing information for 52 weeks to assess the efficacy endpoints. VAFSEO was titrated in increments of 150 mg up to 600 mg to achieve the Hb target. After 52 weeks, patients continued study medication to assess long-term safety until the event-driven major adverse cardiovascular event (MACE) endpoints were reached. Efficacy in each study was based on the difference in mean change of Hb from baseline to the primary evaluation period (Weeks 24 to 36). An additional efficacy endpoint was the difference in mean change of Hb from baseline to the secondary evaluation period (Weeks 40 to 52). MACE was defined as all-cause mortality, non-fatal MI and non-fatal stroke and was evaluated in both trials.

The baseline Hb values were between 8 to 11 g/dL in the United States (US) and 9 to 12 g/dL outside the US. INNO2VATE-1 (NCT02865850) included patients with incident DD-CKD who initiated dialysis within 16 weeks prior to the beginning their trial participation and who were ESA-naive, had limited prior ESA use or were maintained on ESAs. INNO2VATE-2 (NCT02892149) included patients on chronic maintenance dialysis for more than 12 weeks who had converted from prior ESA therapy. In INNO2VATE-1, INNO2VATE-2, and the pooled INNO2VATE program the median and range of time from initiating dialysis to starting vadadustat was 0.1 (0.01 to 0.4), 2.7 (0.2 to 31.3) and 2.3 (0.01 to 31.3) years, respectively. The pooled population from the two trials had a range of 19 to 93 years of age, 55.9% were male, and the percentage of Caucasian, Hispanic, Black (including African Americans) and Asian patients was 64.5%, 38.5%, 24.1% and 4.5%, respectively. In both trials, VAFSEO was non-inferior to darbepoetin alfa in correcting and maintaining Hb levels across geographic-specific target Hb ranges [10 to 11 g/dL in the US and 10 to 12 g/dL outside the US] in adults with DD-CKD at weeks 24 to 36 and weeks 40 to 52.
|howSupplied=150 mg,Round/white tablet shape/colour, 60 count bottle
|storage=Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Keep out of reach of children.
|fdaPatientInfo=*Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Keep out of reach of children.
*That hemoglobin levels will be monitored when initiating or adjusting therapy, every two weeks until stable, then at least monthly
*Of the risk of hepatotoxicity and that liver tests will be measured prior to the initiation of VAFSEO, monthly after initiation for the first 6 months, then as clinically indicated
*Of the risk of hypertension and advise patients of the importance to comply with antihypertensive therapy and monitoring of blood pressure
*Of the risk of seizures and advise patients to contact their healthcare provider for new-onset neurologic symptoms or change in seizure frequency
*Of the risk of gastrointestinal erosions and advise patients to contact their healthcare provider for signs and symptoms of gastric and esophageal erosions and of gastrointestinal bleeding
|alcohol=Alcohol-Vadadustat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=VAFSEO
}}

Meningitis

2025-03-20T09:45:44Z

Alara E. Dagsali:

__NOTOC__
{| class="infobox" style="float:right;"
|-
| [[File:Siren.gif|30px|link=Meningitis resident survival guide]]|| || 
| [[Meningitis resident survival guide|'''Resident''' '''Survival''' '''Guide''']]
|}
{{DiseaseDisorder infobox
| Name = Meningitis
| Image = Illu_meninges.jpg
| Caption = Meninges of the central nervous system: dura mater, arachnoid, and pia mater.
}}
{{Meningitis}}
'''For patient information click [[Meningitis (patient information)|here]].'''

{{CMG}}; {{AE}} {{NE}} [[User: AED| Alara Ece Dagsali, M.D.]] {{MehdiP}} 
{{SK}} Leptomeningitis, Inflammation of meninges
==Overview==
The '''meninges''' (singular '''meninx''') is the system of [[Mesothelium|membrane]]s which envelop the [[central nervous system]]. The meninges consist of three layers: the [[dura mater]], the [[arachnoid mater]], and the [[pia mater]]. The primary function of the meninges and of the cerebrospinal fluid is to protect the [[central nervous system]]. '''Meningitis''' is the [[inflammation]] of these protective membranes. Meningitis may have been described in the Middle Ages, but it was first accurately identified by the Swiss Vieusseux (a scientific-literary association) during an outbreak in Geneva, Switzerland in 1805. In 1661, Thomas Willis first described the inflammation of meninges and an epidemic of meningitis. In the 17th century, Robert Whytt provided a detailed explanation of tuberculous meningitis and its stages. This was further elaborated by John Cheyne in the same century. Meningococcal meningitis was than described by Gaspard Vieusseux, Andre Matthey in Geneva and Elisa North in Massachussetes. Meningitis may develop in response to a number of causes, including infectious agents ([[bacteria]], [[viruses]], [[fungi]], or other organisms) or non-infectious causes, such as systemic illnesses that may involve [[CNS]] (e.g. [[neoplasms]] or [[connective tissue diseases]], such as [[sarcoidosis]], [[systemic lupus erythematosus]] (SLE), and [[Granulomatosis with polyangiitis|wegener's]]) or certain drugs (e.g. [[nonsteroidal antiinflammatory drugs]], [[intravenous immunoglobulin]], intrathecal agents, and [[Sulfamethoxazole-Trimethoprim|trimethoprim-sulfamethoxazole]]). While some forms of meningitis are mild and resolve spontaneously (e.g. viral meningitis), meningitis is a potentially serious condition owing to the proximity of the [[inflammation]] to the [[brain]] and [[spinal cord]]. The potential for serious neurologic damage or even death necessitates prompt medical attention and evaluation. The common presenting features of meningitis are, [[fever]], [[neck stiffness]] and [[headache]]. Other symptoms include, [[photophobia]] (inability to tolerate bright light), [[phonophobia]] (inability to tolerate loud noises), [[irritability]], [[altered mental status]] (in small children), and [[seizure]]. Physical examination of meningitis may vary in adults and infants. In adults, physical examination findings may include [[bradycardia]], [[disorientation]], [[papilledema]], [[neck stiffness]], positive [[Brudzinski's Sign|brudzinski's]] and [[kernig's sign]]. However, [[petechial rash]], bulging [[fontanelle]], [[neck stiffness]], [[jaundice]], and [[convulsions]] are physical examination findings in infants. Diagnosis is based on clinical findings and [[CSF analysis]]. Treatment options are based on etiology and varies from supportive care and observing the patient (viral meningitis) to antibiotic therapy for bacterial meningitis or chemotherapy and/or irradiation for neoplastic meningitis.<ref name="pmid10411200">{{cite journal| author=Attia J, Hatala R, Cook DJ, Wong JG| title=The rational clinical examination. Does this adult patient have acute meningitis? | journal=JAMA | year= 1999 | volume= 282 | issue= 2 | pages= 175-81 | pmid=10411200 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10411200 }} </ref><ref name="abc">https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0047163/ Accessed on Jan 9th, 2017</ref><ref name="pmid20610819">{{cite journal| author=Brouwer MC, Tunkel AR, van de Beek D| title=Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis. | journal=Clin Microbiol Rev | year= 2010 | volume= 23 | issue= 3 | pages= 467-92 | pmid=20610819 | doi=10.1128/CMR.00070-09 | pmc=2901656 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20610819 }} </ref><ref name="pmid8416268">{{cite journal| author=Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick FS, Caviness VS et al.| title=Acute bacterial meningitis in adults. A review of 493 episodes. | journal=N Engl J Med | year= 1993 | volume= 328 | issue= 1 | pages= 21-8 | pmid=8416268 | doi=10.1056/NEJM199301073280104 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8416268 }} </ref><ref name="pmid15509818">{{cite journal| author=van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M| title=Clinical features and prognostic factors in adults with bacterial meningitis. | journal=N Engl J Med | year= 2004 | volume= 351 | issue= 18 | pages= 1849-59 | pmid=15509818 | doi=10.1056/NEJMoa040845 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15509818 }} </ref><ref>{{cite journal |author=van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M |title=Clinical features and prognostic factors in adults with bacterial meningitis |journal=N. Engl. J. Med. |volume=351 |issue=18 |pages=1849-59 |year=2004 |pmid=15509818 |doi=10.1056/NEJMoa040845}}</ref><ref name="pmid8416268">{{cite journal| author=Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick FS, Caviness VS et al.| title=Acute bacterial meningitis in adults. A review of 493 episodes. | journal=N Engl J Med | year= 1993 | volume= 328 | issue= 1 | pages= 21-8 | pmid=8416268 | doi=10.1056/NEJM199301073280104 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8416268 }} </ref><ref name="pmid3403999">{{cite journal| author=Domingo P, Mancebo J, Blanch L, Net A, Nolla J| title=Fever in adult patients with acute bacterial meningitis. | journal=J Infect Dis | year= 1988 | volume= 158 | issue= 2 | pages= 496 | pmid=3403999 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3403999 }} </ref><ref name="pmid12060874">{{cite journal| author=Thomas KE, Hasbun R, Jekel J, Quagliarello VJ| title=The diagnostic accuracy of Kernig's sign, Brudzinski's sign, and nuchal rigidity in adults with suspected meningitis. | journal=Clin Infect Dis | year= 2002 | volume= 35 | issue= 1 | pages= 46-52 | pmid=12060874 | doi=10.1086/340979 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12060874 }} </ref>

==Epidemiology==
Bacterial meningitis can be community acquired or health care associated.

*The major causes of community-acquired bacterial meningitis in adults in developed countries are Streptococcus pneumoniae, Neisseria meningitidis, and, primarily in patients over 50 years of age or those who have deficiencies in cell-mediated immunity, Listeria monocytogenes

*The major causes of health care-associated ventriculitis and meningitis are different (usually staphylococci and aerobic gram-negative bacilli) and occur more commonly after neurosurgical procedures (eg, post-craniotomy, ventriculoperitoneal shunts, lumbar shunts, external ventricular drains or following head trauma such as basilar skull fracture with or without clinical evidence of leak of cerebrospinal fluid)

A more detailed discussion of the epidemiology of and risk factors for bacterial meningitis is presented elsewhere.

==Causes==
 
{| align=center
|-
|
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
!align="center" style="background:#4479BA; color: #FFFFFF;" |Etiology
!align="center" style="background:#4479BA; color: #FFFFFF;" |Common causes
!align="center" style="background:#4479BA; color: #FFFFFF;" |Less common causes
|-
|style="padding: 5px 5px; background: #DCDCDC;" align="center" |Bacterial
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Streptococcus pneumoniae]]
* [[Neisseria meningitis]]
* [[Haemophilus influenzae|Hemophilus influenza]]
* [[Group B streptococcus]]
* [[Listeria monocytogenes]]
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Staphylococcus aureus]]
* [[Klebsiella]]
* [[Pseudomonas]]
* [[Escherichia coli|E. coli]]
* [[Kingella|Kingella Kingae]]
* [[Mycobacterium tuberculosis]]
* [[Corynebacterium|Diphtheroids]]
* [[Propionibacterium acnes]]
* [[Serratia marcescens]]
* [[Salmonella|Salmonella species]]
* [[Brucella|Brucella sp]]
* [[Nocardia]]
* [[Francisella tularensis]]
* [[Streptococcus suis]]
* [[Ehrlichia|Ehrlichia chaffeensis]]

|-
|style="padding: 5px 5px; background: #DCDCDC;" align="center" |Viral
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Enteroviruses]]
* [[Herpes simplex]] [[viruses]] 1 and 2
* [[Arboviruses]]
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Influenza virus]]
* [[Herpes zoster]]
* [[HHV-6 encephalitis|Human Herpes Virus 6]]
* [[Epstein barr virus mononucleosis|Epstein barr virus]] (EBV)
* [[Lymphocytic choriomeningitis virus]]
* [[Mumps]]
* [[Cytomegalovirus|Cytomegalo virus]] (CMV)
* [[Human Immunodeficiency Virus (HIV)|Human immunodeficiency virus]] (HIV)
* [[West nile virus]]
* [[HTLV|Human T cell lymphotrophic virus]] I and II
* [[Varicella zoster virus]]
*[[SARS-CoV-2 virus]] ([[Coronavirus|corona virus]])
|-
|style="padding: 5px 5px; background: #DCDCDC;" align="center" |Fungal
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Cryptococcus neoformans]]
*[[Aspergillus]] sp.
*[[Blastomyces dermatitidis]]
*[[Coccidioides immitis]]
*[[Candida]] spp.
*[[Histoplasma capsulatum]]
*[[Sporothrix schenckii|Sporothrix schencki]]
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
*Xylohypha (formerly [[Cladosporium]]) trichoides and other dark-walled (demateaceous) fungi such as [[Curvularia]] and Drechslera
*[[Mucor]]
*Arthrographis kalrae
*[[Pneumocystis jirovecii]]<ref name="pmid9495679">{{cite journal| author=Villanueva JL, Cordero E, Caballero-Granado FJ, Regordan C, Becerril B, Pachón J| title=Pneumocystis carinii meningoradiculitis in a patient with AIDS. | journal=Eur J Clin Microbiol Infect Dis | year= 1997 | volume= 16 | issue= 12 | pages= 940-2 | pmid=9495679 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9495679 }}</ref><ref name="pmid9629775">{{cite journal| author=Baena Luna MR, Muñoz García J, Grancha Bertolín L, Sanz García M| title=[Presence of Pneumocystis carinii in cerebrospinal fluid]. | journal=An Med Interna | year= 1998 | volume= 15 | issue= 5 | pages= 265-6 | pmid=9629775 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9629775 }}</ref>
*[[Cryptococcus]] albidus<ref name="pmid7185917">{{cite journal| author=Melo JC, Srinivasan S, Scott ML, Raff MJ| title=Cryptococcus albidus meningitis. | journal=J Infect | year= 1980 | volume= 2 | issue= 1 | pages= 79-82 | pmid=7185917 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7185917 }}</ref>

*[[Alternaria]] spp<ref name="pmid13730495">{{cite journal| author=OHASHI Y| title=On a rare disease due to Alternaria tenuis Nees (alternariasis). | journal=Tohoku J Exp Med | year= 1960 | volume= 72 | issue= | pages= 78-82 | pmid=13730495 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13730495 }}</ref>

*[[Rhodotorula]] spp <ref name="pmid18974495">{{cite journal| author=Shinde RS, Mantur BG, Patil G, Parande MV, Parande AM| title=Meningitis due to Rhodotorula glutinis in an HIV infected patient. | journal=Indian J Med Microbiol | year= 2008 | volume= 26 | issue= 4 | pages= 375-7 | pmid=18974495 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18974495 }}</ref>

*[[Acremonium]] spp.<ref name="pmid1956281">{{cite journal| author=Fincher RM, Fisher JF, Lovell RD, Newman CL, Espinel-Ingroff A, Shadomy HJ| title=Infection due to the fungus Acremonium (cephalosporium). | journal=Medicine (Baltimore) | year= 1991 | volume= 70 | issue= 6 | pages= 398-409 | pmid=1956281 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1956281 }}</ref>

*Dreschlera spp<ref name="pmid4739938">{{cite journal| author=Fuste FJ, Ajello L, Threlkeld R, Henry JE| title=Drechslera hawaiiensis: causative agent of a fatal fungal meningo-encephalitis. | journal=Sabouraudia | year= 1973 | volume= 11 | issue= 1 | pages= 59-63 | pmid=4739938 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4739938 }}</ref>

*[[Malassezia]] spp<ref name="pmid15255040">{{cite journal| author=Rosales CM, Jackson MA, Zwick D| title=Malassezia furfur meningitis associated with total parenteral nutrition subdural effusion. | journal=Pediatr Dev Pathol | year= 2004 | volume= 7 | issue= 1 | pages= 86-90 | pmid=15255040 | doi=10.1007/s10024-003-4030-5 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15255040 }}</ref>

*[[Scedosporium apiospermum|Scedosporium]] spp<ref name="pmid16678041">{{cite journal| author=Symoens F, Knoop C, Schrooyen M, Denis O, Estenne M, Nolard N et al.| title=Disseminated Scedosporium apiospermum infection in a cystic fibrosis patient after double-lung transplantation. | journal=J Heart Lung Transplant | year= 2006 | volume= 25 | issue= 5 | pages= 603-7 | pmid=16678041 | doi=10.1016/j.healun.2005.12.011 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16678041 }}</ref>

*Arthrographis spp<ref name="pmid11158158">{{cite journal| author=Chin-Hong PV, Sutton DA, Roemer M, Jacobson MA, Aberg JA| title=Invasive fungal sinusitis and meningitis due to Arthrographis kalrae in a patient with AIDS. | journal=J Clin Microbiol | year= 2001 | volume= 39 | issue= 2 | pages= 804-7 | pmid=11158158 | doi=10.1128/JCM.39.2.804-807.2001 | pmc=87827 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11158158 }}</ref>

*Blastoschizomyces<ref name="pmid1810730">{{cite journal| author=Girmenia C, Micozzi A, Venditti M, Meloni G, Iori AP, Bastianello S et al.| title=Fluconazole treatment of Blastoschizomyces capitatus meningitis in an allogeneic bone marrow recipient. | journal=Eur J Clin Microbiol Infect Dis | year= 1991 | volume= 10 | issue= 9 | pages= 752-6 | pmid=1810730 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1810730 }}</ref><ref name="pmid2324536">{{cite journal| author=Naficy AB, Murray HW| title=Isolated meningitis caused by Blastoschizomyces capitatus. | journal=J Infect Dis | year= 1990 | volume= 161 | issue= 5 | pages= 1041-2 | pmid=2324536 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2324536 }}</ref>

*[[Paecilomyces]]<ref name="pmid12588483">{{cite journal| author=Kantarcioğlu AS, Hatemi G, Yücel A, De Hoog GS, Mandel NM| title=Paecilomyces variotii central nervous system infection in a patient with cancer. | journal=Mycoses | year= 2003 | volume= 46 | issue= 1-2 | pages= 45-50 | pmid=12588483 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12588483 }}</ref><ref name="pmid7192726">{{cite journal| author=Fagerburg R, Suh B, Buckley HR, Lorber B, Karian J| title=Cerebrospinal fluid shunt colonization and obstruction by Paecilomyces variotii. Case report. | journal=J Neurosurg | year= 1981 | volume= 54 | issue= 2 | pages= 257-60 | pmid=7192726 | doi=10.3171/jns.1981.54.2.0257 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7192726 }}</ref>

*[[Aureobasidium]]<ref name="pmid22504065">{{cite journal| author=Kutleša M, Mlinarić-Missoni E, Hatvani L, Voncina D, Simon S, Lepur D et al.| title=Chronic fungal meningitis caused by Aureobasidium proteae. | journal=Diagn Microbiol Infect Dis | year= 2012 | volume= 73 | issue= 3 | pages= 271-2 | pmid=22504065 | doi=10.1016/j.diagmicrobio.2012.03.007 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22504065 }}</ref>

*Clavispora<ref name="pmid10030550">{{cite journal| author=Krcmery V, Mateicka F, Grausova S, Kunova A, Hanzen J| title=Invasive infections due to Clavispora lusitaniae. | journal=FEMS Immunol Med Microbiol | year= 1999 | volume= 23 | issue= 1 | pages= 75-8 | pmid=10030550 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10030550 }}</ref>

*[[Ustilago]]<ref name="pmid20991975">{{cite journal| author=MOORE M, RUSSELL WO, SACHS E| title=Chronic leptomeningitis and ependymitis caused by Ustilago, probably U. zeae (corn smut). | journal=Am J Pathol | year= 1946 | volume= 22 | issue= | pages= 761-77 | pmid=20991975 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20991975 }}</ref>

*[[Exophiala]] (Wangiella)<ref name="pmid12530707">{{cite journal| author=Centers for Disease Control and Prevention (CDC)| title=Exophiala infection from contaminated injectable steroids prepared by a compounding pharmacy--United States, July-November 2002. | journal=MMWR Morb Mortal Wkly Rep | year= 2002 | volume= 51 | issue= 49 | pages= 1109-12 | pmid=12530707 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12530707 }}</ref>

*Exserohilum<ref name="pmid23465119">{{cite journal| author=Pettit AC, Pugh ME| title=Index case for the fungal meningitis outbreak, United States. | journal=N Engl J Med | year= 2013 | volume= 368 | issue= 10 | pages= 970 | pmid=23465119 | doi=10.1056/NEJMc1300630 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23465119 }}</ref>
|-
|style="padding: 5px 5px; background: #DCDCDC;" align="center" |Spirochetal
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Treponema pallidum]]
* [[Borrelia burgdorferi|Borrelia burgdoferi]]
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | --
|-
|style="padding: 5px 5px; background: #DCDCDC;" align="center" |Protozoal and Helminthic
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Amebas (''[[Naegleria]], [[Acanthamoeba]],'' and ''[[Balamuthia mandrillaris|Balamuthia]])''
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Angiostrongylus cantonensis]]
* [[Gnathostoma Infection|Gnathostoma species]]
* [[Baylisascaris|Baylisascaris procyonis]]
* [[Toxocara|Toxocara species]]
* [[Taenia solium]]
|-
|style="padding: 5px 5px; background: #DCDCDC;" align="center" |Noninfectious conditions
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Neoplastic]]
* [[Sarcoidosis]]
* [[Systemic lupus erythematosus]]
* [[Granulomatosis with polyangiitis]] (Wegener's)
* [[Behçet's disease]]
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Fabry's disease|Fabry disease]]
* Central nervous system [[vasculitis]]
* [[Vogt-Koyanagi-Harada syndrome|Vogt-Koyanagi-Harada disease]]
* Chemical or drug-induced meningitis
** [[Nonsteroidal antiinflammatory drugs]]
** [[Intravenous immunoglobulin]]
** [[Intrathecal]] agents
** Certain antibiotics (eg, [[Sulfamethoxazole-Trimethoprim|trimethoprim-sulfamethoxazole]])
|}
 
|}

==Classification==
Meningitis could be classified to two main groups based on etiology:
*Infectious
*Non-infectious
===Infectious meningitis===
Infectious meningitis may be classified as the following algorithm based on chronicity of symptoms. 
{{familytree/start}}
{{familytree | | | | | | | | | | | | | | | A01 |A01='''Infectious Meningitis'''}}
{{familytree | | | | | |,|-|-|-|-|-|-|-|-|-|+|-|-|-|-|-|-|-|-|-|-|-|-|-|-|.| | | }}
{{familytree | | | | | B01 | | | | | | | | B02 | | | | | | | | | | | | | B03 | |B01=[[Viral meningitis|Viral]]|B02=[[Bacterial meningitis|Bacterial]]|B03=[[Fungal meningitis|Fungal]]}}
{{familytree | | | | | | | | | | | |,|-|-|-|+|-|-|-|.| | | | |,|-|-|-|v|-|^|-|v|-|-|-|.|}}
{{familytree | | | | | | | | | | | C01 | | C02 | | C03 | | | C04 | | C05 | | C06 | | |C07 |C01=Acute|C02=Chronic|C03=Recurrent|C04=Acute|C05=Subacute|C06=Chronic|C07=Recurrent|}}
{{familytree/end}} 

===Non-infectious meningitis===
Systemic illnesses, such as malignancies and connective tissue diseases (e.g. [[sarcoidosis]], [[SLE]], and [[Granulomatosis with polyangiitis|wegener's]]) may involve meninges in their course and present as chronic meningitis.

Certain drugs may cause meningeal irritation and resemble as meningitis including:
* [[Nonsteroidal antiinflammatory drugs]] (NSAIDs)
* [[Intravenous immunoglobulin]]
* [[Intrathecal]] agents
* Certain antibiotics (eg, [[Sulfamethoxazole-Trimethoprim|trimethoprim-sulfamethoxazole]])
==Differential diagnosis==
{|
|-style="background: #4479BA; color: #FFFFFF; text-align: center;"
! rowspan="2" |Diseases
! colspan="4" |Symptoms
! colspan="5" |Physical Examination
! rowspan="2" |Past medical history
! colspan="3" |Diagnostic tests
! rowspan="2" |Other Findings
|- style="background: #4479BA; color: #FFFFFF; text-align: center;"
!Headache
!↓LOC
!Motor weakness
!Abnormal sensory
!Motor Deficit
!Sensory deficit
!Speech difficulty
!Gait abnormality
!Cranial nerves
!CT /MRI
!CSF Findings
!Gold standard test
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Meningitis]]
| style="background: #F5F5F5; padding: 5px text-align:center" | +
| style="background: #F5F5F5; padding: 5px text-align:center" | -
| style="background: #F5F5F5; padding: 5px text-align:center" | -
| style="background: #F5F5F5; padding: 5px text-align:center" | -
| style="background: #F5F5F5; padding: 5px text-align:center" | -
| style="background: #F5F5F5; padding: 5px text-align:center" | +
| style="background: #F5F5F5; padding: 5px text-align:center" | +
| style="background: #F5F5F5; padding: 5px text-align:center" | -
| style="background: #F5F5F5; padding: 5px text-align:center" | -
| style="background: #F5F5F5; padding: 5px text-align:center" |History of [[fever]] and [[malaise]]
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px; text-align:center" |'''↑''' [[Leukocytes]],

'''↑''' Protein

↓ Glucose
| style="background: #F5F5F5; padding: 5px;" |[[CSF analysis]]<ref name="pmid19398286">{{cite journal| author=Carbonnelle E| title=[Laboratory diagnosis of bacterial meningitis: usefulness of various tests for the determination of the etiological agent]. | journal=Med Mal Infect | year= 2009 | volume= 39 | issue= 7-8 | pages= 581-605 | pmid=19398286 | doi=10.1016/j.medmal.2009.02.017 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19398286 }}</ref>
| style="background: #F5F5F5; padding: 5px;" |[[Fever]], [[Neck rigidity|neck]]
[[Neck rigidity|rigidity]]
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Encephalitis]]
| style="background: #F5F5F5; padding: 5px text-align:center" | +
| style="background: #F5F5F5; padding: 5px text-align:center" | +
| style="background: #F5F5F5; padding: 5px text-align:center" | +/-
| style="background: #F5F5F5; padding: 5px text-align:center" | +/-
| style="background: #F5F5F5; padding: 5px text-align:center" | -
| style="background: #F5F5F5; padding: 5px text-align:center" | -
| style="background: #F5F5F5; padding: 5px text-align:center" | +
| style="background: #F5F5F5; padding: 5px text-align:center" | +/-
| style="background: #F5F5F5; padding: 5px text-align:center" | +
| style="background: #F5F5F5; padding: 5px text-align:center" |History of [[fever]] and [[malaise]]
| style="background: #F5F5F5; padding: 5px text-align:center" | +
| style="background: #F5F5F5; padding: 5px text-align:center" |'''↑''' [[Leukocytes]], ↓ Glucose
| style="background: #F5F5F5; padding: 5px text-align:center" |CSF [[PCR]]
| style="background: #F5F5F5; padding: 5px text-align:center" |[[Fever]], [[Seizure|seizures]], [[Focal neurologic signs|focal neurologic abnormalities]]
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" | [[Brain tumor]]<ref name="pmid10582668">{{cite journal| author=Morgenstern LB, Frankowski RF| title=Brain tumor masquerading as stroke. | journal=J Neurooncol | year= 1999 | volume= 44 | issue= 1 | pages= 47-52 | pmid=10582668 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10582668 }} </ref>
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" |[[Weight loss]], [[fatigue]]
|style="background: #F5F5F5; padding: 5px; text-align:center"| +
|style="background: #F5F5F5; padding: 5px text-align:center" |Cancer cells<ref name="pmid21371327">{{cite journal| author=Weston CL, Glantz MJ, Connor JR| title=Detection of cancer cells in the cerebrospinal fluid: current methods and future directions. | journal=Fluids Barriers CNS | year= 2011 | volume= 8 | issue= 1 | pages= 14 | pmid=21371327 | doi=10.1186/2045-8118-8-14 | pmc=3059292 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21371327 }}</ref>
|style="background: #F5F5F5; padding: 5px;" |MRI
|style="background: #F5F5F5; padding: 5px;" |[[Cachexia]], gradual progression of symptoms
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Hemorrhagic stroke]]
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" |[[Hypertension]]
|style="background: #F5F5F5; padding: 5px; text-align:center" | +
| style="background: #F5F5F5; padding: 5px;" | -
|style="background: #F5F5F5; padding: 5px;" |CT scan without contrast<ref name="pmid21694755">{{cite journal| author=Birenbaum D, Bancroft LW, Felsberg GJ| title=Imaging in acute stroke. | journal=West J Emerg Med | year= 2011 | volume= 12 | issue= 1 | pages= 67-76 | pmid=21694755 | doi= | pmc=3088377 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21694755 }}</ref><ref name="pmid21807345">{{cite journal| author=DeLaPaz RL, Wippold FJ, Cornelius RS, Amin-Hanjani S, Angtuaco EJ, Broderick DF et al.| title=ACR Appropriateness Criteria® on cerebrovascular disease. | journal=J Am Coll Radiol | year= 2011 | volume= 8 | issue= 8 | pages= 532-8 | pmid=21807345 | doi=10.1016/j.jacr.2011.05.010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21807345 }}</ref>
|style="background: #F5F5F5; padding: 5px;" |[[Neck stiffness]]
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" | [[Subdural hematoma|Subdural hemorrhage]]
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" |[[Trauma]], fall
|style="background: #F5F5F5; padding: 5px; text-align:center" | +
|style="background: #F5F5F5; padding: 5px;" |Xanthochromia<ref name="pmid1198628">{{cite journal| author=Lee MC, Heaney LM, Jacobson RL, Klassen AC| title=Cerebrospinal fluid in cerebral hemorrhage and infarction. | journal=Stroke | year= 1975 | volume= 6 | issue= 6 | pages= 638-41 | pmid=1198628 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1198628 }}</ref>
|style="background: #F5F5F5; padding: 5px;" |CT scan without contrast<ref name="pmid21694755">{{cite journal| author=Birenbaum D, Bancroft LW, Felsberg GJ| title=Imaging in acute stroke. | journal=West J Emerg Med | year= 2011 | volume= 12 | issue= 1 | pages= 67-76 | pmid=21694755 | doi= | pmc=3088377 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21694755 }}</ref><ref name="pmid21807345">{{cite journal| author=DeLaPaz RL, Wippold FJ, Cornelius RS, Amin-Hanjani S, Angtuaco EJ, Broderick DF et al.| title=ACR Appropriateness Criteria® on cerebrovascular disease. | journal=J Am Coll Radiol | year= 2011 | volume= 8 | issue= 8 | pages= 532-8 | pmid=21807345 | doi=10.1016/j.jacr.2011.05.010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21807345 }}</ref>
|style="background: #F5F5F5; padding: 5px;" |[[Confusion]], [[dizziness]], [[nausea]], [[vomiting]]
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Neurosyphilis]]<ref name="pmid22482824">{{cite journal| author=Liu LL, Zheng WH, Tong ML, Liu GL, Zhang HL, Fu ZG et al.| title=Ischemic stroke as a primary symptom of neurosyphilis among HIV-negative emergency patients. | journal=J Neurol Sci | year= 2012 | volume= 317 | issue= 1-2 | pages= 35-9 | pmid=22482824 | doi=10.1016/j.jns.2012.03.003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22482824 }} </ref><ref name="pmid24365430">{{cite journal |vauthors=Berger JR, Dean D |title=Neurosyphilis |journal=Handb Clin Neurol |volume=121 |issue= |pages=1461–72 |year=2014 |pmid=24365430 |doi=10.1016/B978-0-7020-4088-7.00098-5 |url=}}</ref>
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" |[[Sexually transmitted disease|STI]]<nowiki/>s
|style="background: #F5F5F5; padding: 5px; text-align:center" | +
|style="background: #F5F5F5; padding: 5px;" |'''↑''' [[Leukocytes]] and [[protein]]
|style="background: #F5F5F5; padding: 5px;" |CSF [[VDRL]]-specifc
CSF FTA-Ab -sensitive<ref name="pmid22421697">{{cite journal| author=Ho EL, Marra CM| title=Treponemal tests for neurosyphilis--less accurate than what we thought? | journal=Sex Transm Dis | year= 2012 | volume= 39 | issue= 4 | pages= 298-9 | pmid=22421697 | doi=10.1097/OLQ.0b013e31824ee574 | pmc=3746559 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22421697 }}</ref>
|style="background: #F5F5F5; padding: 5px;" |[[Blindness]], [[confusion]], [[depression]],

Abnormal [[gait]]
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" |Complex or atypical [[migraine]]
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" |Family history of [[migraine]]
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
|style="background: #F5F5F5; padding: 5px;" |Clinical assesment
|style="background: #F5F5F5; padding: 5px;" |Presence of aura, [[nausea]], [[vomiting]]
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Hypertensive encephalopathy]]
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" |[[Hypertension]]
|style="background: #F5F5F5; padding: 5px;" | +
|style="background: #F5F5F5; padding: 5px;" | -
|style="background: #F5F5F5; padding: 5px;" |Clinical assesment
|style="background: #F5F5F5; padding: 5px;" |[[Delirium]], [[cortical blindness]], [[cerebral edema]], [[seizure]]
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Wernicke's encephalopathy|Wernicke’s encephalopathy]]
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" |History of alcohal abuse
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" |Clinical assesment and lab findings
|style="background: #F5F5F5; padding: 5px;" |[[Ophthalmoplegia]], [[confusion]]
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Brain abscess|CNS abscess]]
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" |History of [[drug abuse]], [[endocarditis]], [[immunosupression]]
|style="background: #F5F5F5; padding: 5px;" | +
|style="background: #F5F5F5; padding: 5px;" |'''↑''' leukocytes, '''↓''' glucose and '''↑''' protien
|style="background: #F5F5F5; padding: 5px;" |MRI is more sensitive and specific
|style="background: #F5F5F5; padding: 5px;" |High grade [[fever]], [[fatigue]],[[nausea]], [[vomiting]]
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Drug toxicity]]
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" |Drug screen test
|style="background: #F5F5F5; padding: 5px;" |[[Lithium]], [[Sedatives]], [[phenytoin]], [[carbamazepine]]
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Conversion disorder]]
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" |
|style="background: #F5F5F5; padding: 5px text-align:center" |History of [[emotional stress]]
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
|style="background: #F5F5F5; padding: 5px;" |Diagnosis of exclusion
|style="background: #F5F5F5; padding: 5px;" |[[Tremor|Tremors]], [[blindness]], difficulty [[swallowing]]
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" |Metabolic disturbances ([[electrolyte imbalance]], [[hypoglycemia]])
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" |[[Hypoglycemia]], [[Hyponatremia|hypo]] and [[hypernatremia]], [[Hypokalemia|hypo]] and [[hyperkalemia]]
|style="background: #F5F5F5; padding: 5px;" |Depends on the cause
| style="background: #F5F5F5; padding: 5px;" |[[Confusion]], [[seizure]], [[Palpitation|palpitations]], [[sweating]], [[dizziness]], [[hypoglycemia]]
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Multiple sclerosis]] exacerbation
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" |History of relapses and remissions
| style="background: #F5F5F5; padding: 5px; text-align:center" | +
| style="background: #F5F5F5; padding: 5px; text-align:center" |'''↑''' CSF IgG levels
(monoclonal bands)
| style="background: #F5F5F5; padding: 5px;" |Clinical assesment and [[MRI]] <ref name="pmid8274111">{{cite journal| author=Giang DW, Grow VM, Mooney C, Mushlin AI, Goodman AD, Mattson DH et al.| title=Clinical diagnosis of multiple sclerosis. The impact of magnetic resonance imaging and ancillary testing. Rochester-Toronto Magnetic Resonance Study Group. | journal=Arch Neurol | year= 1994 | volume= 51 | issue= 1 | pages= 61-6 | pmid=8274111 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8274111 }}</ref>
| style="background: #F5F5F5; padding: 5px;" |[[Blurred vision|Blurry vision]], [[urinary incontinence]], [[fatigue]]
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Seizure]]
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" |Previous history of [[seizures]]
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" |Mass lesion
| style="background: #F5F5F5; padding: 5px;" |Clinical assesment and [[EEG]] <ref name="pmid11385043">{{cite journal| author=Manford M| title=Assessment and investigation of possible epileptic seizures. | journal=J Neurol Neurosurg Psychiatry | year= 2001 | volume= 70 Suppl 2 | issue= | pages= II3-8 | pmid=11385043 | doi= | pmc=1765557 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11385043 }}</ref>
| style="background: #F5F5F5; padding: 5px;" |[[Confusion]], [[apathy]], [[irritability]],
|}

==Diagnosis==
Diagnosis of meningitis, is based on clinical presentation in combination with CSF analysis. CSF analysis has major role for diagnosis and rule out other possibilities. The following table summarizes the CSF findings in different types of meningitis.<ref name="pmid23717798">{{cite journal| author=Le Rhun E, Taillibert S, Chamberlain MC| title=Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. | journal=Surg Neurol Int | year= 2013 | volume= 4 | issue= Suppl 4 | pages= S265-88 | pmid=23717798 | doi=10.4103/2152-7806.111304 | pmc=3656567 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23717798 }} </ref><ref name="pmid24326618">{{cite journal| author=Chow E, Troy SB| title=The differential diagnosis of hypoglycorrhachia in adult patients. | journal=Am J Med Sci | year= 2014 | volume= 348 | issue= 3 | pages= 186-90 | pmid=24326618 | doi=10.1097/MAJ.0000000000000217 | pmc=4065645 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24326618 }} </ref><ref name="pmid22880096">{{cite journal| author=Leen WG, Willemsen MA, Wevers RA, Verbeek MM| title=Cerebrospinal fluid glucose and lactate: age-specific reference values and implications for clinical practice. | journal=PLoS One | year= 2012 | volume= 7 | issue= 8 | pages= e42745 | pmid=22880096 | doi=10.1371/journal.pone.0042745 | pmc=3412827 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22880096 }} </ref><ref name="pmid10654948">{{cite journal| author=Negrini B, Kelleher KJ, Wald ER| title=Cerebrospinal fluid findings in aseptic versus bacterial meningitis. | journal=Pediatrics | year= 2000 | volume= 105 | issue= 2 | pages= 316-9 | pmid=10654948 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10654948 }} </ref><ref name="pmid20610819">{{cite journal| author=Brouwer MC, Tunkel AR, van de Beek D| title=Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis. | journal=Clin Microbiol Rev | year= 2010 | volume= 23 | issue= 3 | pages= 467-92 | pmid=20610819 | doi=10.1128/CMR.00070-09 | pmc=2901656 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20610819 }} </ref>
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
|+
! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|Cerebrospinal fluid level}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Normal level}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Bacterial meningitis}}<ref name="pmid10654948">{{cite journal| author=Negrini B, Kelleher KJ, Wald ER| title=Cerebrospinal fluid findings in aseptic versus bacterial meningitis. | journal=Pediatrics | year= 2000 | volume= 105 | issue= 2 | pages= 316-9 | pmid=10654948 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10654948 }} </ref>
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Viral meningitis (except SARS-CoV-2 meningitis)}} <ref name="pmid10654948">{{cite journal| author=Negrini B, Kelleher KJ, Wald ER| title=Cerebrospinal fluid findings in aseptic versus bacterial meningitis. | journal=Pediatrics | year= 2000 | volume= 105 | issue= 2 | pages= 316-9 | pmid=10654948 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10654948 }} </ref>
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|SARS-CoV-2 associated meningitis}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Fungal meningitis}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Tuberculous meningitis}}<ref name="pmid20146981">{{cite journal| author=Caudie C, Tholance Y, Quadrio I, Peysson S| title=[Contribution of CSF analysis to diagnosis and follow-up of tuberculous meningitis]. | journal=Ann Biol Clin (Paris) | year= 2010 | volume= 68 | issue= 1 | pages= 107-11 | pmid=20146981 | doi=10.1684/abc.2010.0407 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20146981 }} </ref>
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Neoplastic meningitis}}<ref name="pmid23717798">{{cite journal| author=Le Rhun E, Taillibert S, Chamberlain MC| title=Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. | journal=Surg Neurol Int | year= 2013 | volume= 4 | issue= Suppl 4 | pages= S265-88 | pmid=23717798 | doi=10.4103/2152-7806.111304 | pmc=3656567 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23717798 }} </ref>
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''Cells/ul'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''< 5'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''>300'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''10-1000'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''10-1000'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''10-500'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''50-500'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''>4'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Cells'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''[[Lymphocyte]]'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''[[Leukocyte]] > [[Lymphocyte]]'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''[[Lymphocyte]] > [[Leukocyte]]'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''[[Lymphocyte]] > [[Neutrophil]]'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''[[Lymphocyte]] > [[Leukocyte]]'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''[[Lymphocyte]] > [[Leukocyte]]'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''[[Lymphocyte]] > [[Leukocyte]]'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Total protein (mg/dl''')
| style="padding: 5px 5px; background: #F5F5F5;" |'''45-60'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Typically 100-500'''
| style="padding: 5px 5px; background: #F5F5F5;" | '''Normal or slightly high'''
| style="padding: 5px 5px; background: #F5F5F5;" | '''Normal or slightly high'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''High'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Typically 100-200'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''>50'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Glucose ratio (CSF/plasma)<ref name="pmid24326618">{{cite journal| author=Chow E, Troy SB| title=The differential diagnosis of hypoglycorrhachia in adult patients. | journal=Am J Med Sci | year= 2014 | volume= 348 | issue= 3 | pages= 186-90 | pmid=24326618 | doi=10.1097/MAJ.0000000000000217 | pmc=4065645 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24326618 }} </ref>'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''> 0.5'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''< 0.3'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''> 0.6'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''> 0.6'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''<0.3'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''< 0.5'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''<0.5'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Lactate (mmols/l)<ref name="pmid22880096">{{cite journal| author=Leen WG, Willemsen MA, Wevers RA, Verbeek MM| title=Cerebrospinal fluid glucose and lactate: age-specific reference values and implications for clinical practice. | journal=PLoS One | year= 2012 | volume= 7 | issue= 8 | pages= e42745 | pmid=22880096 | doi=10.1371/journal.pone.0042745 | pmc=3412827 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22880096 }} </ref>'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''< 2.1'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''> 2.1'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''< 2.1'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''NA'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''>3.2'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''> 2.1'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''>2.1'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Others'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''[[Intracranial pressure|Intra-cranial pressure]] (ICP) = 6-12 (cm H2O)'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''CSF [[gram stain]], CSF culture, CSF bacterial antigen'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''[[PCR]] of HSV-DNA, VZV'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''RT-PCR for detection of viral RNA i n CSF ( not approved by FDA)'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''CSF [[gram stain]], CSF india ink'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''[[PCR]] of TB-DNA'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''CSF tumour markers such as [[Alpha-fetoprotein|alpha fetoprotein]], [[CEA]]'''
|-
|}

==Treatment==
===Medical Therapy===

*Empiric therapy for meningitis must be initiated after CSF obtained.
*The choice of empiric antibiotic therapy is depend on patient age and underlying comorbid disease.
*Adapted from IDSA guidlines.
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
|+
! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|Predisposing factor}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Common bacterial pathogen}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Antimicrobial therapy}}
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''1 month'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Streptococcus agalactiae, Escherichia coli, Listeriamonocytogenes, Klebsiellaspecie'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Ampicillin plus cefotaxime or ampicillin plus anaminoglycoside'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''1–23 months'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Streptococcus pneumoniae, Neisseria meningitidis,S. agalactiae, Haemophilus influenzae, E. coli'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Ampicillin plus cefotaxime or ampicillin plus anaminoglycoside'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''2–50 years,150 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''N . meningitidis, S. pneumoniae,S. pneumoniae, N. meningitidis, L. monocytogenes,aerobic gram-negative bacill'''
| style="padding: 5px 5px; background: #F5F5F5;" | '''Vancomycin plus a third-generation cephalosporin,Vancomycin plus ampicillin plus a third-generationcephalosporina,'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''Head traumaBasilar skull fracture'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''S. pneumoniae, H. influenzae,group Ab-hemolyticstreptococci'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Vancomycin plus a third-generation cephalospori'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''Penetrating trauma'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Staphylococcus aureus,coagulase-negative staphylo-cocci (especiallyStaphylococcus epidermidis),aer-obic gram-negative bacilli (includingPseudomonasaeruginosa)'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Vancomycin plus cefepime, vancomycin plus ceftazi-dime, or vancomycin plus meropenem'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''Postneurosurgery'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Aerobic gram-negative bacilli (includingP. aeruginosa),S . aureus, coagulase-negative staphylococci (es-peciallyS. epidermidis)'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''ancomycin plus cefepime, vancomycin plus ceftazi-dime, or vancomycin plus meropenem'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''CSF shunt'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Coagulase-negative staphylococci (especiallyS. epi-dermidis), S. aureus,aerobic gram-negative bacilli(includingP. aeruginosa), Propionibacterium acnes'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''ancomycin plus cefepime, vancomycin plus ceftazi-dime, or vancomycin plus meropenem'''
|-
|}

*Recommendations for antimicrobial therapy in adult patients with presumptive pathogen identification by positive Gram stain.
*Adapted from IDSA guidlines.
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
|+
! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|Microorganism}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Recommended therapy}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Alternative therapies}}
! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|Duration oftherapy, days}}
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''Streptococcus pneumoniae'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Vancomycin plus a third-generationcephalosporina,'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Meropenem , fluoroquinolonec'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''7'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''Neisseria meningitidis'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Third-generation cephalospori'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Penicillin G, ampicillin, chloramphenicol, fluoro-quinolone, aztreonam'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''7'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''Listeria monocytogenes'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Ampicillindor penicillin G'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Trimethoprim-sulfamethoxazole, meropenem'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''10-14'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''Streptococcus agalactiae'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Ampicillindor penicillin G'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Third-generation cephalosporin'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''14-21'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''Haemophilus influenzae'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Third-generation cephalospori'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Chloramphenicol, cefepime , meropenem ,fluoroquinolon'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''21'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''Escherichia coli'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Third-generation cephalospori'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Cefepime, meropenem, aztreonam, fluoroquino-lone, trimethoprim-sulfamethoxazole'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''>21'''
|-
|}

===Surgery===
*Surgical intervention is not recommended for the management of meningitis.

===Primary Prevention===
*Adapted from the recommendations of the United States Centers for Disease Control and Prevention's (CDC's) Advisory Committee on Immunization Practices (ACIP) for the use of meningococcal vaccines.

{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
|+
! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|Targeted group by age and/or risk factor}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Primary dose(s)}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Booster dose(s)}}
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For ages 11 through 18 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give one dose of Menactra or Menveo, preferably at age 11 or 12 years.

Discuss serogroup B meningococcus vaccination (Trumenba or Bexsero)*, which may be administered to adolescents and young adults 16 through 23 years of age; the preferred age for vaccination is 16 through 18 years of age (perhaps at the time of Menactra or Menveo booster).'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''If primary dose was given at age ≤12 years, give Menactra or Menveo booster at age 16 years. If primary dose was given at age 13 to 15 years, give Menactra or Menveo booster at age 16 to 18 years'''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For individuals ages 19 through 21 years who are first year college students living in residence halls'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''If not yet received a dose of vaccine, give one dose of Menactra or Menveo.

Discuss serogroup B meningococcus vaccination (Trumenba or Bexsero)*, which may be administered to adolescents and young adults 16 through 23 years of age; the preferred age for vaccination is 16 through 18 years of age.'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menactra or Menveo booster if previous dose given at age younger than 16 years.'''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''|Patients with HIV infection'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age <2 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give four doses of Menveo (at ages 2, 4, 6, and 12 to 15 months) or give two doses of MenactraΔ (at age 9 to 23 months, 12 weeks apart).'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give additional dose of Menveo or Menactra three years after primary series. Booster doses should be repeated every five years thereafter.'''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age ≥2 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give two doses of Menveo or Menactra 8 to 12 weeks apart.'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''For individuals age <7 years at previous dose, give additional dose of Menveo or Menactra three years after primary series. If the most recent dose was received before age 7 years, a booster dose should be readministered three years later. Booster doses should be repeated every five years thereafter.

For individuals age ≥7 years at previous dose, give additional dose of Menveo or Menactra five years after primary series; booster doses should be repeated every five years thereafter'''

|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''Travelers to or residents of countries where meningococcal disease is hyperendemic or epidemic'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 2 months through 18 months'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menveo at ages 2, 4, 6, and 12 to 15 months'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''If risk continues, give initial booster after three years followed by boosters every five years.'''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For children age 7 months through 23 months who have not initiated a series of Menveo'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menveo (if age 7 to 23 months)§ or Menactra (if age 9 to 23 months); administer two doses separated by three months'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''If risk continues, give initial booster after three years followed by boosters every five years.'''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 2 years through 55 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give one dose of Menactra or Menveo.'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Boost every five years with Menactra or Menveo'''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 56 years and older'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give one dose of Menactra or Menveo'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Boost every five years with Menactra or Menveo'''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''People with prolonged increased risk for exposure (eg, military recruits, microbiologists routinely working with Neisseria meningitidis)'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 10 years and older'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give one dose of Menactra or Menveo.

Give either Trumenba (three doses administered at 0, 1 to 2, and 6 months) or Bexsero (two doses administered at least one month apart)'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Boost every five years with Menactra or Menveo.

Boost with one dose MenB (Trumenba or Bexsero) one year after primary series; revaccinate every 2 to 3 years if risk remains.'''

|-

| style="padding: 5px 5px; background: #DCDCDC;" | '''People present during outbreaks caused by a meningococcal vaccine serogroup'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 2 months through 18 months'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menveo at ages 2, 4, 6, and 12 to 15 months.'''
| style="padding: 5px 5px; background: #F5F5F5;" |''''''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For children age 7 months through 23 months who have not initiated a series of Menveo'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menveo (if age 7 to 23 months)§ or Menactra (if age 9 to 23 months); administer two doses separated by 3 months'''
| style="padding: 5px 5px; background: #F5F5F5;" |''''''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 2 years through 9 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give one dose of Menactra or Menveo'''
| style="padding: 5px 5px; background: #F5F5F5;" |''''''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 10 years through 55 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give one dose of Menactra or Menveo.

Give either Trumenba (three doses administered at 0, 1 to 2, and 6 months) or Bexsero (two doses administered at least one month apart)'''
| style="padding: 5px 5px; background: #F5F5F5;" |''''''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 56 years and older'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give one dose of Menactra or Menveo.

Give either Trumenba (three doses administered at 0, 1 to 2, and 6 months) or Bexsero (two doses administered at least one month apart)'''
| style="padding: 5px 5px; background: #F5F5F5;" |''''''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''People with persistent complement component deficiencies'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 2 months through 18 months'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menveo at ages 2, 4, 6, and 12 to 15 months.'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menactra or Menveo booster after three years followed by boosters every five years thereafter.'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For children age 7 months through 23 months who have not initiated a series of Menveo'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menveo (if age 7 to 23 months)§ or Menactra (if age 9 to 23 months); administer two doses separated by three months.'''
| style="padding: 5px 5px; background: #F5F5F5;" |''''''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 2 years through 9 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give two doses of Menactra or Menveo two months apart.'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Boost every five years with Menactra or Menveo'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 10 years through 55 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''ive two doses of Menactra or Menveo two months apart and either Trumenba (three doses administered at 0, 1 to 2, and 6 months) or Bexsero (two doses administered at least one month apart)'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Boost every five years with Menactra or Menveo.

Boost with one dose MenB (Trumenba or Bexsero) one year after primary series; revaccinate every 2 to 3 years if risk remains.'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 56 years and older'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give two doses of Menactra or Menveo two months apart and either Trumenba (three doses administered at 0, 1 to 2, and 6 months) or Bexsero (two doses administered at least one month apart)'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Boost every five years with Menactra or Menveo.

Boost with one dose MenB (Trumenba or Bexsero) one year after primary series; revaccinate every 2 to 3 years if risk remains.'''
|-

| style="padding: 5px 5px; background: #F5F5F5;" |'''People with functional or anatomic asplenia, including sickle cell disease'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 2 months through 18 months'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menveo at ages 2, 4, 6, and 12 months.'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menactra or Menveo booster after three years followed by boosters every five years thereafter.'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For children age 19 months through 23 months who have not initiated a series of Menveo'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give two doses of Menveo three months apart.'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menactra or Menveo booster after three years followed by boosters every five years thereafter.'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 2 years through 9 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give two doses of Menactra or Menveo two months apart'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Boost every five years with Menactra or Menveo'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 10 years through 55 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give two doses of Menactra or Menveo two months apart and either Trumenba (three doses administered at 0, 1 to 2, and 6 months) or Bexsero (two doses administered at least one month apart)'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Boost every five years with Menactra or Menveo.

Boost with one dose MenB (Trumenba or Bexsero) one year after primary series; revaccinate every 2 to 3 years if risk remains'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 56 years and older'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give two doses of Menactra or Menveo two months apart and either Trumenba (three doses administered at 0, 1 to 2, and 6 months) or Bexsero (two doses administered at least one month apart).'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Boost every five years with Menactra or Menveo.

Boost with one dose MenB (Trumenba or Bexsero) one year after primary series; revaccinate every 2 to 3 years if risk remains.'''
|-
|}
The quadrivalent meningococcal conjugate vaccines (MenACWY) are Menactra (MenACWY-DT) and Menveo (MenACWY-CRM); these have replaced the quadrivalent meningococcal polysaccharide vaccine Menomune (MPSV4). MenHibrix (HibMenCY), a combination conjugate vaccine against meningococcus serogroups C and Y and Haemophilus influenzae type b, was discontinued in 2017. Trumenba (MenB-FHbp) and Bexsero (MenB-4C) are meningococcus serogroup B vaccines.

===Secondary Prevention===
*Secondary prevention with Antimicrobial chemoprophylaxis is necessary for individuals who have close contact with patients with invasive meningococcal disease. Close contacts include:
*1.household members , 2.child-care center contacts ,3.anyone directly exposed to the patient's oral secretions (e.g., through kissing, mouth-to-mouth resuscitation, endotracheal intubation, or endotracheal tube management) in the 7 days before symptom onset. Health-care personnel should receive chemoprophylaxis if they were managing an airway or exposed to respiratory secretions of a patient with meningococcal disease. For travelers, antimicrobial chemoprophylaxis should be considered for any passenger who had direct contact with respiratory secretions from an index-patient or for anyone seated directly next to an index-patient on a prolonged flight (i.e., one lasting ≥8 hours)

*Recommended chemoprophylaxis regimens for protection against meningococcal disease — Advisory Committee on Immunization Practices (ACIP), United States, 2012
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
|+
! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|Drug}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Age group}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Dosage}}
! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|Duration and route of administration}}
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''Rifampin'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Children aged <1 mo'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''5 mg/kg every 12 hrs'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''2 days'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''Rifampin'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Children aged ≥1 mo'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''10 mg/kg every 12 hrs'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''2 days'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''Rifampin'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Adults'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''600 mg every 12 hrs'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''2 days'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''Ciprofloxacin'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Adults'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''500 mg'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Single dose'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''Ceftriaxone'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Children age <15 yrs'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''125 mg'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Single IM dose'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''Ceftriaxone'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Adults'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''250 mg'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Single IM dose'''
|-
|}

==References==
{{reflist|2}}

{{WikiDoc Help Menu}}
{{WikiDoc Sources}}

Meningitis

2025-03-20T09:44:46Z

Alara E. Dagsali:

__NOTOC__
{| class="infobox" style="float:right;"
|-
| [[File:Siren.gif|30px|link=Meningitis resident survival guide]]|| || 
| [[Meningitis resident survival guide|'''Resident''' '''Survival''' '''Guide''']]
|}
{{DiseaseDisorder infobox
| Name = Meningitis
| Image = Illu_meninges.jpg
| Caption = Meninges of the central nervous system: dura mater, arachnoid, and pia mater.
}}
{{Meningitis}}
'''For patient information click [[Meningitis (patient information)|here]].'''

{{CMG}}; {{AE}} {{NE}}{{MehdiP}} [[User: AED| Alara Ece Dagsali, M.D.]]
{{SK}} Leptomeningitis, Inflammation of meninges
==Overview==
The '''meninges''' (singular '''meninx''') is the system of [[Mesothelium|membrane]]s which envelop the [[central nervous system]]. The meninges consist of three layers: the [[dura mater]], the [[arachnoid mater]], and the [[pia mater]]. The primary function of the meninges and of the cerebrospinal fluid is to protect the [[central nervous system]]. '''Meningitis''' is the [[inflammation]] of these protective membranes. Meningitis may have been described in the Middle Ages, but it was first accurately identified by the Swiss Vieusseux (a scientific-literary association) during an outbreak in Geneva, Switzerland in 1805. In 1661, Thomas Willis first described the inflammation of meninges and an epidemic of meningitis. In the 17th century, Robert Whytt provided a detailed explanation of tuberculous meningitis and its stages. This was further elaborated by John Cheyne in the same century. Meningococcal meningitis was than described by Gaspard Vieusseux, Andre Matthey in Geneva and Elisa North in Massachussetes. Meningitis may develop in response to a number of causes, including infectious agents ([[bacteria]], [[viruses]], [[fungi]], or other organisms) or non-infectious causes, such as systemic illnesses that may involve [[CNS]] (e.g. [[neoplasms]] or [[connective tissue diseases]], such as [[sarcoidosis]], [[systemic lupus erythematosus]] (SLE), and [[Granulomatosis with polyangiitis|wegener's]]) or certain drugs (e.g. [[nonsteroidal antiinflammatory drugs]], [[intravenous immunoglobulin]], intrathecal agents, and [[Sulfamethoxazole-Trimethoprim|trimethoprim-sulfamethoxazole]]). While some forms of meningitis are mild and resolve spontaneously (e.g. viral meningitis), meningitis is a potentially serious condition owing to the proximity of the [[inflammation]] to the [[brain]] and [[spinal cord]]. The potential for serious neurologic damage or even death necessitates prompt medical attention and evaluation. The common presenting features of meningitis are, [[fever]], [[neck stiffness]] and [[headache]]. Other symptoms include, [[photophobia]] (inability to tolerate bright light), [[phonophobia]] (inability to tolerate loud noises), [[irritability]], [[altered mental status]] (in small children), and [[seizure]]. Physical examination of meningitis may vary in adults and infants. In adults, physical examination findings may include [[bradycardia]], [[disorientation]], [[papilledema]], [[neck stiffness]], positive [[Brudzinski's Sign|brudzinski's]] and [[kernig's sign]]. However, [[petechial rash]], bulging [[fontanelle]], [[neck stiffness]], [[jaundice]], and [[convulsions]] are physical examination findings in infants. Diagnosis is based on clinical findings and [[CSF analysis]]. Treatment options are based on etiology and varies from supportive care and observing the patient (viral meningitis) to antibiotic therapy for bacterial meningitis or chemotherapy and/or irradiation for neoplastic meningitis.<ref name="pmid10411200">{{cite journal| author=Attia J, Hatala R, Cook DJ, Wong JG| title=The rational clinical examination. Does this adult patient have acute meningitis? | journal=JAMA | year= 1999 | volume= 282 | issue= 2 | pages= 175-81 | pmid=10411200 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10411200 }} </ref><ref name="abc">https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0047163/ Accessed on Jan 9th, 2017</ref><ref name="pmid20610819">{{cite journal| author=Brouwer MC, Tunkel AR, van de Beek D| title=Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis. | journal=Clin Microbiol Rev | year= 2010 | volume= 23 | issue= 3 | pages= 467-92 | pmid=20610819 | doi=10.1128/CMR.00070-09 | pmc=2901656 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20610819 }} </ref><ref name="pmid8416268">{{cite journal| author=Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick FS, Caviness VS et al.| title=Acute bacterial meningitis in adults. A review of 493 episodes. | journal=N Engl J Med | year= 1993 | volume= 328 | issue= 1 | pages= 21-8 | pmid=8416268 | doi=10.1056/NEJM199301073280104 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8416268 }} </ref><ref name="pmid15509818">{{cite journal| author=van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M| title=Clinical features and prognostic factors in adults with bacterial meningitis. | journal=N Engl J Med | year= 2004 | volume= 351 | issue= 18 | pages= 1849-59 | pmid=15509818 | doi=10.1056/NEJMoa040845 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15509818 }} </ref><ref>{{cite journal |author=van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M |title=Clinical features and prognostic factors in adults with bacterial meningitis |journal=N. Engl. J. Med. |volume=351 |issue=18 |pages=1849-59 |year=2004 |pmid=15509818 |doi=10.1056/NEJMoa040845}}</ref><ref name="pmid8416268">{{cite journal| author=Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick FS, Caviness VS et al.| title=Acute bacterial meningitis in adults. A review of 493 episodes. | journal=N Engl J Med | year= 1993 | volume= 328 | issue= 1 | pages= 21-8 | pmid=8416268 | doi=10.1056/NEJM199301073280104 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8416268 }} </ref><ref name="pmid3403999">{{cite journal| author=Domingo P, Mancebo J, Blanch L, Net A, Nolla J| title=Fever in adult patients with acute bacterial meningitis. | journal=J Infect Dis | year= 1988 | volume= 158 | issue= 2 | pages= 496 | pmid=3403999 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3403999 }} </ref><ref name="pmid12060874">{{cite journal| author=Thomas KE, Hasbun R, Jekel J, Quagliarello VJ| title=The diagnostic accuracy of Kernig's sign, Brudzinski's sign, and nuchal rigidity in adults with suspected meningitis. | journal=Clin Infect Dis | year= 2002 | volume= 35 | issue= 1 | pages= 46-52 | pmid=12060874 | doi=10.1086/340979 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12060874 }} </ref>

==Epidemiology==
Bacterial meningitis can be community acquired or health care associated.

*The major causes of community-acquired bacterial meningitis in adults in developed countries are Streptococcus pneumoniae, Neisseria meningitidis, and, primarily in patients over 50 years of age or those who have deficiencies in cell-mediated immunity, Listeria monocytogenes

*The major causes of health care-associated ventriculitis and meningitis are different (usually staphylococci and aerobic gram-negative bacilli) and occur more commonly after neurosurgical procedures (eg, post-craniotomy, ventriculoperitoneal shunts, lumbar shunts, external ventricular drains or following head trauma such as basilar skull fracture with or without clinical evidence of leak of cerebrospinal fluid)

A more detailed discussion of the epidemiology of and risk factors for bacterial meningitis is presented elsewhere.

==Causes==
 
{| align=center
|-
|
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
!align="center" style="background:#4479BA; color: #FFFFFF;" |Etiology
!align="center" style="background:#4479BA; color: #FFFFFF;" |Common causes
!align="center" style="background:#4479BA; color: #FFFFFF;" |Less common causes
|-
|style="padding: 5px 5px; background: #DCDCDC;" align="center" |Bacterial
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Streptococcus pneumoniae]]
* [[Neisseria meningitis]]
* [[Haemophilus influenzae|Hemophilus influenza]]
* [[Group B streptococcus]]
* [[Listeria monocytogenes]]
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Staphylococcus aureus]]
* [[Klebsiella]]
* [[Pseudomonas]]
* [[Escherichia coli|E. coli]]
* [[Kingella|Kingella Kingae]]
* [[Mycobacterium tuberculosis]]
* [[Corynebacterium|Diphtheroids]]
* [[Propionibacterium acnes]]
* [[Serratia marcescens]]
* [[Salmonella|Salmonella species]]
* [[Brucella|Brucella sp]]
* [[Nocardia]]
* [[Francisella tularensis]]
* [[Streptococcus suis]]
* [[Ehrlichia|Ehrlichia chaffeensis]]

|-
|style="padding: 5px 5px; background: #DCDCDC;" align="center" |Viral
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Enteroviruses]]
* [[Herpes simplex]] [[viruses]] 1 and 2
* [[Arboviruses]]
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Influenza virus]]
* [[Herpes zoster]]
* [[HHV-6 encephalitis|Human Herpes Virus 6]]
* [[Epstein barr virus mononucleosis|Epstein barr virus]] (EBV)
* [[Lymphocytic choriomeningitis virus]]
* [[Mumps]]
* [[Cytomegalovirus|Cytomegalo virus]] (CMV)
* [[Human Immunodeficiency Virus (HIV)|Human immunodeficiency virus]] (HIV)
* [[West nile virus]]
* [[HTLV|Human T cell lymphotrophic virus]] I and II
* [[Varicella zoster virus]]
*[[SARS-CoV-2 virus]] ([[Coronavirus|corona virus]])
|-
|style="padding: 5px 5px; background: #DCDCDC;" align="center" |Fungal
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Cryptococcus neoformans]]
*[[Aspergillus]] sp.
*[[Blastomyces dermatitidis]]
*[[Coccidioides immitis]]
*[[Candida]] spp.
*[[Histoplasma capsulatum]]
*[[Sporothrix schenckii|Sporothrix schencki]]
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
*Xylohypha (formerly [[Cladosporium]]) trichoides and other dark-walled (demateaceous) fungi such as [[Curvularia]] and Drechslera
*[[Mucor]]
*Arthrographis kalrae
*[[Pneumocystis jirovecii]]<ref name="pmid9495679">{{cite journal| author=Villanueva JL, Cordero E, Caballero-Granado FJ, Regordan C, Becerril B, Pachón J| title=Pneumocystis carinii meningoradiculitis in a patient with AIDS. | journal=Eur J Clin Microbiol Infect Dis | year= 1997 | volume= 16 | issue= 12 | pages= 940-2 | pmid=9495679 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9495679 }}</ref><ref name="pmid9629775">{{cite journal| author=Baena Luna MR, Muñoz García J, Grancha Bertolín L, Sanz García M| title=[Presence of Pneumocystis carinii in cerebrospinal fluid]. | journal=An Med Interna | year= 1998 | volume= 15 | issue= 5 | pages= 265-6 | pmid=9629775 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9629775 }}</ref>
*[[Cryptococcus]] albidus<ref name="pmid7185917">{{cite journal| author=Melo JC, Srinivasan S, Scott ML, Raff MJ| title=Cryptococcus albidus meningitis. | journal=J Infect | year= 1980 | volume= 2 | issue= 1 | pages= 79-82 | pmid=7185917 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7185917 }}</ref>

*[[Alternaria]] spp<ref name="pmid13730495">{{cite journal| author=OHASHI Y| title=On a rare disease due to Alternaria tenuis Nees (alternariasis). | journal=Tohoku J Exp Med | year= 1960 | volume= 72 | issue= | pages= 78-82 | pmid=13730495 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13730495 }}</ref>

*[[Rhodotorula]] spp <ref name="pmid18974495">{{cite journal| author=Shinde RS, Mantur BG, Patil G, Parande MV, Parande AM| title=Meningitis due to Rhodotorula glutinis in an HIV infected patient. | journal=Indian J Med Microbiol | year= 2008 | volume= 26 | issue= 4 | pages= 375-7 | pmid=18974495 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18974495 }}</ref>

*[[Acremonium]] spp.<ref name="pmid1956281">{{cite journal| author=Fincher RM, Fisher JF, Lovell RD, Newman CL, Espinel-Ingroff A, Shadomy HJ| title=Infection due to the fungus Acremonium (cephalosporium). | journal=Medicine (Baltimore) | year= 1991 | volume= 70 | issue= 6 | pages= 398-409 | pmid=1956281 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1956281 }}</ref>

*Dreschlera spp<ref name="pmid4739938">{{cite journal| author=Fuste FJ, Ajello L, Threlkeld R, Henry JE| title=Drechslera hawaiiensis: causative agent of a fatal fungal meningo-encephalitis. | journal=Sabouraudia | year= 1973 | volume= 11 | issue= 1 | pages= 59-63 | pmid=4739938 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4739938 }}</ref>

*[[Malassezia]] spp<ref name="pmid15255040">{{cite journal| author=Rosales CM, Jackson MA, Zwick D| title=Malassezia furfur meningitis associated with total parenteral nutrition subdural effusion. | journal=Pediatr Dev Pathol | year= 2004 | volume= 7 | issue= 1 | pages= 86-90 | pmid=15255040 | doi=10.1007/s10024-003-4030-5 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15255040 }}</ref>

*[[Scedosporium apiospermum|Scedosporium]] spp<ref name="pmid16678041">{{cite journal| author=Symoens F, Knoop C, Schrooyen M, Denis O, Estenne M, Nolard N et al.| title=Disseminated Scedosporium apiospermum infection in a cystic fibrosis patient after double-lung transplantation. | journal=J Heart Lung Transplant | year= 2006 | volume= 25 | issue= 5 | pages= 603-7 | pmid=16678041 | doi=10.1016/j.healun.2005.12.011 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16678041 }}</ref>

*Arthrographis spp<ref name="pmid11158158">{{cite journal| author=Chin-Hong PV, Sutton DA, Roemer M, Jacobson MA, Aberg JA| title=Invasive fungal sinusitis and meningitis due to Arthrographis kalrae in a patient with AIDS. | journal=J Clin Microbiol | year= 2001 | volume= 39 | issue= 2 | pages= 804-7 | pmid=11158158 | doi=10.1128/JCM.39.2.804-807.2001 | pmc=87827 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11158158 }}</ref>

*Blastoschizomyces<ref name="pmid1810730">{{cite journal| author=Girmenia C, Micozzi A, Venditti M, Meloni G, Iori AP, Bastianello S et al.| title=Fluconazole treatment of Blastoschizomyces capitatus meningitis in an allogeneic bone marrow recipient. | journal=Eur J Clin Microbiol Infect Dis | year= 1991 | volume= 10 | issue= 9 | pages= 752-6 | pmid=1810730 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1810730 }}</ref><ref name="pmid2324536">{{cite journal| author=Naficy AB, Murray HW| title=Isolated meningitis caused by Blastoschizomyces capitatus. | journal=J Infect Dis | year= 1990 | volume= 161 | issue= 5 | pages= 1041-2 | pmid=2324536 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2324536 }}</ref>

*[[Paecilomyces]]<ref name="pmid12588483">{{cite journal| author=Kantarcioğlu AS, Hatemi G, Yücel A, De Hoog GS, Mandel NM| title=Paecilomyces variotii central nervous system infection in a patient with cancer. | journal=Mycoses | year= 2003 | volume= 46 | issue= 1-2 | pages= 45-50 | pmid=12588483 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12588483 }}</ref><ref name="pmid7192726">{{cite journal| author=Fagerburg R, Suh B, Buckley HR, Lorber B, Karian J| title=Cerebrospinal fluid shunt colonization and obstruction by Paecilomyces variotii. Case report. | journal=J Neurosurg | year= 1981 | volume= 54 | issue= 2 | pages= 257-60 | pmid=7192726 | doi=10.3171/jns.1981.54.2.0257 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7192726 }}</ref>

*[[Aureobasidium]]<ref name="pmid22504065">{{cite journal| author=Kutleša M, Mlinarić-Missoni E, Hatvani L, Voncina D, Simon S, Lepur D et al.| title=Chronic fungal meningitis caused by Aureobasidium proteae. | journal=Diagn Microbiol Infect Dis | year= 2012 | volume= 73 | issue= 3 | pages= 271-2 | pmid=22504065 | doi=10.1016/j.diagmicrobio.2012.03.007 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22504065 }}</ref>

*Clavispora<ref name="pmid10030550">{{cite journal| author=Krcmery V, Mateicka F, Grausova S, Kunova A, Hanzen J| title=Invasive infections due to Clavispora lusitaniae. | journal=FEMS Immunol Med Microbiol | year= 1999 | volume= 23 | issue= 1 | pages= 75-8 | pmid=10030550 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10030550 }}</ref>

*[[Ustilago]]<ref name="pmid20991975">{{cite journal| author=MOORE M, RUSSELL WO, SACHS E| title=Chronic leptomeningitis and ependymitis caused by Ustilago, probably U. zeae (corn smut). | journal=Am J Pathol | year= 1946 | volume= 22 | issue= | pages= 761-77 | pmid=20991975 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20991975 }}</ref>

*[[Exophiala]] (Wangiella)<ref name="pmid12530707">{{cite journal| author=Centers for Disease Control and Prevention (CDC)| title=Exophiala infection from contaminated injectable steroids prepared by a compounding pharmacy--United States, July-November 2002. | journal=MMWR Morb Mortal Wkly Rep | year= 2002 | volume= 51 | issue= 49 | pages= 1109-12 | pmid=12530707 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12530707 }}</ref>

*Exserohilum<ref name="pmid23465119">{{cite journal| author=Pettit AC, Pugh ME| title=Index case for the fungal meningitis outbreak, United States. | journal=N Engl J Med | year= 2013 | volume= 368 | issue= 10 | pages= 970 | pmid=23465119 | doi=10.1056/NEJMc1300630 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23465119 }}</ref>
|-
|style="padding: 5px 5px; background: #DCDCDC;" align="center" |Spirochetal
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Treponema pallidum]]
* [[Borrelia burgdorferi|Borrelia burgdoferi]]
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | --
|-
|style="padding: 5px 5px; background: #DCDCDC;" align="center" |Protozoal and Helminthic
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Amebas (''[[Naegleria]], [[Acanthamoeba]],'' and ''[[Balamuthia mandrillaris|Balamuthia]])''
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Angiostrongylus cantonensis]]
* [[Gnathostoma Infection|Gnathostoma species]]
* [[Baylisascaris|Baylisascaris procyonis]]
* [[Toxocara|Toxocara species]]
* [[Taenia solium]]
|-
|style="padding: 5px 5px; background: #DCDCDC;" align="center" |Noninfectious conditions
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Neoplastic]]
* [[Sarcoidosis]]
* [[Systemic lupus erythematosus]]
* [[Granulomatosis with polyangiitis]] (Wegener's)
* [[Behçet's disease]]
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Fabry's disease|Fabry disease]]
* Central nervous system [[vasculitis]]
* [[Vogt-Koyanagi-Harada syndrome|Vogt-Koyanagi-Harada disease]]
* Chemical or drug-induced meningitis
** [[Nonsteroidal antiinflammatory drugs]]
** [[Intravenous immunoglobulin]]
** [[Intrathecal]] agents
** Certain antibiotics (eg, [[Sulfamethoxazole-Trimethoprim|trimethoprim-sulfamethoxazole]])
|}
 
|}

==Classification==
Meningitis could be classified to two main groups based on etiology:
*Infectious
*Non-infectious
===Infectious meningitis===
Infectious meningitis may be classified as the following algorithm based on chronicity of symptoms. 
{{familytree/start}}
{{familytree | | | | | | | | | | | | | | | A01 |A01='''Infectious Meningitis'''}}
{{familytree | | | | | |,|-|-|-|-|-|-|-|-|-|+|-|-|-|-|-|-|-|-|-|-|-|-|-|-|.| | | }}
{{familytree | | | | | B01 | | | | | | | | B02 | | | | | | | | | | | | | B03 | |B01=[[Viral meningitis|Viral]]|B02=[[Bacterial meningitis|Bacterial]]|B03=[[Fungal meningitis|Fungal]]}}
{{familytree | | | | | | | | | | | |,|-|-|-|+|-|-|-|.| | | | |,|-|-|-|v|-|^|-|v|-|-|-|.|}}
{{familytree | | | | | | | | | | | C01 | | C02 | | C03 | | | C04 | | C05 | | C06 | | |C07 |C01=Acute|C02=Chronic|C03=Recurrent|C04=Acute|C05=Subacute|C06=Chronic|C07=Recurrent|}}
{{familytree/end}} 

===Non-infectious meningitis===
Systemic illnesses, such as malignancies and connective tissue diseases (e.g. [[sarcoidosis]], [[SLE]], and [[Granulomatosis with polyangiitis|wegener's]]) may involve meninges in their course and present as chronic meningitis.

Certain drugs may cause meningeal irritation and resemble as meningitis including:
* [[Nonsteroidal antiinflammatory drugs]] (NSAIDs)
* [[Intravenous immunoglobulin]]
* [[Intrathecal]] agents
* Certain antibiotics (eg, [[Sulfamethoxazole-Trimethoprim|trimethoprim-sulfamethoxazole]])
==Differential diagnosis==
{|
|-style="background: #4479BA; color: #FFFFFF; text-align: center;"
! rowspan="2" |Diseases
! colspan="4" |Symptoms
! colspan="5" |Physical Examination
! rowspan="2" |Past medical history
! colspan="3" |Diagnostic tests
! rowspan="2" |Other Findings
|- style="background: #4479BA; color: #FFFFFF; text-align: center;"
!Headache
!↓LOC
!Motor weakness
!Abnormal sensory
!Motor Deficit
!Sensory deficit
!Speech difficulty
!Gait abnormality
!Cranial nerves
!CT /MRI
!CSF Findings
!Gold standard test
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Meningitis]]
| style="background: #F5F5F5; padding: 5px text-align:center" | +
| style="background: #F5F5F5; padding: 5px text-align:center" | -
| style="background: #F5F5F5; padding: 5px text-align:center" | -
| style="background: #F5F5F5; padding: 5px text-align:center" | -
| style="background: #F5F5F5; padding: 5px text-align:center" | -
| style="background: #F5F5F5; padding: 5px text-align:center" | +
| style="background: #F5F5F5; padding: 5px text-align:center" | +
| style="background: #F5F5F5; padding: 5px text-align:center" | -
| style="background: #F5F5F5; padding: 5px text-align:center" | -
| style="background: #F5F5F5; padding: 5px text-align:center" |History of [[fever]] and [[malaise]]
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px; text-align:center" |'''↑''' [[Leukocytes]],

'''↑''' Protein

↓ Glucose
| style="background: #F5F5F5; padding: 5px;" |[[CSF analysis]]<ref name="pmid19398286">{{cite journal| author=Carbonnelle E| title=[Laboratory diagnosis of bacterial meningitis: usefulness of various tests for the determination of the etiological agent]. | journal=Med Mal Infect | year= 2009 | volume= 39 | issue= 7-8 | pages= 581-605 | pmid=19398286 | doi=10.1016/j.medmal.2009.02.017 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19398286 }}</ref>
| style="background: #F5F5F5; padding: 5px;" |[[Fever]], [[Neck rigidity|neck]]
[[Neck rigidity|rigidity]]
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Encephalitis]]
| style="background: #F5F5F5; padding: 5px text-align:center" | +
| style="background: #F5F5F5; padding: 5px text-align:center" | +
| style="background: #F5F5F5; padding: 5px text-align:center" | +/-
| style="background: #F5F5F5; padding: 5px text-align:center" | +/-
| style="background: #F5F5F5; padding: 5px text-align:center" | -
| style="background: #F5F5F5; padding: 5px text-align:center" | -
| style="background: #F5F5F5; padding: 5px text-align:center" | +
| style="background: #F5F5F5; padding: 5px text-align:center" | +/-
| style="background: #F5F5F5; padding: 5px text-align:center" | +
| style="background: #F5F5F5; padding: 5px text-align:center" |History of [[fever]] and [[malaise]]
| style="background: #F5F5F5; padding: 5px text-align:center" | +
| style="background: #F5F5F5; padding: 5px text-align:center" |'''↑''' [[Leukocytes]], ↓ Glucose
| style="background: #F5F5F5; padding: 5px text-align:center" |CSF [[PCR]]
| style="background: #F5F5F5; padding: 5px text-align:center" |[[Fever]], [[Seizure|seizures]], [[Focal neurologic signs|focal neurologic abnormalities]]
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" | [[Brain tumor]]<ref name="pmid10582668">{{cite journal| author=Morgenstern LB, Frankowski RF| title=Brain tumor masquerading as stroke. | journal=J Neurooncol | year= 1999 | volume= 44 | issue= 1 | pages= 47-52 | pmid=10582668 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10582668 }} </ref>
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" |[[Weight loss]], [[fatigue]]
|style="background: #F5F5F5; padding: 5px; text-align:center"| +
|style="background: #F5F5F5; padding: 5px text-align:center" |Cancer cells<ref name="pmid21371327">{{cite journal| author=Weston CL, Glantz MJ, Connor JR| title=Detection of cancer cells in the cerebrospinal fluid: current methods and future directions. | journal=Fluids Barriers CNS | year= 2011 | volume= 8 | issue= 1 | pages= 14 | pmid=21371327 | doi=10.1186/2045-8118-8-14 | pmc=3059292 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21371327 }}</ref>
|style="background: #F5F5F5; padding: 5px;" |MRI
|style="background: #F5F5F5; padding: 5px;" |[[Cachexia]], gradual progression of symptoms
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Hemorrhagic stroke]]
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" |[[Hypertension]]
|style="background: #F5F5F5; padding: 5px; text-align:center" | +
| style="background: #F5F5F5; padding: 5px;" | -
|style="background: #F5F5F5; padding: 5px;" |CT scan without contrast<ref name="pmid21694755">{{cite journal| author=Birenbaum D, Bancroft LW, Felsberg GJ| title=Imaging in acute stroke. | journal=West J Emerg Med | year= 2011 | volume= 12 | issue= 1 | pages= 67-76 | pmid=21694755 | doi= | pmc=3088377 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21694755 }}</ref><ref name="pmid21807345">{{cite journal| author=DeLaPaz RL, Wippold FJ, Cornelius RS, Amin-Hanjani S, Angtuaco EJ, Broderick DF et al.| title=ACR Appropriateness Criteria® on cerebrovascular disease. | journal=J Am Coll Radiol | year= 2011 | volume= 8 | issue= 8 | pages= 532-8 | pmid=21807345 | doi=10.1016/j.jacr.2011.05.010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21807345 }}</ref>
|style="background: #F5F5F5; padding: 5px;" |[[Neck stiffness]]
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" | [[Subdural hematoma|Subdural hemorrhage]]
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" |[[Trauma]], fall
|style="background: #F5F5F5; padding: 5px; text-align:center" | +
|style="background: #F5F5F5; padding: 5px;" |Xanthochromia<ref name="pmid1198628">{{cite journal| author=Lee MC, Heaney LM, Jacobson RL, Klassen AC| title=Cerebrospinal fluid in cerebral hemorrhage and infarction. | journal=Stroke | year= 1975 | volume= 6 | issue= 6 | pages= 638-41 | pmid=1198628 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1198628 }}</ref>
|style="background: #F5F5F5; padding: 5px;" |CT scan without contrast<ref name="pmid21694755">{{cite journal| author=Birenbaum D, Bancroft LW, Felsberg GJ| title=Imaging in acute stroke. | journal=West J Emerg Med | year= 2011 | volume= 12 | issue= 1 | pages= 67-76 | pmid=21694755 | doi= | pmc=3088377 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21694755 }}</ref><ref name="pmid21807345">{{cite journal| author=DeLaPaz RL, Wippold FJ, Cornelius RS, Amin-Hanjani S, Angtuaco EJ, Broderick DF et al.| title=ACR Appropriateness Criteria® on cerebrovascular disease. | journal=J Am Coll Radiol | year= 2011 | volume= 8 | issue= 8 | pages= 532-8 | pmid=21807345 | doi=10.1016/j.jacr.2011.05.010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21807345 }}</ref>
|style="background: #F5F5F5; padding: 5px;" |[[Confusion]], [[dizziness]], [[nausea]], [[vomiting]]
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Neurosyphilis]]<ref name="pmid22482824">{{cite journal| author=Liu LL, Zheng WH, Tong ML, Liu GL, Zhang HL, Fu ZG et al.| title=Ischemic stroke as a primary symptom of neurosyphilis among HIV-negative emergency patients. | journal=J Neurol Sci | year= 2012 | volume= 317 | issue= 1-2 | pages= 35-9 | pmid=22482824 | doi=10.1016/j.jns.2012.03.003 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22482824 }} </ref><ref name="pmid24365430">{{cite journal |vauthors=Berger JR, Dean D |title=Neurosyphilis |journal=Handb Clin Neurol |volume=121 |issue= |pages=1461–72 |year=2014 |pmid=24365430 |doi=10.1016/B978-0-7020-4088-7.00098-5 |url=}}</ref>
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" |[[Sexually transmitted disease|STI]]<nowiki/>s
|style="background: #F5F5F5; padding: 5px; text-align:center" | +
|style="background: #F5F5F5; padding: 5px;" |'''↑''' [[Leukocytes]] and [[protein]]
|style="background: #F5F5F5; padding: 5px;" |CSF [[VDRL]]-specifc
CSF FTA-Ab -sensitive<ref name="pmid22421697">{{cite journal| author=Ho EL, Marra CM| title=Treponemal tests for neurosyphilis--less accurate than what we thought? | journal=Sex Transm Dis | year= 2012 | volume= 39 | issue= 4 | pages= 298-9 | pmid=22421697 | doi=10.1097/OLQ.0b013e31824ee574 | pmc=3746559 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22421697 }}</ref>
|style="background: #F5F5F5; padding: 5px;" |[[Blindness]], [[confusion]], [[depression]],

Abnormal [[gait]]
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" |Complex or atypical [[migraine]]
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" |Family history of [[migraine]]
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
|style="background: #F5F5F5; padding: 5px;" |Clinical assesment
|style="background: #F5F5F5; padding: 5px;" |Presence of aura, [[nausea]], [[vomiting]]
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Hypertensive encephalopathy]]
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" |[[Hypertension]]
|style="background: #F5F5F5; padding: 5px;" | +
|style="background: #F5F5F5; padding: 5px;" | -
|style="background: #F5F5F5; padding: 5px;" |Clinical assesment
|style="background: #F5F5F5; padding: 5px;" |[[Delirium]], [[cortical blindness]], [[cerebral edema]], [[seizure]]
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Wernicke's encephalopathy|Wernicke’s encephalopathy]]
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" |History of alcohal abuse
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" |Clinical assesment and lab findings
|style="background: #F5F5F5; padding: 5px;" |[[Ophthalmoplegia]], [[confusion]]
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Brain abscess|CNS abscess]]
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" |History of [[drug abuse]], [[endocarditis]], [[immunosupression]]
|style="background: #F5F5F5; padding: 5px;" | +
|style="background: #F5F5F5; padding: 5px;" |'''↑''' leukocytes, '''↓''' glucose and '''↑''' protien
|style="background: #F5F5F5; padding: 5px;" |MRI is more sensitive and specific
|style="background: #F5F5F5; padding: 5px;" |High grade [[fever]], [[fatigue]],[[nausea]], [[vomiting]]
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Drug toxicity]]
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" |Drug screen test
|style="background: #F5F5F5; padding: 5px;" |[[Lithium]], [[Sedatives]], [[phenytoin]], [[carbamazepine]]
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Conversion disorder]]
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" |
|style="background: #F5F5F5; padding: 5px text-align:center" |History of [[emotional stress]]
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" | -
|style="background: #F5F5F5; padding: 5px;" |Diagnosis of exclusion
|style="background: #F5F5F5; padding: 5px;" |[[Tremor|Tremors]], [[blindness]], difficulty [[swallowing]]
|-
|style="background: #DCDCDC; padding: 5px; text-align: center;" |Metabolic disturbances ([[electrolyte imbalance]], [[hypoglycemia]])
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" |[[Hypoglycemia]], [[Hyponatremia|hypo]] and [[hypernatremia]], [[Hypokalemia|hypo]] and [[hyperkalemia]]
|style="background: #F5F5F5; padding: 5px;" |Depends on the cause
| style="background: #F5F5F5; padding: 5px;" |[[Confusion]], [[seizure]], [[Palpitation|palpitations]], [[sweating]], [[dizziness]], [[hypoglycemia]]
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Multiple sclerosis]] exacerbation
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" |History of relapses and remissions
| style="background: #F5F5F5; padding: 5px; text-align:center" | +
| style="background: #F5F5F5; padding: 5px; text-align:center" |'''↑''' CSF IgG levels
(monoclonal bands)
| style="background: #F5F5F5; padding: 5px;" |Clinical assesment and [[MRI]] <ref name="pmid8274111">{{cite journal| author=Giang DW, Grow VM, Mooney C, Mushlin AI, Goodman AD, Mattson DH et al.| title=Clinical diagnosis of multiple sclerosis. The impact of magnetic resonance imaging and ancillary testing. Rochester-Toronto Magnetic Resonance Study Group. | journal=Arch Neurol | year= 1994 | volume= 51 | issue= 1 | pages= 61-6 | pmid=8274111 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8274111 }}</ref>
| style="background: #F5F5F5; padding: 5px;" |[[Blurred vision|Blurry vision]], [[urinary incontinence]], [[fatigue]]
|-
| style="background: #DCDCDC; padding: 5px; text-align: center;" |[[Seizure]]
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | -
|style="background: #F5F5F5; padding: 5px text-align:center" | +
|style="background: #F5F5F5; padding: 5px text-align:center" |Previous history of [[seizures]]
| style="background: #F5F5F5; padding: 5px;" | -
| style="background: #F5F5F5; padding: 5px;" |Mass lesion
| style="background: #F5F5F5; padding: 5px;" |Clinical assesment and [[EEG]] <ref name="pmid11385043">{{cite journal| author=Manford M| title=Assessment and investigation of possible epileptic seizures. | journal=J Neurol Neurosurg Psychiatry | year= 2001 | volume= 70 Suppl 2 | issue= | pages= II3-8 | pmid=11385043 | doi= | pmc=1765557 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11385043 }}</ref>
| style="background: #F5F5F5; padding: 5px;" |[[Confusion]], [[apathy]], [[irritability]],
|}

==Diagnosis==
Diagnosis of meningitis, is based on clinical presentation in combination with CSF analysis. CSF analysis has major role for diagnosis and rule out other possibilities. The following table summarizes the CSF findings in different types of meningitis.<ref name="pmid23717798">{{cite journal| author=Le Rhun E, Taillibert S, Chamberlain MC| title=Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. | journal=Surg Neurol Int | year= 2013 | volume= 4 | issue= Suppl 4 | pages= S265-88 | pmid=23717798 | doi=10.4103/2152-7806.111304 | pmc=3656567 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23717798 }} </ref><ref name="pmid24326618">{{cite journal| author=Chow E, Troy SB| title=The differential diagnosis of hypoglycorrhachia in adult patients. | journal=Am J Med Sci | year= 2014 | volume= 348 | issue= 3 | pages= 186-90 | pmid=24326618 | doi=10.1097/MAJ.0000000000000217 | pmc=4065645 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24326618 }} </ref><ref name="pmid22880096">{{cite journal| author=Leen WG, Willemsen MA, Wevers RA, Verbeek MM| title=Cerebrospinal fluid glucose and lactate: age-specific reference values and implications for clinical practice. | journal=PLoS One | year= 2012 | volume= 7 | issue= 8 | pages= e42745 | pmid=22880096 | doi=10.1371/journal.pone.0042745 | pmc=3412827 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22880096 }} </ref><ref name="pmid10654948">{{cite journal| author=Negrini B, Kelleher KJ, Wald ER| title=Cerebrospinal fluid findings in aseptic versus bacterial meningitis. | journal=Pediatrics | year= 2000 | volume= 105 | issue= 2 | pages= 316-9 | pmid=10654948 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10654948 }} </ref><ref name="pmid20610819">{{cite journal| author=Brouwer MC, Tunkel AR, van de Beek D| title=Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis. | journal=Clin Microbiol Rev | year= 2010 | volume= 23 | issue= 3 | pages= 467-92 | pmid=20610819 | doi=10.1128/CMR.00070-09 | pmc=2901656 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20610819 }} </ref>
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
|+
! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|Cerebrospinal fluid level}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Normal level}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Bacterial meningitis}}<ref name="pmid10654948">{{cite journal| author=Negrini B, Kelleher KJ, Wald ER| title=Cerebrospinal fluid findings in aseptic versus bacterial meningitis. | journal=Pediatrics | year= 2000 | volume= 105 | issue= 2 | pages= 316-9 | pmid=10654948 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10654948 }} </ref>
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Viral meningitis (except SARS-CoV-2 meningitis)}} <ref name="pmid10654948">{{cite journal| author=Negrini B, Kelleher KJ, Wald ER| title=Cerebrospinal fluid findings in aseptic versus bacterial meningitis. | journal=Pediatrics | year= 2000 | volume= 105 | issue= 2 | pages= 316-9 | pmid=10654948 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10654948 }} </ref>
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|SARS-CoV-2 associated meningitis}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Fungal meningitis}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Tuberculous meningitis}}<ref name="pmid20146981">{{cite journal| author=Caudie C, Tholance Y, Quadrio I, Peysson S| title=[Contribution of CSF analysis to diagnosis and follow-up of tuberculous meningitis]. | journal=Ann Biol Clin (Paris) | year= 2010 | volume= 68 | issue= 1 | pages= 107-11 | pmid=20146981 | doi=10.1684/abc.2010.0407 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20146981 }} </ref>
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Neoplastic meningitis}}<ref name="pmid23717798">{{cite journal| author=Le Rhun E, Taillibert S, Chamberlain MC| title=Carcinomatous meningitis: Leptomeningeal metastases in solid tumors. | journal=Surg Neurol Int | year= 2013 | volume= 4 | issue= Suppl 4 | pages= S265-88 | pmid=23717798 | doi=10.4103/2152-7806.111304 | pmc=3656567 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23717798 }} </ref>
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''Cells/ul'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''< 5'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''>300'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''10-1000'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''10-1000'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''10-500'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''50-500'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''>4'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Cells'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''[[Lymphocyte]]'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''[[Leukocyte]] > [[Lymphocyte]]'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''[[Lymphocyte]] > [[Leukocyte]]'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''[[Lymphocyte]] > [[Neutrophil]]'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''[[Lymphocyte]] > [[Leukocyte]]'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''[[Lymphocyte]] > [[Leukocyte]]'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''[[Lymphocyte]] > [[Leukocyte]]'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Total protein (mg/dl''')
| style="padding: 5px 5px; background: #F5F5F5;" |'''45-60'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Typically 100-500'''
| style="padding: 5px 5px; background: #F5F5F5;" | '''Normal or slightly high'''
| style="padding: 5px 5px; background: #F5F5F5;" | '''Normal or slightly high'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''High'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Typically 100-200'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''>50'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Glucose ratio (CSF/plasma)<ref name="pmid24326618">{{cite journal| author=Chow E, Troy SB| title=The differential diagnosis of hypoglycorrhachia in adult patients. | journal=Am J Med Sci | year= 2014 | volume= 348 | issue= 3 | pages= 186-90 | pmid=24326618 | doi=10.1097/MAJ.0000000000000217 | pmc=4065645 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24326618 }} </ref>'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''> 0.5'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''< 0.3'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''> 0.6'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''> 0.6'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''<0.3'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''< 0.5'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''<0.5'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Lactate (mmols/l)<ref name="pmid22880096">{{cite journal| author=Leen WG, Willemsen MA, Wevers RA, Verbeek MM| title=Cerebrospinal fluid glucose and lactate: age-specific reference values and implications for clinical practice. | journal=PLoS One | year= 2012 | volume= 7 | issue= 8 | pages= e42745 | pmid=22880096 | doi=10.1371/journal.pone.0042745 | pmc=3412827 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22880096 }} </ref>'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''< 2.1'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''> 2.1'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''< 2.1'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''NA'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''>3.2'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''> 2.1'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''>2.1'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''Others'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''[[Intracranial pressure|Intra-cranial pressure]] (ICP) = 6-12 (cm H2O)'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''CSF [[gram stain]], CSF culture, CSF bacterial antigen'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''[[PCR]] of HSV-DNA, VZV'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''RT-PCR for detection of viral RNA i n CSF ( not approved by FDA)'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''CSF [[gram stain]], CSF india ink'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''[[PCR]] of TB-DNA'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''CSF tumour markers such as [[Alpha-fetoprotein|alpha fetoprotein]], [[CEA]]'''
|-
|}

==Treatment==
===Medical Therapy===

*Empiric therapy for meningitis must be initiated after CSF obtained.
*The choice of empiric antibiotic therapy is depend on patient age and underlying comorbid disease.
*Adapted from IDSA guidlines.
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
|+
! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|Predisposing factor}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Common bacterial pathogen}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Antimicrobial therapy}}
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''1 month'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Streptococcus agalactiae, Escherichia coli, Listeriamonocytogenes, Klebsiellaspecie'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Ampicillin plus cefotaxime or ampicillin plus anaminoglycoside'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''1–23 months'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Streptococcus pneumoniae, Neisseria meningitidis,S. agalactiae, Haemophilus influenzae, E. coli'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Ampicillin plus cefotaxime or ampicillin plus anaminoglycoside'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''2–50 years,150 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''N . meningitidis, S. pneumoniae,S. pneumoniae, N. meningitidis, L. monocytogenes,aerobic gram-negative bacill'''
| style="padding: 5px 5px; background: #F5F5F5;" | '''Vancomycin plus a third-generation cephalosporin,Vancomycin plus ampicillin plus a third-generationcephalosporina,'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''Head traumaBasilar skull fracture'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''S. pneumoniae, H. influenzae,group Ab-hemolyticstreptococci'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Vancomycin plus a third-generation cephalospori'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''Penetrating trauma'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Staphylococcus aureus,coagulase-negative staphylo-cocci (especiallyStaphylococcus epidermidis),aer-obic gram-negative bacilli (includingPseudomonasaeruginosa)'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Vancomycin plus cefepime, vancomycin plus ceftazi-dime, or vancomycin plus meropenem'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''Postneurosurgery'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Aerobic gram-negative bacilli (includingP. aeruginosa),S . aureus, coagulase-negative staphylococci (es-peciallyS. epidermidis)'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''ancomycin plus cefepime, vancomycin plus ceftazi-dime, or vancomycin plus meropenem'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''CSF shunt'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Coagulase-negative staphylococci (especiallyS. epi-dermidis), S. aureus,aerobic gram-negative bacilli(includingP. aeruginosa), Propionibacterium acnes'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''ancomycin plus cefepime, vancomycin plus ceftazi-dime, or vancomycin plus meropenem'''
|-
|}

*Recommendations for antimicrobial therapy in adult patients with presumptive pathogen identification by positive Gram stain.
*Adapted from IDSA guidlines.
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
|+
! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|Microorganism}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Recommended therapy}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Alternative therapies}}
! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|Duration oftherapy, days}}
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''Streptococcus pneumoniae'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Vancomycin plus a third-generationcephalosporina,'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Meropenem , fluoroquinolonec'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''7'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''Neisseria meningitidis'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Third-generation cephalospori'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Penicillin G, ampicillin, chloramphenicol, fluoro-quinolone, aztreonam'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''7'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''Listeria monocytogenes'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Ampicillindor penicillin G'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Trimethoprim-sulfamethoxazole, meropenem'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''10-14'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''Streptococcus agalactiae'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Ampicillindor penicillin G'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Third-generation cephalosporin'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''14-21'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''Haemophilus influenzae'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Third-generation cephalospori'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Chloramphenicol, cefepime , meropenem ,fluoroquinolon'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''21'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''Escherichia coli'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Third-generation cephalospori'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Cefepime, meropenem, aztreonam, fluoroquino-lone, trimethoprim-sulfamethoxazole'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''>21'''
|-
|}

===Surgery===
*Surgical intervention is not recommended for the management of meningitis.

===Primary Prevention===
*Adapted from the recommendations of the United States Centers for Disease Control and Prevention's (CDC's) Advisory Committee on Immunization Practices (ACIP) for the use of meningococcal vaccines.

{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
|+
! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|Targeted group by age and/or risk factor}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Primary dose(s)}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Booster dose(s)}}
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For ages 11 through 18 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give one dose of Menactra or Menveo, preferably at age 11 or 12 years.

Discuss serogroup B meningococcus vaccination (Trumenba or Bexsero)*, which may be administered to adolescents and young adults 16 through 23 years of age; the preferred age for vaccination is 16 through 18 years of age (perhaps at the time of Menactra or Menveo booster).'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''If primary dose was given at age ≤12 years, give Menactra or Menveo booster at age 16 years. If primary dose was given at age 13 to 15 years, give Menactra or Menveo booster at age 16 to 18 years'''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For individuals ages 19 through 21 years who are first year college students living in residence halls'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''If not yet received a dose of vaccine, give one dose of Menactra or Menveo.

Discuss serogroup B meningococcus vaccination (Trumenba or Bexsero)*, which may be administered to adolescents and young adults 16 through 23 years of age; the preferred age for vaccination is 16 through 18 years of age.'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menactra or Menveo booster if previous dose given at age younger than 16 years.'''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''|Patients with HIV infection'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age <2 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give four doses of Menveo (at ages 2, 4, 6, and 12 to 15 months) or give two doses of MenactraΔ (at age 9 to 23 months, 12 weeks apart).'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give additional dose of Menveo or Menactra three years after primary series. Booster doses should be repeated every five years thereafter.'''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age ≥2 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give two doses of Menveo or Menactra 8 to 12 weeks apart.'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''For individuals age <7 years at previous dose, give additional dose of Menveo or Menactra three years after primary series. If the most recent dose was received before age 7 years, a booster dose should be readministered three years later. Booster doses should be repeated every five years thereafter.

For individuals age ≥7 years at previous dose, give additional dose of Menveo or Menactra five years after primary series; booster doses should be repeated every five years thereafter'''

|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''Travelers to or residents of countries where meningococcal disease is hyperendemic or epidemic'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 2 months through 18 months'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menveo at ages 2, 4, 6, and 12 to 15 months'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''If risk continues, give initial booster after three years followed by boosters every five years.'''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For children age 7 months through 23 months who have not initiated a series of Menveo'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menveo (if age 7 to 23 months)§ or Menactra (if age 9 to 23 months); administer two doses separated by three months'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''If risk continues, give initial booster after three years followed by boosters every five years.'''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 2 years through 55 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give one dose of Menactra or Menveo.'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Boost every five years with Menactra or Menveo'''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 56 years and older'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give one dose of Menactra or Menveo'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Boost every five years with Menactra or Menveo'''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''People with prolonged increased risk for exposure (eg, military recruits, microbiologists routinely working with Neisseria meningitidis)'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 10 years and older'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give one dose of Menactra or Menveo.

Give either Trumenba (three doses administered at 0, 1 to 2, and 6 months) or Bexsero (two doses administered at least one month apart)'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Boost every five years with Menactra or Menveo.

Boost with one dose MenB (Trumenba or Bexsero) one year after primary series; revaccinate every 2 to 3 years if risk remains.'''

|-

| style="padding: 5px 5px; background: #DCDCDC;" | '''People present during outbreaks caused by a meningococcal vaccine serogroup'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 2 months through 18 months'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menveo at ages 2, 4, 6, and 12 to 15 months.'''
| style="padding: 5px 5px; background: #F5F5F5;" |''''''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For children age 7 months through 23 months who have not initiated a series of Menveo'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menveo (if age 7 to 23 months)§ or Menactra (if age 9 to 23 months); administer two doses separated by 3 months'''
| style="padding: 5px 5px; background: #F5F5F5;" |''''''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 2 years through 9 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give one dose of Menactra or Menveo'''
| style="padding: 5px 5px; background: #F5F5F5;" |''''''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 10 years through 55 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give one dose of Menactra or Menveo.

Give either Trumenba (three doses administered at 0, 1 to 2, and 6 months) or Bexsero (two doses administered at least one month apart)'''
| style="padding: 5px 5px; background: #F5F5F5;" |''''''

|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 56 years and older'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give one dose of Menactra or Menveo.

Give either Trumenba (three doses administered at 0, 1 to 2, and 6 months) or Bexsero (two doses administered at least one month apart)'''
| style="padding: 5px 5px; background: #F5F5F5;" |''''''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''People with persistent complement component deficiencies'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 2 months through 18 months'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menveo at ages 2, 4, 6, and 12 to 15 months.'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menactra or Menveo booster after three years followed by boosters every five years thereafter.'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For children age 7 months through 23 months who have not initiated a series of Menveo'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menveo (if age 7 to 23 months)§ or Menactra (if age 9 to 23 months); administer two doses separated by three months.'''
| style="padding: 5px 5px; background: #F5F5F5;" |''''''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 2 years through 9 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give two doses of Menactra or Menveo two months apart.'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Boost every five years with Menactra or Menveo'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 10 years through 55 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''ive two doses of Menactra or Menveo two months apart and either Trumenba (three doses administered at 0, 1 to 2, and 6 months) or Bexsero (two doses administered at least one month apart)'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Boost every five years with Menactra or Menveo.

Boost with one dose MenB (Trumenba or Bexsero) one year after primary series; revaccinate every 2 to 3 years if risk remains.'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 56 years and older'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give two doses of Menactra or Menveo two months apart and either Trumenba (three doses administered at 0, 1 to 2, and 6 months) or Bexsero (two doses administered at least one month apart)'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Boost every five years with Menactra or Menveo.

Boost with one dose MenB (Trumenba or Bexsero) one year after primary series; revaccinate every 2 to 3 years if risk remains.'''
|-

| style="padding: 5px 5px; background: #F5F5F5;" |'''People with functional or anatomic asplenia, including sickle cell disease'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 2 months through 18 months'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menveo at ages 2, 4, 6, and 12 months.'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menactra or Menveo booster after three years followed by boosters every five years thereafter.'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For children age 19 months through 23 months who have not initiated a series of Menveo'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give two doses of Menveo three months apart.'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give Menactra or Menveo booster after three years followed by boosters every five years thereafter.'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 2 years through 9 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give two doses of Menactra or Menveo two months apart'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Boost every five years with Menactra or Menveo'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 10 years through 55 years'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give two doses of Menactra or Menveo two months apart and either Trumenba (three doses administered at 0, 1 to 2, and 6 months) or Bexsero (two doses administered at least one month apart)'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Boost every five years with Menactra or Menveo.

Boost with one dose MenB (Trumenba or Bexsero) one year after primary series; revaccinate every 2 to 3 years if risk remains'''
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''For age 56 years and older'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Give two doses of Menactra or Menveo two months apart and either Trumenba (three doses administered at 0, 1 to 2, and 6 months) or Bexsero (two doses administered at least one month apart).'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Boost every five years with Menactra or Menveo.

Boost with one dose MenB (Trumenba or Bexsero) one year after primary series; revaccinate every 2 to 3 years if risk remains.'''
|-
|}
The quadrivalent meningococcal conjugate vaccines (MenACWY) are Menactra (MenACWY-DT) and Menveo (MenACWY-CRM); these have replaced the quadrivalent meningococcal polysaccharide vaccine Menomune (MPSV4). MenHibrix (HibMenCY), a combination conjugate vaccine against meningococcus serogroups C and Y and Haemophilus influenzae type b, was discontinued in 2017. Trumenba (MenB-FHbp) and Bexsero (MenB-4C) are meningococcus serogroup B vaccines.

===Secondary Prevention===
*Secondary prevention with Antimicrobial chemoprophylaxis is necessary for individuals who have close contact with patients with invasive meningococcal disease. Close contacts include:
*1.household members , 2.child-care center contacts ,3.anyone directly exposed to the patient's oral secretions (e.g., through kissing, mouth-to-mouth resuscitation, endotracheal intubation, or endotracheal tube management) in the 7 days before symptom onset. Health-care personnel should receive chemoprophylaxis if they were managing an airway or exposed to respiratory secretions of a patient with meningococcal disease. For travelers, antimicrobial chemoprophylaxis should be considered for any passenger who had direct contact with respiratory secretions from an index-patient or for anyone seated directly next to an index-patient on a prolonged flight (i.e., one lasting ≥8 hours)

*Recommended chemoprophylaxis regimens for protection against meningococcal disease — Advisory Committee on Immunization Practices (ACIP), United States, 2012
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
|+
! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|Drug}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Age group}}
! style="background: #4479BA; width: 350px;" | {{fontcolor|#FFF|Dosage}}
! style="background: #4479BA; width: 150px;" | {{fontcolor|#FFF|Duration and route of administration}}
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''Rifampin'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Children aged <1 mo'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''5 mg/kg every 12 hrs'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''2 days'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''Rifampin'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Children aged ≥1 mo'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''10 mg/kg every 12 hrs'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''2 days'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''Rifampin'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Adults'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''600 mg every 12 hrs'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''2 days'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''Ciprofloxacin'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Adults'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''500 mg'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Single dose'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''Ceftriaxone'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Children age <15 yrs'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''125 mg'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Single IM dose'''
|-
| style="padding: 5px 5px; background: #F5F5F5;" |'''Ceftriaxone'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Adults'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''250 mg'''
| style="padding: 5px 5px; background: #F5F5F5;" |'''Single IM dose'''
|-
|}

==References==
{{reflist|2}}

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