https://www.wikidoc.org/api.php?action=feedcontributions&user=Zach+Leibowitz&feedformat=atomwikidoc - User contributions [en]2024-03-29T15:59:00ZUser contributionsMediaWiki 1.40.0https://www.wikidoc.org/index.php?title=Libtayo&diff=1578206Libtayo2019-08-02T16:04:26Z<p>Zach Leibowitz: ←Redirected page to Cemiplimab-rwlc</p>
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<div>#redirect[[Cemiplimab-rwlc]]</div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=Cemiplimab-rwlc&diff=1578204Cemiplimab-rwlc2019-08-02T16:03:33Z<p>Zach Leibowitz: Created page with "{{DrugProjectFormSinglePage |authorTag={{ZL}} |genericName=cemiplimab-rwlc |aOrAn=a |drugClass=programmed death receptor-1 (PD-1) blocking antibody |indication=patients wi..."</p>
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<div>{{DrugProjectFormSinglePage<br />
|authorTag={{ZL}}<br />
|genericName=cemiplimab-rwlc<br />
|aOrAn=a<br />
|drugClass=programmed death receptor-1 (PD-1) blocking [[antibody]]<br />
|indication=patients with metastatic [[cutaneous squamous cell carcinoma]] (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation<br />
|indicationType=treatment<br />
|hasBlackBoxWarning=<br />
|blackBoxWarningTitle=<br />
|blackBoxWarningBody=<br />
|fdaLIADAdult=<br />
Indication<br />
*Cemiplimab-rwlc is indicated for the treatment of patients with metastatic [[cutaneous squamous cell carcinoma]] (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation.<br />
Dosage<br />
*The recommended dosage of cemiplimab-rwlc is 350 mg administered as an [[intravenous infusion]] over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.<br />
|offLabelAdultGuideSupport=<br />
There is limited information regarding cemiplimab-rwlc Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.<br />
|offLabelAdultNoGuideSupport=<br />
There is limited information regarding cemiplimab-rwlc Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.<br />
|fdaLIADPed=<br />
The safety and effectiveness of cemiplimab-rwlc have not been established in pediatric patients.<br />
|offLabelPedGuideSupport=<br />
There is limited information regarding cemiplimab-rwlc Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.<br />
|offLabelPedNoGuideSupport=<br />
There is limited information regarding cemiplimab-rwlc Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.<br />
|contraindications=<br />
None.<br />
|warnings=<br />
=====Severe and Fatal Immune-Mediated Adverse Reactions=====<br />
*Cemiplimab-rwlc is a [[monoclonal antibody]] that belongs to a class of drugs that binds to the programmed death receptor-1 (PD-1), blocking the PD-1/[[PD-L1]] pathway, thereby removing inhibition of the [[immune response]] with the potential for breaking of peripheral tolerance and induction of immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not be inclusive of all possible immune-mediated reactions.<br />
*Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment with PD-1/[[PD-L1]] blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/[[PD-L1]] blocking [[antibodies]].<br />
*Early identification and management are essential to ensure safe use of PD-1/[[PD-L1]] blocking [[antibodies]]. Monitor for symptoms and signs of immune-mediated adverse reactions. Evaluate clinical chemistries, including liver tests and thyroid function tests, at baseline and periodically during treatment. Institute medical management promptly to include specialty consultation as appropriate.<br />
*In general, withhold cemiplimab-rwlc for Grade 3 or 4 and certain Grade 2 immune-mediated adverse reactions. Permanently discontinue cemiplimab-rwlc for Grade 4 and certain Grade 3 immune-mediated adverse reactions. For Grade 3 or 4 and certain Grade 2 immune-mediated adverse reactions, administer [[corticosteroids]] (1 to 2 mg/kg/day prednisone or equivalent) or other appropriate therapy until improvement to Grade 1 or less followed by a corticosteroid taper over one month. Consider administration of other systemic [[immunosuppressants]] in patients whose immune-mediated adverse reaction is not controlled with corticosteroids. Institute [[hormone replacement therapy]] for endocrinopathies as warranted.<br />
Immune-Mediated Pneumonitis<br />
*Immune-mediated [[pneumonitis]] occurred in 2.4% of 534 patients receiving cemiplimab-rwlc, including Grade 5 (0.2%), Grade 3 (0.7%) and Grade 2 (1.3%). Pneumonitis led to permanent discontinuation of cemiplimab-rwlc in 1.3% of patients. Systemic [[corticosteroids]] were required in all patients with pneumonitis, including 85% who received [[prednisone]] ≥ 40 mg per day or equivalent. Pneumonitis resolved in 62% of patients.<br />
Immune-Mediated Colitis<br />
*Immune-mediated [[colitis]] occurred in 0.9% of 534 patients receiving cemiplimab-rwlc, including Grade 3 (0.4%) and Grade 2 (0.6%). Colitis led to permanent discontinuation of cemiplimab-rwlc in 0.2% of patients. Systemic [[corticosteroids]] were required in all patients with colitis, including 60% who received [[prednisone]] ≥ 40 mg per day or equivalent. Colitis resolved in 80% of patients.<br />
Immune-Mediated Hepatitis<br />
*Immune-mediated [[hepatitis]] occurred in 2.1% of 534 patients receiving cemiplimab-rwlc, including Grade 5 (0.2%), Grade 4 (0.2%), and Grade 3 (1.7%). Hepatitis led to permanent discontinuation of cemiplimab-rwlc in 0.9% of patients. Systemic [[corticosteroids]] were required in all patients with hepatitis, including 91% who received [[prednisone]] ≥ 40 mg per day or equivalent. Hepatitis resolved in 64% of patients.<br />
Immune-Mediated Endocrinopathies <br><br />
''Adrenal Insufficiency''<br />
*[[Adrenal insufficiency]] occurred in 0.4% of 534 patients receiving cemiplimab-rwlc, including Grade 3 (0.2%), and Grade 2 (0.2%).<br />
''Hypophysitis''<br />
*[[Hypophysitis]], which can result in [[hypopituitarism]], occurred in 0.2% of 534 patients receiving cemiplimab-rwlc, which consisted of one patient with Grade 3 hypophysitis.<br />
''Hypothyroidism''<br />
*[[Hypothyroidism]] occurred in 6% of 534 patients receiving cemiplimab-rwlc, including Grade 3 (0.2%) and Grade 2 (5.6%). No patients discontinued hormone replacement therapy.<br />
''Hyperthyroidism''<br />
*[[Hyperthyroidism]] occurred in 1.5% of 534 patients receiving cemiplimab-rwlc, including Grade 3 (0.2%) and Grade 2 (0.4%). Hyperthyroidism resolved in 38% of patients.<br />
''Type 1 Diabetes Mellitus''<br />
*Type 1 [[diabetes mellitus]], which can present with [[diabetic ketoacidosis]], occurred in 0.7% of 534 patients, including Grade 4 (0.4%) and Grade 3 (0.4%). Type 1 diabetes mellitus led to permanent discontinuation of cemiplimab-rwlc in 0.2% of patients.<br />
Immune-Mediated Nephritis with Renal Dysfunction<br />
*Immune-mediated [[nephritis]] occurred in 0.6% of 534 patients receiving cemiplimab-rwlc, including Grade 3 (0.4%) and Grade 2 (0.2%). Nephritis led to permanent discontinuation of cemiplimab-rwlc in 0.2% of patients. Systemic [[corticosteroids]] were required in all patients with nephritis, including 67% who received [[prednisone]] ≥ 40 mg per day or equivalent. Nephritis resolved in all patients.<br />
Immune-Mediated Dermatologic Adverse Reactions<br />
*Immune-mediated dermatologic reactions, including [[erythema multiforme]] and [[pemphigoid]], occurred in 1.7% of 534 patients receiving cemiplimab-rwlc, including Grade 3 (1.1%) and Grade 2 (0.6%). In addition, [[SJS]] and [[TEN]] have been observed with cemiplimab-rwlc and with other products in this class. Systemic [[corticosteroids]] were required in all patients with dermatologic reactions, including 89% who received [[prednisone]] ≥ 40 mg per day or equivalent. Dermatologic reactions resolved in 33% of patients. Approximately 22% of patients had recurrence of dermatologic reactions after re-initiation of cemiplimab-rwlc.<br />
Other Immune-Mediated Adverse Reactions<br />
*The following clinically significant immune-mediated adverse reactions occurred at an incidence of < 1% in 534 patients who received cemiplimab-rwlc or were reported with the use of other PD-1/[[PD-L1]] blocking [[antibodies]]. Severe or fatal cases have been reported for some of these adverse reactions.<br />
*Neurological: [[Meningitis]], [[encephalitis]], [[myelitis]] and [[demyelination]], myasthenic syndrome / [[myasthenia gravis]], [[Guillain-Barre syndrome]], nerve [[paresis]], [[autoimmune]] [[neuropathy]].<br />
*Cardiovascular: [[Myocarditis]], [[pericarditis]], [[vasculitides]].<br />
*Ocular: [[Uveitis]], [[iritis]], and other ocular inflammatory toxicities. Some cases can be associated with [[retinal detachment]]. Various grades of visual impairment to include [[blindness]] can occur. If [[uveitis]] occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada like syndrome, as this may require treatment with systemic [[corticosteroids]] to reduce the risk of permanent [[vision loss]].<br />
*Gastrointestinal: [[Pancreatitis]] to include increases in [[serum amylase]] and [[lipase]] levels, [[gastritis]], [[duodenitis]].<br />
*Musculoskeletal and Connective Tissue: [[Myositis]], [[rhabdomyolysis]] and associated [[sequelae]] including [[renal failure]], [[arthritis]], [[polymyalgia rheumatica]].<br />
*Hematological and Immunological: [[Hemolytic anemia]], [[aplastic anemia]], [[hemophagocytic lymphohistiocytosis]], [[systemic inflammatory response syndrome]], [[histiocytic necrotizing lymphadenitis]] (Kikuchi lymphadenitis), [[sarcoidosis]], [[immune thrombocytopenic purpura]], solid [[organ transplant]] rejection.<br />
=====Infusion-Related Reactions=====<br />
*Severe [[infusion-related reactions]] (Grade 3) occurred in 0.2% of patients receiving cemiplimab-rwlc. Monitor patients for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion or permanently discontinue cemiplimab-rwlc based on severity of reaction.<br />
=====Embryo-Fetal Toxicity=====<br />
*Based on its mechanism of action, cemiplimab-rwlc can cause fetal harm when administered to a [[pregnant]] woman. Animal studies have demonstrated that inhibition of the PD-1/[[PD-L1]] pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective [[contraception]] during treatment with cemiplimab-rwlc and for at least 4 months after the last dose.<br />
|adverseReactions=[[fatigue]], [[rash]] and [[diarrhea]]<br />
|clinicalTrials=<br />
*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.<br />
*The data described in WARNINGS AND PRECAUTIONS reflect exposure to cemiplimab-rwlc in 534 patients in two open-label, single-arm, multicohort studies (Study 1423 and Study 1540), including 98 patients with metastatic (nodal or distant) CSCC, 65 patients with locally advanced CSCC, and 371 patients with other advanced [[solid tumors]]. Cemiplimab-rwlc as a single agent or in combination with [[chemotherapy]] or [[radiation]] was administered intravenously at doses of 1 mg/kg every 2 weeks (n=27), 3 mg/kg every 2 weeks (n=446), 3 mg/kg every 3 weeks (n=12), 10 mg/kg every 2 weeks (n=6), 200 mg every 2 weeks (n=20) or 350 mg every 3 weeks (n=23). Among the 534 patients, 38% were exposed for ≥ 6 months and 16% were exposed for ≥ 12 months.<br />
*The data described below reflect exposure to cemiplimab-rwlc in 163 patients with advanced CSCC (metastatic or locally advanced disease) in Study 1423 and Study 1540 [see CLINICAL STUDIES (14)]. Patients received cemiplimab-rwlc 1 mg/kg every 2 weeks (n=1), 3 mg/kg every 2 weeks (n=139) or 350 mg every 3 weeks (n=23) as an [[intravenous infusion]] until disease progression, unacceptable toxicity, or completion of planned treatment. The median duration of exposure was 20 weeks (3 days to 1.4 years).<br />
*The safety population characteristics were: median age of 71 years (38 to 96 years), 85% male, 96% white, and ECOG performance score (PS) of 0 (44%) or 1 (56%).<br />
*The most common adverse reactions reported in at least 20% of patients were [[fatigue]], [[rash]] and [[diarrhea]]. The most common Grade 3-4 adverse reactions (≥ 2%) were [[cellulitis]], [[sepsis]], [[hypertension]], [[pneumonia]], [[musculoskeletal pain]], [[skin infection]], [[urinary tract infection]] and [[fatigue]]. Cemiplimab-rwlc was permanently discontinued due to adverse reactions in 5% of patients; adverse reactions resulting in permanent discontinuation were [[pneumonitis]], autoimmune [[myocarditis]], [[hepatitis]], [[aseptic meningitis]], [[complex regional pain syndrome]], [[cough]], and [[muscular weakness]]. Serious adverse reactions occurred in 28% of patients. Serious adverse reactions that occurred in at least 2% of patients were [[cellulitis]], [[sepsis]], [[pneumonia]], [[pneumonitis]] and [[urinary tract infection]].<br />
*Table 2 summarizes the adverse reactions that occurred in ≥ 10% of patients and Table 3 summarizes Grade 3 and 4 laboratory abnormalities worsening from baseline in ≥ 1% of patients receiving cemiplimab-rwlc.<br />
[[File:CemiplimabTable2.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
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[[File:CemiplimabTable3.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
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===Immunogenicity===<br />
*As with all therapeutic proteins, there is a potential for [[immunogenicity]]. The detection of [[antibody]] formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of [[antibody]] (including neutralizing [[antibody]]) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to cemiplimab-rwlc in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.<br />
*Anti-drug antibodies (ADA) were tested in 398 of 534 patients who received cemiplimab-rwlc and the incidence of cemiplimab-rwlc treatment-emergent ADAs was 1.3% using an electrochemiluminescent (ECL) bridging immunoassay; 0.3% were persistent ADA responses. In the patients who developed anti-cemiplimab-rwlc antibodies, there was no evidence of an altered pharmacokinetic profile of cemiplimab-rwlc.<br />
|postmarketing=<br />
|drugInteractions=<br />
|FDAPregCat=<br />
|useInPregnancyFDA=<br />
Risk Summary<br />
*Based on its mechanism of action, cemiplimab-rwlc can cause fetal harm when administered to a [[pregnant]] woman. There are no available data on the use of cemiplimab-rwlc in pregnant women. Animal studies have demonstrated that inhibition of the PD-1/[[PD-L1]] pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. Human IgG4 [[immunoglobulins]] (IgG4) are known to cross the [[placenta]]; therefore, cemiplimab-rwlc has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to a fetus.<br />
*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.<br />
Animal Data<br />
*Animal reproduction studies have not been conducted with cemiplimab-rwlc to evaluate its effect on reproduction and fetal development. A central function of the PD-1/[[PD-L1]] pathway is to preserve [[pregnancy]] by maintaining maternal immune tolerance to the fetus. In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering cemiplimab-rwlc during pregnancy include increased rates of [[abortion]] or [[stillbirth]]. As reported in the literature, there were no malformations related to the blockade of PD-1/PD-L1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to cemiplimab-rwlc may increase the risk of developing immune-mediated disorders or altering the normal immune response.<br />
|AUSPregCat=<br />
|useInPregnancyAUS=<br />
|useInLaborDelivery=<br />
|useInNursing=<br />
Risk Summary<br />
*There is no information regarding the presence of cemiplimab-rwlc in human 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 and for at least 4 months after the last dose of cemiplimab-rwlc.<br />
|useInPed=<br />
*The safety and effectiveness of cemiplimab-rwlc have not been established in pediatric patients.<br />
|useInGeri=<br />
*Of the 163 patients with metastatic and locally advanced CSCC who received cemiplimab-rwlc in clinical studies, 72% were 65 years or older and 37% were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.<br />
|useInGender=<br />
|useInRace=<br />
|useInRenalImpair=<br />
|useInHepaticImpair=<br />
|useInReproPotential=<br />
Pregnancy Testing<br />
*Verify [[pregnancy]] status in females of reproductive potential prior to initiating cemiplimab-rwlc.<br />
Contraception<br />
*Cemiplimab-rwlc can cause fetal harm when administered to a pregnant woman.<br />
Females<br />
*Advise females of reproductive potential to use effective [[contraception]] during treatment with cemiplimab-rwlc and for at least 4 months after the last dose.<br />
|useInImmunocomp=<br />
|othersTitle=<br />
|useInOthers=<br />
|administration=<br />
=====Recommended Dosage=====<br />
*The recommended dosage of cemiplimab-rwlc is 350 mg administered as an [[intravenous infusion]] over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.<br />
=====Dosage Modifications for Adverse Reactions=====<br />
*Withhold or discontinue cemiplimab-rwlc to manage adverse reactions as described in Table 1. No dose reduction of cemiplimab-rwlc is recommended.<br />
[[File:CemiplimabTable1.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
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=====Preparation and Administration=====<br />
*Visually inspect for particulate matter and discoloration prior to administration. Cemiplimab-rwlc is a clear to slightly opalescent, colorless to pale yellow solution that may contain trace amounts of translucent to white particles. Discard the vial if the solution is cloudy, discolored or contains extraneous particulate matter other than trace amounts of translucent to white particles.<br />
Preparation<br />
*Do not shake.<br />
*Withdraw 7 mL from a vial and dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to a final concentration between 1 mg/mL to 20 mg/mL.<br />
*Mix diluted solution by gentle inversion. Do not shake.<br />
*Discard any unused medicinal product or waste material.<br />
Storage of Infusion Solution<br />
*Store at room temperature up to 25°C (77°F) for no more than 8 hours from the time of preparation to the end of the infusion or at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of preparation to the end of infusion.<br />
*Allow the diluted solution to come to room temperature prior to administration.<br />
*Do not freeze.<br />
Administration<br />
*Administer by [[intravenous infusion]] over 30 minutes through an intravenous line containing a sterile, in-line or add-on 0.2-micron to 5-micron filter.<br />
|monitoring=<br />
|IVCompat=<br />
*Cemiplimab-rwlc is administered as an [[intravenous infusion]].<br />
|overdose=<br />
|drugBox=<br />
{{drugbox2<br />
| type = mab<br />
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| mab_type = mab<br />
| source = u<br />
| target = [[PD-1]]<br />
<!-- Clinical data --><br />
| pronounce =<br />
| tradename = Libtayo<br />
| Drugs.com = <br />
| MedlinePlus = <br />
| pregnancy_AU = <!-- A/B1/B2/B3/C/D/X --><br />
| pregnancy_US = <!-- A/B/C/D/X --><br />
| pregnancy_category= <br />
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| legal_AU_comment =<br />
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<!-- Pharmacokinetic data --><br />
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<!-- Identifiers --><br />
| CAS_number = 1801342-60-8<br />
| ATC_prefix = L01<br />
| ATC_suffix = XC33<br />
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| UNII = 6QVL057INT<br />
| KEGG = D11108<br />
| synonyms = REGN-2810<br />
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| C = 6380<br />
| H = 9808<br />
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| S = 44<br />
| molecular_weight = 143.6 g/mol<br />
}}<br />
|mechAction=<br />
=====Mechanism of Action=====<br />
*Binding of the PD-1 ligands [[PD-L1]] and PD-L2, to the PD-1 receptor found on [[T cells]], inhibits T-cell proliferation and [[cytokine]] production. Upregulation of PD-1 [[ligands]] occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors.<br />
*Cemiplimab-rwlc is a recombinant human immunoglobulin G4 (IgG4) [[monoclonal antibody]] that binds to PD-1 and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.<br />
|structure=<br />
|PD=<br />
|PK=<br />
*Cemiplimab-rwlc pharmacokinetic (PK) data were collected in 505 patients with various solid tumors, including 135 patients with CSCC. The PK of cemiplimab-rwlc was linear and dose proportional in the dose range of 1 mg/kg to 10 mg/kg administered intravenously every two weeks and 350 mg intravenously administered every three weeks.<br />
*After a dose of 350 mg cemiplimab-rwlc administered intravenously every 3 weeks, median steady-state concentrations (CV%) of cemiplimab-rwlc ranged between a maximum concentration (C<sub>max,ss</sub>) of 166 mcg/mL (28%) and a minimum concentration (C<sub>min,ss</sub>) of 59 mcg/mL (48%). Steady-state exposure is achieved after approximately 4 months of treatment.<br />
Distribution<br />
*The volume of distribution of cemiplimab-rwlc at steady state is 5.3 L (25%).<br />
Elimination<br />
*Cemiplimab-rwlc clearance (CV%) after the first dose is 0.32 L/day (39%) and decreases over time by 34%, resulting in a steady-state clearance (CL<sub>ss</sub>) (CV%) of 0.21 L/day (39%). The elimination half-life (CV%) at steady state is 19 days (30%).<br />
Specific Populations<br />
*The following factors have no clinically important effect on the exposure of cemiplimab-rwlc: age (27 to 96 years), sex, body weight (31 to 156 kg), race (White, Black, Asian and other), cancer type, [[albumin]] level (22 to 48 g/L), [[renal function]] (creatinine clearance determined by Cockcroft-Gault 25 mL/min or greater) and [[hepatic]] function (total [[bilirubin]] 0.35 to 45 µmol/L). Cemiplimab-rwlc has not been studied in patients with moderate or severe hepatic impairment.<br />
|nonClinToxic=<br />
=====Carcinogenesis, Mutagenesis, Impairment of Fertility=====<br />
*No studies have been performed to assess the potential of cemiplimab-rwlc for [[carcinogenicity]] or [[genotoxicity]].<br />
*In a 3-month repeat-dose toxicology study in sexually mature cynomolgus monkeys, there were no cemiplimab-rwlc-related effects on [[fertility]] parameters ([[menstrual cycle]], [[semen analysis]], or testicular measurements) or in male or female reproductive organs at doses up to the highest dose tested, 50 mg/kg/week (approximately 5.5 to 25.5 times the human exposure based on AUC at the clinical dose of 350 mg once every 3 weeks).<br />
=====Animal Toxicology and/or Pharmacology=====<br />
*In animal models, inhibition of [[PD-L1]]/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. ‘’M. tuberculosis’’–infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and [[inflammatory responses]] in these animals. PD-L1 and PD-1 knockout mice and mice receiving PD-L1 blocking [[antibody]] have also shown decreased survival following [[infection]] with [[lymphocytic choriomeningitis virus]].<br />
|clinicalStudies=<br />
*The efficacy of cemiplimab-rwlc in patients with metastatic (nodal or distant) [[cutaneous squamous cell carcinoma]] (CSCC) or locally advanced CSCC who were not candidates for curative surgery or curative radiation was evaluated in two open-label, multi-center, non-randomized, multicohort studies: Study 1423 (NCT02383212) and 1540 (NCT02760498). Both studies excluded patients with [[autoimmune disease]] that required systemic therapy with [[immunosuppressant]] agents within 5 years; history of solid [[organ transplant]]; prior treatment with anti–PD-1/[[PD-L1]] blocking [[antibodies]] or other immune checkpoint inhibitor therapy; infection with [[HIV]], [[hepatitis B]] or [[hepatitis C]]; or ECOG performance score (PS) ≥ 2.<br />
*Patients received cemiplimab-rwlc 3 mg/kg intravenously every 2 weeks for up to 48 weeks in Study 1423 or up to 96 weeks in Study 1540. Treatment continued until progression of disease, unacceptable toxicity, or completion of planned treatment. Tumor response assessments were performed every 8 weeks. The major efficacy outcome measures were confirmed objective response rate (ORR), as assessed by independent central review (ICR) and ICR-assessed duration of response. For patients with metastatic CSCC without externally visible target lesions, ORR was determined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1). For patients with externally visible target lesions (locally advanced and metastatic CSCC), ORR was determined by a composite endpoint that integrated ICR assessments of radiologic data (RECIST 1.1) and digital medical photography (WHO criteria). The efficacy analysis was conducted when all patients had the opportunity for at least 6 months of follow-up.<br />
*A total of 26 patients with CSCC were enrolled in Study 1423 and 82 patients were enrolled in Study 1540. Of these 108 patients, 75 had metastatic CSCC and 33 had locally advanced CSCC. The median age was 71 years (38 to 96 years); 85% were male; 97% were White; 43% had ECOG PS 0 and 57% had ECOG PS 1; 50% received at least one prior anti-cancer systemic therapy; 96% received prior cancer-related surgery; and 79% received prior [[radiotherapy]]. Among patients with metastatic CSCC, 69% had distant metastases and 31% had only nodal metastases.<br />
*Efficacy results are presented in Table 4.<br />
[[File:CemiplimabTable4.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
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|howSupplied=<br />
*Cemiplimab-rwlc [[injection]] is a clear to slightly opalescent, colorless to pale yellow solution that may contain trace amounts of translucent to white particles. It is supplied in a carton containing 1 single-dose vial of:<br />
**350 mg/7 mL (50 mg/mL) (NDC 61755-008-01)<br />
|NDC=<br />
|storage=<br />
*Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Protect from light. Do not freeze or shake.<br />
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|drugImages=<br />
|packLabel=<br />
[[File:CemiplimabStructure.jpeg|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
|fdaPatientInfo=<br />
Immune-Mediated Adverse Reactions<br />
*Advise patients that cemiplimab-rwlc can cause immune-mediated adverse reactions including the following:<br />
*[[Pneumonitis]]: Advise patients to contact their healthcare provider immediately for signs or symptoms of pneumonitis, including new or worsening symptoms of [[cough]], [[chest pain]], or [[shortness of breath]].<br />
*Colitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of [[colitis]], including [[diarrhea]], blood or mucus in stools, or severe [[abdominal pain]].<br />
*Hepatitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of [[hepatitis]].<br />
*Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of [[hypothyroidism]], [[hyperthyroidism]], [[adrenal insufficiency]], [[hypophysitis]], or [[type 1 diabetes mellitus]].<br />
*Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of [[nephritis]].<br />
*Dermatologic Adverse Reactions: Advise patients to contact their healthcare provider immediately if they develop a new [[rash]].<br />
Infusion-Related Reactions<br />
*Advise patients to contact their healthcare provider immediately for signs or symptoms of [[infusion-related reactions]].<br />
Embryo-Fetal Toxicity<br />
*Advise females of reproductive potential that cemiplimab-rwlc can cause harm to a fetus and to inform their healthcare provider of a known or suspected [[pregnancy]].<br />
*Advise females of reproductive potential to use effective [[contraception]] during treatment and for at least 4 months after the last dose of cemiplimab-rwlc.<br />
Lactation<br />
*Advise female patients not to breastfeed while taking cemiplimab-rwlc and for at least 4 months after the last dose.<br />
=====Medication Guide=====<br />
[[File:CemiplimabMedGuide.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
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|nlmPatientInfo=<br />
|alcohol=<br />
|brandNames=[[Libtayo]]<br />
|lookAlike=<br />
|drugShortage=<br />
|price=<br />
}}</div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:CemiplimabStructure.jpeg&diff=1578150File:CemiplimabStructure.jpeg2019-08-02T14:15:10Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:CemiplimabMedGuide.png&diff=1578149File:CemiplimabMedGuide.png2019-08-02T14:14:14Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:CemiplimabTable4.png&diff=1578148File:CemiplimabTable4.png2019-08-02T14:06:27Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:CemiplimabTable3.png&diff=1578147File:CemiplimabTable3.png2019-08-02T14:05:55Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:CemiplimabTable2.png&diff=1578146File:CemiplimabTable2.png2019-08-02T14:05:15Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:CemiplimabTable1.png&diff=1578144File:CemiplimabTable1.png2019-08-02T14:03:35Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=Vizimpro&diff=1578024Vizimpro2019-08-01T18:47:46Z<p>Zach Leibowitz: ←Redirected page to Dacomitinib</p>
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<div>#redirect[[Dacomitinib]]</div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=Dacomitinib&diff=1578023Dacomitinib2019-08-01T18:47:04Z<p>Zach Leibowitz: Created page with "{{DrugProjectFormSinglePage |authorTag={{ZL}} |genericName=dacomitinib |aOrAn=a |drugClass=kinase inhibitor |indication=patients with metastatic non-small cell lung canc..."</p>
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<div>{{DrugProjectFormSinglePage<br />
|authorTag={{ZL}}<br />
|genericName=dacomitinib<br />
|aOrAn=a<br />
|drugClass=[[kinase inhibitor]]<br />
|indication=patients with metastatic [[non-small cell lung cancer]] ([[NSCLC]]) with [[epidermal growth factor receptor]] ([[EGFR]]) exon 19 deletion or exon 21 L858R substitution [[mutations]] as detected by an FDA-approved test<br />
|indicationType=first-line treatment<br />
|hasBlackBoxWarning=<br />
|blackBoxWarningTitle=<br />
|blackBoxWarningBody=<br />
|fdaLIADAdult=<br />
Indication<br />
*Dacomitinib is indicated for the first-line treatment of patients with metastatic [[non-small cell lung cancer]] ([[NSCLC]]) with [[epidermal growth factor receptor]] ([[EGFR]]) exon 19 deletion or exon 21 L858R substitution [[mutations]] as detected by an FDA-approved test.<br />
Dosage<br />
*Recommended Dosage: 45 mg orally once daily with or without food.<br />
|offLabelAdultGuideSupport=<br />
There is limited information regarding dacomitinib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.<br />
|offLabelAdultNoGuideSupport=<br />
There is limited information regarding dacomitinib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.<br />
|fdaLIADPed=<br />
The safety and effectiveness of dacomitinib in pediatrics have not been established.<br />
|offLabelPedGuideSupport=<br />
There is limited information regarding dacomitinib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.<br />
|offLabelPedNoGuideSupport=<br />
There is limited information regarding dacomitinib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.<br />
|contraindications=<br />
None.<br />
|warnings=<br />
=====Interstitial Lung Disease ([[ILD]])=====<br />
*Severe and fatal [[ILD]]/[[pneumonitis]] occurred in patients treated with dacomitinib and occurred in 0.5% of the 394 dacomitinib-treated patients; 0.3% of cases were fatal.<br />
*Monitor patients for [[pulmonary]] symptoms indicative of [[ILD]]/[[pneumonitis]]. Withhold dacomitinib and promptly investigate for [[ILD]] in patients who present with worsening of respiratory symptoms which may be indicative of [[ILD]] (e.g., [[dyspnea]], [[cough]], and [[fever]]). Permanently discontinue dacomitinib if [[ILD]] is confirmed.<br />
=====Diarrhea=====<br />
*Severe and fatal [[diarrhea]] occurred in patients treated with dacomitinib. Diarrhea occurred in 86% of the 394 dacomitinib-treated patients; Grade 3 or 4 diarrhea was reported in 11% of patients and 0.3% of cases were fatal.<br />
*Withhold dacomitinib for Grade 2 or greater [[diarrhea]] until recovery to less than or equal to Grade 1 severity, then resume dacomitinib at the same or a reduced dose depending on the severity of diarrhea. Promptly initiate [[anti-diarrheal]] treatment ([[loperamide]] or [[diphenoxylate hydrochloride and atropine sulfate]]) for diarrhea.<br />
=====Dermatologic Adverse Reactions=====<br />
*[[Rash]] and exfoliative skin reactions occurred in patients treated with dacomitinib. Rash occurred in 78% of the 394 dacomitinib-treated patients; Grade 3 or 4 rash was reported in 21% of patients. Exfoliative skin reactions of any severity were reported in 7% of patients. Grade 3 or 4 exfoliative skin reactions were reported in 1.8% of patients.<br />
*Withhold dacomitinib for persistent Grade 2 or any Grade 3 or 4 dermatologic adverse reaction until recovery to less than or equal to Grade 1 severity, then resume dacomitinib at the same or a reduced dose depending on the severity of the dermatologic adverse reaction. The incidence and severity of [[rash]] and exfoliative skin reactions may increase with sun exposure. At the time of initiation of dacomitinib, initiate use of [[moisturizer]]s and appropriate measures to limit [[sun exposure]]. Upon development of Grade 1 rash, initiate treatment with topical [[antibiotics]] and topical [[steroids]]. Initiate oral antibiotics for Grade 2 or more severe dermatologic adverse reactions.<br />
=====Embryo-Fetal Toxicity=====<br />
*Based on findings from animal studies and its mechanism of action, dacomitinib can cause fetal harm when administered to a [[pregnant]] woman. In animal reproduction studies, oral administration of dacomitinib to pregnant rats during the period of [[organogenesis]] resulted in an increased incidence of post-implantation loss and reduced fetal body weight at doses resulting in exposures near the exposure at the 45 mg human dose. The absence of [[EGFR]] signaling has been shown to result in embryolethality as well as post-natal death in animals. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective [[contraception]] during treatment with dacomitinib and for at least 17 days after the final dose.<br />
|adverseReactions=[[diarrhea]], [[rash]], [[paronychia]], [[stomatitis]], [[decreased appetite]], [[dry skin]], [[decreased weight]], [[alopecia]], [[cough]], and [[pruritus]]<br />
|clinicalTrials=<br />
*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.<br />
*The data in the Warnings and Precautions section reflect exposure to dacomitinib in 394 patients with first-line or previously treated [[NSCLC]] with [[EGFR]] exon 19 deletion or exon 21 L858R substitution [[mutations]] who received dacomitinib at the recommended dose of 45 mg once daily in 4 randomized, active-controlled trials [ARCHER 1050 (N=227), Study A7471009 (N=38), Study A7471011 (N=83), and Study A7471028 (N=16)] and one single-arm trial [Study A7471017 (N=30)]. The median duration of exposure to dacomitinib was 10.8 months (range 0.07–68)<br />
*The data described below reflect exposure to dacomitinib in 227 patients with [[EGFR]] mutation-positive, metastatic [[NSCLC]] enrolled in a randomized, active-controlled trial (ARCHER 1050); 224 patients received [[was]] 250 mg orally once daily in the active control arm. Patients were excluded if they had a history of [[ILD]], interstitial [[pneumonitis]], or [[brain metastases]]. The median duration of exposure to dacomitinib was 15 months (range 0.07–37).<br />
*The most common (>20%) adverse reactions in patients treated with dacomitinib were [[diarrhea]] (87%), [[rash]] (69%), [[paronychia]] (64%), [[stomatitis]] (45%), [[decreased appetite]] (31%), [[dry skin]] (30%), [[decreased weight]] (26%), [[alopecia]] (23%), [[cough]] (21%), and [[pruritus]] (21%).<br />
*Serious adverse reactions occurred in 27% of patients treated with dacomitinib. The most common (≥1%) serious adverse reactions were [[diarrhea]] (2.2%) and [[interstitial lung disease]] (1.3%). Dose interruptions occurred in 57% of patients treated with dacomitinib. The most frequent (>5%) adverse reactions leading to dose interruptions were [[rash]] (23%), [[paronychia]] (13%), and [[diarrhea]] (10%). Dose reductions occurred in 66% of patients treated with dacomitinib. The most frequent (>5%) adverse reactions leading to dose reductions were [[rash]] (29%), [[paronychia]] (17%), and [[diarrhea]] (8%).<br />
*Adverse reactions leading to permanent discontinuation of dacomitinib occurred in 18% of patients. The most common (>0.5%) adverse reactions leading to permanent discontinuation of dacomitinib were: [[rash]] (2.6%), [[interstitial lung disease]] (1.8%), [[stomatitis]] (0.9%), and [[diarrhea]] (0.9%).<br />
*Tables 3 and 4 summarize the most common adverse reactions and laboratory abnormalities, respectively, in ARCHER 1050. ARCHER 1050 was not designed to demonstrate a statistically significant difference in adverse reaction rates for dacomitinib or for [[gefitinib]] for any adverse reaction or laboratory value listed in Table 3 or 4.<br />
[[File:DacomitinibTable3.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
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*Additional adverse reactions (All Grades) that were reported in <10% of patients who received dacomitinib in ARCHER 1050 include:<br />
**General: [[fatigue]] 9%<br />
**[[Skin]] and [[subcutaneous]] tissue: skin fissures 9%, [[hypertrichosis]] 1.3%, skin [[exfoliation]]/exfoliative skin reactions 3.5%<br />
**Gastrointestinal: [[vomiting]] 9%<br />
**Nervous system: [[dysgeusia]] 7%<br />
**Respiratory: [[interstitial lung disease]] 2.6%<br />
**Ocular: [[keratitis]] 1.8%<br />
**Metabolism and nutrition: [[dehydration]] 1.3%<br />
[[File:DacomitinibTable4.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
|postmarketing=<br />
|drugInteractions=<br />
=====Effect of Other Drugs on Dacomitinib=====<br />
*Concomitant use with a [[PPI]] decreases dacomitinib concentrations, which may reduce dacomitinib efficacy. Avoid the concomitant use of PPIs with dacomitinib. As an alternative to PPIs, use locally-acting [[antacids]] or an [[H2]]-receptor antagonist. Administer dacomitinib at least 6 hours before or 10 hours after taking an H2-receptor antagonist.<br />
=====Effect of Dacomitinib on CYP2D6 Substrates=====<br />
*Concomitant use of dacomitinib increases the concentration of drugs that are [[CYP2D6]] substrates which may increase the risk of toxicities of these drugs. Avoid concomitant use of dacomitinib with CYP2D6 substrates where minimal increases in concentration of the CYP2D6 substrate may lead to serious or life-threatening toxicities.<br />
|FDAPregCat=<br />
|useInPregnancyFDA=<br />
Risk Summary<br />
*Based on findings from animal studies and its mechanism of action, dacomitinib can cause fetal harm when administered to a [[pregnant]] woman. There are no available data on dacomitinib use in pregnant women. In animal reproduction studies, oral administration of dacomitinib to pregnant rats during the period of [[organogenesis]] resulted in an increased incidence of post-implantation loss and reduced fetal body weight at doses resulting in exposures near the exposure at the 45 mg human dose. The absence of [[EGFR]] signaling has been shown to result in embryolethality as well as post-natal death in animals. Advise pregnant women of the potential risk to a fetus.<br />
*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.<br />
Animal Data<br />
*Daily oral administration of dacomitinib to [[pregnant]] rats during the period of [[organogenesis]] resulted in an increased incidence of post-implantation loss, maternal toxicity, and reduced fetal body weight at 5 mg/kg/day (approximately 1.2 times the exposure based on area under the curve [AUC] at the 45 mg human dose).<br />
*Disruption or depletion of [[EGFR]] in mouse models has shown [[EGFR]] is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/post-natal survival and development. Reduction or elimination of embryo-fetal or maternal [[EGFR]] signaling in mice can prevent implantation, and can cause embryo-fetal loss during various stages of [[gestation]] (through effects on placental development), developmental anomalies, early death in surviving fetuses, and adverse developmental outcomes in multiple organs in embryos/[[neonates]].<br />
|AUSPregCat=<br />
|useInPregnancyAUS=<br />
|useInLaborDelivery=<br />
|useInNursing=<br />
Risk Summary<br />
*There is no information regarding the presence of dacomitinib or its metabolites in human milk or their effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from dacomitinib, advise women not to breastfeed during treatment with dacomitinib and for at least 17 days after the last dose.<br />
|useInPed=<br />
*The safety and effectiveness of dacomitinib in pediatrics have not been established.<br />
|useInGeri=<br />
*Of the total number of patients (N=394) in five clinical studies with [[EGFR]] mutation-positive [[NSCLC]] who received dacomitinib at a dose of 45 mg orally once daily [ARCHER 1050 (N=227), Study A7471009 (N=38), Study A7471011 (N=83), Study A7471028 (N=16), and Study A7471017 (N=30)] 40% were 65 years of age and older.<br />
*Exploratory analyses across this population suggest a higher incidence of Grade 3 and 4 adverse reactions (67% versus 56%, respectively), more frequent dose interruptions (53% versus 45%, respectively), and more frequent discontinuations (24% versus 10%, respectively) for adverse reactions in patients 65 years or older as compared to those younger than 65 years.<br />
|useInGender=<br />
|useInRace=<br />
|useInRenalImpair=<br />
*No dose adjustment is recommended for patients with mild or moderate [[renal impairment]] ([[creatinine]] clearance [CLcr] 30 to 89 mL/min estimated by Cockcroft-Gault). The recommended dose of dacomitinib has not been established for patients with severe renal impairment (CLcr <30 mL/min).<br />
|useInHepaticImpair=<br />
*No dose adjustment is recommended in patients with mild (total [[bilirubin]] ≤ upper limit of normal [ULN] with [[AST]] > ULN or total bilirubin > 1 to 1.5 × ULN with any AST) or moderate (total bilirubin > 1.5 to 3 × ULN and any AST) [[hepatic impairment]]. The recommended dose of dacomitinib has not been established for patients with severe hepatic impairment (total bilirubin > 3 to 10 × ULN and any AST).<br />
|useInReproPotential=<br />
Pregnancy Testing<br />
*Verify the [[pregnancy]] status of females of reproductive potential prior to initiating dacomitinib.<br />
Contraception<br />
*Dacomitinib can cause fetal harm when administered to a [[pregnant]] woman.<br />
''Females''<br />
*Advise females of reproductive potential to use effective [[contraception]] during treatment with dacomitinib and for at least 17 days after the final dose.<br />
|useInImmunocomp=<br />
|othersTitle=<br />
|useInOthers=<br />
|administration=<br />
=====Patient Selection=====<br />
*Select patients for the first-line treatment of metastatic [[NSCLC]] with dacomitinib based on the presence of an [[EGFR]] exon 19 deletion or exon 21 L858R substitution mutation in tumor specimens. Information on FDA-approved tests for the detection of [[EGFR]] [[mutations]] in [[NSCLC]] is available at: http://www.fda.gov/CompanionDiagnostics.<br />
=====Recommended Dosage=====<br />
*The recommended dosage of dacomitinib is 45 mg taken orally once daily, until disease progression or unacceptable toxicity occurs. Dacomitinib can be taken with or without food.<br />
*Take dacomitinib the same time each day. If the patient vomits or misses a dose, do not take an additional dose or make up a missed dose but continue with the next scheduled dose.<br />
=====Dosage Modifications for Adverse Reactions=====<br />
*Reduce the dose of dacomitinib for adverse reactions as described in Table 1. Dosage modifications for specific adverse reactions are provided in Table 2.<br />
[[File:DacomitinibTable1.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
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[[File:DacomitinibTable2.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
=====Dosage Modifications for Acid-Reducing Agents=====<br />
*Avoid the concomitant use of [[proton pump inhibitors]] (PPIs) while taking dacomitinib. As an alternative to PPIs, use locally-acting [[antacids]] or if using an [[histamine]] 2 ([[H2]])-receptor antagonist, administer dacomitinib at least 6 hours before or 10 hours after taking an H2-receptor antagonist.<br />
|monitoring=<br />
|IVCompat=<br />
|overdose=<br />
|drugBox=<br />
{{drugbox2<br />
| IUPAC_name = (2''E'')-''N''-{4-[(3-Chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl}-4-(1-piperidinyl)-2-butenamide<br />
| image = DacomitinibStructure.png<br />
| alt = <br />
| caption =<br />
<!-- Clinical data --><br />
| pronounce =<br />
| tradename = Vizimpro<br />
| Drugs.com = {{drugs.com|parent|vizimpro}}<br />
| MedlinePlus = <br />
| pregnancy_AU = <!-- A/B1/B2/B3/C/D/X --><br />
| pregnancy_AU_comment = <br />
| pregnancy_US = <!-- A/B/C/D/X/N --><br />
| pregnancy_category= <br />
| routes_of_administration = <br />
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--><br />
| legal_AU_comment =<br />
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F--><br />
| legal_BR_comment =<br />
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII --><br />
| legal_DE = <!-- Anlage I, II, III --><br />
| legal_NZ = <!-- Class A, B, C --><br />
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C --><br />
| legal_US = Rx-only<br />
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV--><br />
| legal_status = <!-- Free text --><br />
<!-- Pharmacokinetic data --><br />
| bioavailability = 80%<br />
| protein_bound = 98%<br />
| metabolism = [[CYP2D6]], [[CYP3A4]]<br />
| metabolites = O-desmethyl-dacomitinib<br />
| onset = <br />
| elimination_half-life = 70 hrs<br />
| duration_of_action =<br />
| excretion = 79% faeces, 3% urine<br />
<!-- Identifiers --><br />
| CAS_number_Ref = {{cascite|correct|CAS}}<br />
| CAS_number = 1110813-31-4<br />
| class = <br />
| ATCvet = <br />
| ATC_prefix = L01<br />
| ATC_suffix = XE47<br />
| PubChem = 11511120<br />
| DrugBank = DB11963<br />
| ChemSpiderID = 9685914<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = 2XJX250C20<br />
| KEGG = D09883<br />
| ChEBI = 132268<br />
| ChEMBL = 2105719<br />
| IUPHAR_ligand = 7422<br />
| synonyms = PF-00299804<br />
<!-- Chemical and physical data --><br />
| chemical_formula = <br />
| C=24 | H=25 | Cl=1 | F=1 | N=5 | O=2<br />
| molecular_weight = <br />
| smiles = COC1=C(C=C2C(=C1)N=CN=C2NC3=CC(=C(C=C3)F)Cl)NC(=O)/C=C/CN4CCCCC4<br />
| StdInChI = 1S/C24H25ClFN5O2/c1-33-22-14-20-17(24(28-15-27-20)29-16-7-8-19(26)18(25)12-16)13-21(22)30-23(32)6-5-11-31-9-3-2-4-10-31/h5-8,12-15H,2-4,9-11H2,1H3,(H,30,32)(H,27,28,29)/b6-5+<br />
| StdInChIKey = LVXJQMNHJWSHET-AATRIKPKSA-N<br />
}}<br />
|mechAction=<br />
*Dacomitinib is an irreversible inhibitor of the [[kinase]] activity of the human [[EGFR]] family ([[EGFR]]/HER1, [[HER2]], and HER4) and certain [[EGFR]] activating [[mutations]] (exon 19 deletion or the exon 21 L858R substitution mutation). In vitro dacomitinib also inhibited the activity of [[DDR1]], [[EPHA6]], LCK, DDR2, and MNK1 at clinically relevant concentrations.<br />
*Dacomitinib demonstrated dose-dependent inhibition of [[EGFR]] and HER2 autophosphorylation and tumor growth in mice bearing subcutaneously implanted human tumor xenografts driven by HER family targets including mutated [[EGFR]]. Dacomitinib also exhibited antitumor activity in orally-dosed mice bearing intracranial human tumor xenografts driven by [[EGFR]] amplifications.<br />
|structure=<br />
*Dacomitinib is an oral [[kinase inhibitor]] with a molecular formula of C<sub>24</sub>H<sub>25</sub>ClFN<sub>5</sub>O<sub>2</sub> ∙ H<sub>2</sub>O and a molecular weight of 487.95 Daltons.<br />
[[File:DacomitinibStructure.jpeg|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
|PD=<br />
Cardiac Electrophysiology<br />
*The effect of dacomitinib on the [[QT interval]] corrected for [[heart rate]] (QTc) was evaluated using time-matched [[electrocardiograms]] (ECGs) evaluating the change from baseline and corresponding pharmacokinetic data in 32 patients with advanced [[NSCLC]]. Dacomitinib had no large effect on QTc (i.e., >20 ms) at maximum dacomitinib concentrations achieved with dacomitinib 45 mg orally once daily.<br />
Exposure-Response Relationships<br />
*Higher exposures, across the range of exposures with the recommended dose of 45 mg daily, correlated with an increased probability of Grade ≥3 adverse events, specifically dermatologic toxicities and [[diarrhea]].<br />
|PK=<br />
*The maximum dacomitinib plasma concentration (C<sub>max</sub>) and AUC at steady state increased proportionally over the dose range of dacomitinib 2 mg to 60 mg orally once daily (0.04 to 1.3 times the recommended dose) across dacomitinib studies in patients with cancer. At a dose of 45 mg orally once daily, the geometric mean [coefficient of variation (CV%)] C<sub>max</sub> was 108 ng/mL (35%) and the AUC<sub>0–24h</sub> was 2213 ng∙h/mL (35%) at steady state in a dose-finding clinical study conducted in patients with solid tumors. Steady state was achieved within 14 days following repeated dosing and the estimated geometric mean (CV%) accumulation ratio was 5.7 (28%) based on AUC.<br />
Absorption<br />
*The mean absolute bioavailability of dacomitinib is 80% after oral administration. The median dacomitinib time to reach maximum concentration (T<sub>max</sub>) occurred at approximately 6.0 hours (range 2.0 to 24 hours) after a single oral dose of dacomitinib 45 mg in patients with [[cancer]].<br />
''Effect of Food''<br />
*Administration of dacomitinib with a high-fat, high-calorie meal (approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories from [[protein]], [[carbohydrate]] and [[fat]], respectively) had no clinically meaningful effect on dacomitinib pharmacokinetics.<br />
Distribution<br />
*The geometric mean (CV%) volume of distribution of dacomitinib (V<sub>ss</sub>) was 1889 L (18%). In vitro binding of dacomitinib to human plasma proteins is approximately 98% and is independent of drug concentrations from 250 ng/mL to 1000 ng/mL.<br />
Elimination<br />
*Following a single 45 mg oral dose of dacomitinib in patients with cancer, the mean (CV%) plasma half-life of dacomitinib was 70 hours (21%), and the geometric mean (CV%) apparent plasma clearance of dacomitinib was 24.9 L/h (36%).<br />
''Metabolism''<br />
*[[Hepatic]] metabolism is the main route of clearance of dacomitinib, with [[oxidation]] and [[glutathione]] conjugation as the major pathways. Following oral administration of a single 45 mg dose of [<sup>14</sup>C] dacomitinib, the most abundant circulating metabolite was O-desmethyl dacomitinib, which had similar in vitro pharmacologic activity as dacomitinib. The steady-state plasma trough concentration of O-desmethyl dacomitinib ranges from 7.4% to 19% of the parent. In vitro studies indicated that [[cytochrome P450]] (CYP) 2D6 was the major [[isozyme]] involved in the formation of O-desmethyl dacomitinib, while [[CYP3A4]] contributed to the formation of other minor oxidative metabolites.<br />
''Excretion''<br />
*Following a single oral 45 mg dose of [<sup>14</sup>C] radiolabeled dacomitinib, 79% of the radioactivity was recovered in feces (20% as dacomitinib) and 3% in urine (<1% as dacomitinib).<br />
Specific Populations <br><br />
''Patients with Renal Impairment''<br />
*Based on population pharmacokinetic analyses, mild (60 mL/min ≤ CLcr <90 mL/min; N=590) and moderate (30 mL/min ≤ CLcr <60 mL/min; N=218) [[renal impairment]] did not alter dacomitinib pharmacokinetics, relative to the pharmacokinetics in patients with normal [[renal function]] (CLcr ≥90 mL/min; N=567). The pharmacokinetics of dacomitinib has not been adequately characterized in patients with severe renal impairment (CLcr <30 mL/min) (N=4) or studied in patients requiring [[hemodialysis]].<br />
''Patients with Hepatic Impairment''<br />
*In a dedicated [[hepatic impairment]] trial, following a single oral dose of 30 mg dacomitinib, dacomitinib exposure (AUC<sub>inf</sub> and C<sub>max</sub>) was unchanged in subjects with mild hepatic impairment (Child-Pugh A; N=8) and decreased by 15% and 20%, respectively in subjects with moderate hepatic impairment (Child-Pugh B; N=9) when compared to subjects with normal hepatic function (N=8). Based on this trial, mild and moderate hepatic impairment had no clinically important effects on pharmacokinetics of dacomitinib. In addition, based on a population pharmacokinetic analysis of 1381 patients, in which 158 patients had mild hepatic impairment (total [[bilirubin]] ≤ ULN and [[AST]] > ULN, or total bilirubin > 1 to 1.5 × ULN with any AST) and 5 patients had moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN and any AST), no effects on pharmacokinetics of dacomitinib were observed. The effect of severe hepatic impairment (total bilirubin > 3 to 10 × ULN and any AST) on dacomitinib pharmacokinetics is unknown.<br />
Drug Interaction Studies <br><br />
''Clinical Studies'' <br><br />
''Effect of Acid-Reducing Agents on Dacomitinib''<br />
*Coadministration of a single 45 mg dose of dacomitinib with multiple doses of [[rabeprazole]] (a [[proton pump inhibitor]]) decreased dacomitinib C<sub>max</sub> by 51% and AUC<sub>0–96h</sub> by 39%.<br />
*Coadministration of dacomitinib with a local [[antacid]] ([[Maalox]]® Maximum Strength, 400 mg/5 mL) did not cause clinically relevant changes dacomitinib concentrations.<br />
*The effect of [[H2]] receptor antagonists on dacomitinib pharmacokinetics has not been studied.<br />
''Effect of Strong CYP2D6 Inhibitors on Dacomitinib''<br />
*Coadministration of a single 45 mg dose of dacomitinib with multiple doses of paroxetine (a strong [[CYP2D6]] inhibitor) in healthy subjects increased the total AUC<sub>last</sub> of dacomitinib plus its active metabolite (O-desmethyl dacomitinib) in plasma by approximately 6%, which is not considered clinically relevant.<br />
''Effect of Dacomitinib on CYP2D6 Substrates''<br />
*Coadministration of a single 45 mg oral dose of dacomitinib increased [[dextromethorphan]] (a [[CYP2D6]] substrate) C<sub>max</sub> by 9.7-fold and AUC<sub>last</sub> by 9.6-fold.<br />
In Vitro Studies<br />
*Effect of Dacomitinib and O-desmethyl Dacomitinib on CYP Enzymes: Dacomitinib and its metabolite O-desmethyl dacomitinib do not inhibit [[CYP1A2]], [[CYP2B6]], [[CYP2C8]], [[CYP2C9]], [[CYP2C19]], or [[CYP3A4]]/5. Dacomitinib does not induce [[CYP1A2]], [[CYP2B6]], or [[CYP3A4]].<br />
*Effect of Dacomitinib on Uridine 5' diphospho-glucuronosyltransferase (UGT) Enzymes: Dacomitinib inhibits [[UGT1A1]]. Dacomitinib does not inhibit [[UGT1A4]], [[UGT1A6]], [[UGT1A9]], [[UGT2B7]], or [[UGT2B15]].<br />
*Effect of Dacomitinib on Transporter Systems: Dacomitinib is a substrate for the membrane transport protein [[P-glycoprotein]] (P-gp) and Breast Cancer Resistance Protein (BCRP). Dacomitinib inhibits P-gp, BCRP, and organic cation transporter (OCT)1. Dacomitinib does not inhibit organic anion transporters (OAT)1 and OAT3, OCT2, organic anion transporting polypeptide (OATP)1B1, and OATP1B3.<br />
|nonClinToxic=<br />
=====Carcinogenesis, Mutagenesis, Impairment of Fertility=====<br />
*[[Carcinogenicity]] studies have not been performed with dacomitinib.<br />
*Dacomitinib was not [[mutagenic]] in a bacterial reverse mutation (Ames) assay or [[clastogenic]] in an in vitro human [[lymphocyte]] chromosome aberration assay or clastogenic or aneugenic in an in vivo rat bone marrow micronucleus assay.<br />
*Daily oral administration of dacomitinib at doses ≥ 0.5 mg/kg/day to female rats (approximately 0.14 times the exposure based on AUC at the 45 mg human dose) resulted in reversible epithelial [[atrophy]] in the cervix and vagina. Oral administration of dacomitinib at 2 mg/kg/day to male rats (approximately 0.6 times the human exposure based on AUC at the 45 mg clinical dose) resulted in reversible decreased secretion in the [[prostate gland]].<br />
|clinicalStudies=<br />
*The efficacy of dacomitinib was demonstrated in a randomized, multicenter, multinational, open-label study (ARCHER 1050; [NCT01774721]). Patients were required to have unresectable, metastatic [[NSCLC]] with no prior therapy for metastatic disease or recurrent disease with a minimum of 12 months disease-free after completion of systemic therapy; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; [[EGFR]] exon 19 deletion or exon 21 L858R substitution [[mutations]]. [[EGFR]] mutation status was prospectively determined by local laboratory or commercially available tests (e.g., therascreen® [[EGFR]] RGQ [[PCR]] and cobas® [[EGFR]] Mutation Test).<br />
*Patients were randomized (1:1) to receive dacomitinib 45 mg orally once daily or [[gefitinib]] 250 mg orally once daily until disease progression or unacceptable toxicity. Randomization was stratified by region (Japanese versus mainland Chinese versus other East Asian versus non-East Asian), and [[EGFR]] mutation status (exon 19 deletions versus exon 21 L858R substitution mutation). The major efficacy outcome measure was progression-free survival (PFS) as determined by blinded Independent Radiologic Central (IRC) review per RECIST v1.1. Additional efficacy outcome measures were overall response rate (ORR), duration of response (DoR), and overall survival (OS).<br />
*A total of 452 patients were randomized to receive dacomitinib (N=227) or [[gefitinib]] (N=225). The demographic characteristics were 60% female; median age 62 years (range: 28 to 87), with 40% aged 65 years and older; and 23% White, 77% Asian, and less than 1% Black. Prognostic and tumor characteristics were ECOG performance status 0 (30%) or 1 (70%); 59% with exon 19 deletion and 41% with exon 21 L858R substitution; Stage IIIB (8%) and Stage IV (92%); 64% were never smokers; and 1% received prior adjuvant or neoadjuvant therapy.<br />
*ARCHER 1050 demonstrated a statistically significant improvement in PFS as determined by the IRC. Results are summarized in Table 5 and Figures 1 and 2.<br />
*The hierarchical statistical testing order was PFS followed by ORR and then OS. No formal testing of OS was conducted since the formal comparison of ORR was not statistically significant.<br />
[[File:DacomitinibTable5.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
[[File:DacomitinibFigure1.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
[[File:DacomitinibFigure2.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
|howSupplied=<br />
*Dacomitinib is supplied in strengths and package configurations as described in Table 6 below:<br />
[[File:DacomitinibTable6.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
|NDC=<br />
|storage=<br />
*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).<br />
|manBy= <br />
|distBy=<br />
|drugImages=<br />
|packLabel=<br />
[[File:DacomitinibLabel1.jpeg|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
[[File:DacomitinibLabel2.jpeg|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
[[File:DacomitinibLabel3.jpeg|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
|fdaPatientInfo=<br />
Interstitial Lung Disease ([[ILD]])<br />
*Advise patients of the risks of severe or fatal [[ILD]], including [[pneumonitis]]. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms.<br />
Diarrhea<br />
*Advise patients to contact their healthcare provider at the first signs of [[diarrhea]]. Advise patients that [[intravenous]] hydration and/or [[anti-diarrheal]] medication (e.g., [[loperamide]]) may be required to manage diarrhea.<br />
Dermatologic Adverse Reactions<br />
*Advise patients to initiate use of [[moisturizer]]s and to minimize sun exposure with protective clothing and use of sunscreen at the time of initiation of dacomitinib. Advise patients to contact their healthcare provider immediately to report new or worsening [[rash]], [[erythematous]] and exfoliative reactions.<br />
Drug Interactions<br />
*Advise patients to avoid use of PPIs while taking dacomitinib. Short-acting [[antacids]] or [[H2]] receptor antagonists may be used if needed. Advise patients to take dacomitinib at least 6 hours before or 10 hours after taking an H2-receptor antagonist.<br />
Embryo-Fetal Toxicity<br />
*Advise females of reproductive potential that dacomitinib can result in fetal harm and to use effective [[contraception]] during treatment with dacomitinib and for 17 days after the last dose of dacomitinib. Advise females of reproductive potential to contact their healthcare provider with a known or suspected [[pregnancy]].<br />
Lactation<br />
*Advise women not to breastfeed during treatment with dacomitinib and for 17 days after the last dose of dacomitinib.<br />
=====Patient Package Insert=====<br />
[[File:DacomitinibMedGuide.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
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|nlmPatientInfo=<br />
|alcohol=<br />
|brandNames=[[Vizimpro]]<br />
|lookAlike=<br />
|drugShortage=<br />
|price=<br />
}}</div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:DacomitinibLabel3.jpeg&diff=1577967File:DacomitinibLabel3.jpeg2019-08-01T15:25:08Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:DacomitinibStructure.jpeg&diff=1577963File:DacomitinibStructure.jpeg2019-08-01T15:23:06Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:DacomitinibTable6.png&diff=1577950File:DacomitinibTable6.png2019-08-01T15:15:01Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:DacomitinibTable3.png&diff=1577944File:DacomitinibTable3.png2019-08-01T15:12:12Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:DacomitinibTable2.png&diff=1577943File:DacomitinibTable2.png2019-08-01T15:11:26Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:DacomitinibTable1.png&diff=1577942File:DacomitinibTable1.png2019-08-01T15:10:44Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=Emgality&diff=1577719Emgality2019-07-31T18:20:17Z<p>Zach Leibowitz: ←Redirected page to Galcanezumab-gnlm</p>
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<div>#redirect[[Galcanezumab-gnlm]]</div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=Galcanezumab-gnlm&diff=1577718Galcanezumab-gnlm2019-07-31T18:19:18Z<p>Zach Leibowitz: Created page with "{{DrugProjectFormSinglePage |authorTag={{ZL}} |genericName=galcanezumab-gnlm |aOrAn=a |drugClass=calcitonin-gene related peptide antagonist |indication=of migraine..."</p>
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<div>{{DrugProjectFormSinglePage<br />
|authorTag={{ZL}}<br />
|genericName=galcanezumab-gnlm<br />
|aOrAn=a<br />
|drugClass=[[calcitonin]]-gene related [[peptide]] antagonist<br />
|indication=of [[migraine]] and the treatment of episodic [[cluster headache]]<br />
|indicationType=preventive treatment<br />
|hasBlackBoxWarning=<br />
|blackBoxWarningTitle=<br />
|blackBoxWarningBody=<br />
|fdaLIADAdult=<br />
=====Indication=====<br />
Migraine<br />
*Galcanezumab-gnlm is indicated for the preventive treatment of [[migraine]] in adults.<br />
Episodic Cluster Headache<br />
*Galcanezumab-gnlm is indicated for the treatment of episodic [[cluster headache]] in adults.<br />
=====Dosage=====<br />
Recommended Dosing for [[Migraine]]<br />
*240 mg loading dose (administered as two consecutive injections of 120 mg each), followed by monthly doses of 120 mg.<br />
Recommended Dosing for Episodic [[Cluster Headache]]<br />
*300 mg (administered as three consecutive injections of 100 mg each) at the onset of the cluster period, and then monthly until the end of the cluster period.<br />
|offLabelAdultGuideSupport=<br />
There is limited information regarding galcanezumab-gnlm Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.<br />
|offLabelAdultNoGuideSupport=<br />
There is limited information regarding galcanezumab-gnlm Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.<br />
|fdaLIADPed=<br />
Safety and effectiveness in pediatric patients have not been established.<br />
|offLabelPedGuideSupport=<br />
There is limited information regarding galcanezumab-gnlm Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.<br />
|offLabelPedNoGuideSupport=<br />
There is limited information regarding galcanezumab-gnlm Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.<br />
|contraindications=<br />
*Galcanezumab-gnlm is contraindicated in patients with serious [[hypersensitivity]] to galcanezumab-gnlm or to any of the excipients.<br />
|warnings=<br />
=====Hypersensitivity Reactions=====<br />
*[[Hypersensitivity reactions]], including [[anaphylaxis]], [[angioedema]], [[dyspnea]], [[urticaria]], and [[rash]], have been reported with galcanezumab-gnlm. If a serious or severe [[hypersensitivity reaction]] occurs, discontinue administration of galcanezumab-gnlm and initiate appropriate therapy. Hypersensitivity reactions can occur days after administration and may be prolonged.<br />
|adverseReactions=[[injection site reactions]]<br />
|clinicalTrials=<br />
*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 clinical trials of another drug and may not reflect the rates observed in clinical practice.<br />
Migraine<br />
*The safety of galcanezumab-gnlm has been evaluated in 2586 patients with [[migraine]] who received at least one dose of galcanezumab-gnlm, representing 1487 patient-years of exposure. Of these, 1920 patients were exposed to galcanezumab-gnlm once monthly for at least 6 months, and 526 patients were exposed for 12 months.<br />
*In placebo-controlled clinical studies (Studies 1, 2, and 3), 705 patients received at least one dose of galcanezumab-gnlm 120 mg once monthly, and 1451 patients received placebo, during 3 months or 6 months of double-blind treatment. Of the galcanezumab-gnlm-treated patients, approximately 85% were female, 77% were white, and the mean age was 41 years at study entry.<br />
*The most common adverse reaction was [[injection site reactions]]. In Studies 1, 2, and 3, 1.8% of patients discontinued double-blind treatment because of adverse events. TABLE 1 summarizes the adverse reactions that occurred within up to 6 months of treatment in the [[migraine]] studies.<br />
[[File:GalcanezumabTable1.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
Episodic Cluster Headache<br />
*Galcanezumab-gnlm was studied for up to 2 months in a placebo-controlled trial in patients with episodic [[cluster headache]] (Study 4). A total of 106 patients were studied (49 on galcanezumab-gnlm and 57 on placebo). Of the galcanezumab-gnlm-treated patients, approximately 84% were male, 88% were white, and the mean age was 47 years at study entry. Two galcanezumab-gnlm-treated patients discontinued double-blind treatment because of adverse events.<br />
*Overall, the safety profile observed in patients with episodic [[cluster headache]] treated with galcanezumab-gnlm 300 mg monthly is consistent with the safety profile in [[migraine]] patients.<br />
===Immunogenicity===<br />
*As with all therapeutic proteins, there is potential for [[immunogenicity]]. The detection of [[antibody]] formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.<br />
*For these reasons, comparison of the incidence of [[antibodies]] to galcanezumab-gnlm in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.<br />
*The [[immunogenicity]] of galcanezumab-gnlm has been evaluated using an in vitro [[immunoassay]] for the detection of binding anti-galcanezumab-gnlm [[antibodies]]. For patients whose sera tested positive in the screening immunoassay, an in vitro [[ligand]]-binding immunoassay was performed to detect neutralizing antibodies.<br />
*In controlled studies with galcanezumab-gnlm up to 6 months (Study 1, Study 2, and Study 3), the incidence of anti-galcanezumab-gnlm [[antibody]] development was 4.8% (33/688) in patients receiving galcanezumab-gnlm once monthly (32 out of 33 of whom had in vitro neutralizing activity). With 12 months of treatment in an open-label study, up to 12.5% (16/128) of galcanezumab-gnlm-treated patients developed anti-galcanezumab-gnlm antibodies, most of whom tested positive for neutralizing antibodies.<br />
*Although anti-galcanezumab-gnlm antibody development was not found to affect the pharmacokinetics, safety or efficacy of galcanezumab-gnlm in these patients, the available data are too limited to make definitive conclusions.<br />
|postmarketing=<br />
*The following adverse reactions have been identified during post-approval use of galcanezumab-gnlm. 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 galcanezumab-gnlm exposure.<br />
**Immune System Disorders — [[Anaphylaxis]], [[angioedema]].<br />
**Skin and [[Subcutaneous]] Tissue Disorders — [[Rash]].<br />
|drugInteractions=<br />
|FDAPregCat=<br />
|useInPregnancyFDA=<br />
Risk Summary<br />
*There are no adequate data on the developmental risk associated with the use of galcanezumab-gnlm in [[pregnant]] women. Administration of galcanezumab-gnlm to rats and rabbits during the period of organogenesis or to rats throughout pregnancy and lactation at plasma exposures greater than that expected clinically did not result in adverse effects on development (see Animal Data).<br />
*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. The estimated rate of major birth defects (2.2% - 2.9%) and miscarriage (17%) among deliveries to women with [[migraine]] are similar to rates reported in women without [[migraine]].<br />
Clinical Considerations <br><br />
''Disease-Associated Maternal and/or Embryo/Fetal Risk''<br />
*Published data have suggested that women with [[migraine]] may be at increased risk of [[preeclampsia]] during [[pregnancy]].<br />
Animal Data<br />
*When galcanezumab-gnlm was administered to female rats by [[subcutaneous injection]] in two studies (0, 30, or 100 mg/kg; 0 or 250 mg/kg) prior to and during mating and continuing throughout [[organogenesis]], no adverse effects on embryofetal development were observed. The highest dose tested (250 mg/kg) was associated with a plasma exposure (C<sub>ave, ss</sub>) 38 or 18 times that in humans at the recommended human dose (RHD) for [[migraine]] (120 mg) or episodic [[cluster headache]] (300 mg), respectively. Administration of galcanezumab-gnlm (0, 30, or 100 mg/kg) by [[subcutaneous injection]] to pregnant rabbits throughout the period of [[organogenesis]] produced no adverse effects on embryofetal development. The higher dose tested was associated with a plasma C<sub>ave, ss</sub> 64 or 29 times that in humans at 120 mg or 300 mg, respectively.<br />
*Administration of galcanezumab-gnlm (0, 30, or 250 mg/kg) by [[subcutaneous injection]] to rats throughout [[pregnancy]] and [[lactation]] produced no adverse effects on pre- and postnatal development. The higher dose tested was associated with a plasma C<sub>ave, ss</sub> 34 or 16 times that in humans at 120 mg or 300 mg, respectively.<br />
|AUSPregCat=<br />
|useInPregnancyAUS=<br />
|useInLaborDelivery=<br />
|useInNursing=<br />
Risk Summary<br />
*There are no data on the presence of galcanezumab-gnlm in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of [[breastfeeding]] should be considered along with the mother's clinical need for galcanezumab-gnlm and any potential adverse effects on the breastfed infant from galcanezumab-gnlm or from the underlying maternal condition.<br />
|useInPed=<br />
*Safety and effectiveness in pediatric patients have not been established.<br />
|useInGeri=<br />
*Clinical studies of galcanezumab-gnlm did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.<br />
|useInGender=<br />
|useInRace=<br />
|useInRenalImpair=<br />
|useInHepaticImpair=<br />
|useInReproPotential=<br />
|useInImmunocomp=<br />
|othersTitle=<br />
|useInOthers=<br />
|administration=<br />
=====Recommended Dosing for Migraine=====<br />
*The recommended dosage of galcanezumab-gnlm is 240 mg (two consecutive [[subcutaneous injection]]s of 120 mg each) once as a [[loading dose]], followed by monthly doses of 120 mg injected subcutaneously.<br />
*If a dose of galcanezumab-gnlm is missed, administer as soon as possible. Thereafter, galcanezumab-gnlm can be scheduled monthly from the date of the last dose.<br />
=====Recommended Dosing for Episodic Cluster Headache=====<br />
*The recommended dosage of galcanezumab-gnlm is 300 mg (three consecutive [[subcutaneous injection]]s of 100 mg each) at the onset of the cluster period, and then monthly until the end of the cluster period.<br />
*If a dose of galcanezumab-gnlm is missed during a cluster period, administer as soon as possible. Thereafter, galcanezumab-gnlm can be scheduled monthly from the date of the last dose until the end of the cluster period.<br />
=====Important Administration Instructions=====<br />
*Galcanezumab-gnlm is for [[subcutaneous]] use only.<br />
*Galcanezumab-gnlm is intended for patient self-administration. Prior to use, provide proper training to patients and/or caregivers on how to prepare and administer galcanezumab-gnlm using the single-dose prefilled pen or single-dose prefilled syringe, including [[aseptic technique]]:<br />
**Protect galcanezumab-gnlm from direct sunlight.<br />
**Prior to [[subcutaneous]] administration, allow galcanezumab-gnlm to sit at room temperature for 30 minutes. Do not warm by using a heat source such as hot water or a microwave.<br />
**Do not shake the product.<br />
**Inspect galcanezumab-gnlm visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use galcanezumab-gnlm if it is cloudy or there are visible particles.<br />
**Administer galcanezumab-gnlm in the abdomen, thigh, back of the upper arm, or buttocks subcutaneously. Do not inject into areas where the skin is tender, bruised, red, or hard.<br />
**Both the prefilled pen and prefilled syringe are single-dose and deliver the entire contents.<br />
|monitoring=<br />
|IVCompat=<br />
|overdose=<br />
|drugBox=<br />
{{drugbox2<br />
| type = mab<br />
| image = <br />
| alt = <br />
| mab_type = mab<br />
| source = zu<br />
| target = [[CALCA]], [[CALCB]]<br />
| tradename = Emgality<br />
| synonyms = LY2951742<br />
| Drugs.com = <br />
| MedlinePlus = <br />
| pregnancy_AU = <br />
| pregnancy_US = <br />
| pregnancy_category= <br />
| legal_AU = <br />
| legal_CA = <br />
| legal_UK = <br />
| legal_US = <br />
| legal_status = <br />
| routes_of_administration = <br />
| bioavailability = <br />
| protein_bound = <br />
| metabolism = <br />
| elimination_half-life = <br />
| excretion = <br />
| CAS_number = 1578199-75-3<br />
| ATC_prefix = N02<br />
| ATC_suffix = CX08<br />
| PubChem = <br />
| ChemSpiderID = none<br />
| DrugBank = DB14042<br />
| C = 6392 | H = 9854 | N = 1686 | O = 2018 | S = 46<br />
| molecular_weight = 144.1 kDa<br />
| UNII = 55KHL3P693<br />
| KEGG = D10936<br />
}}<br />
|mechAction=<br />
*Galcanezumab-gnlm is a humanized [[monoclonal antibody]] that binds to [[calcitonin]] gene-related [[peptide]] ([[CGRP]]) [[ligand]] and blocks its binding to the receptor.<br />
|structure=<br />
|PD=<br />
*There are no relevant data on the pharmacodynamic effects of galcanezumab-gnlm.<br />
|PK=<br />
*Galcanezumab-gnlm exhibits linear pharmacokinetics and exposure increases proportionally with doses between 1 and 600 mg.<br />
*A [[loading dose]] of 240 mg achieved the serum galcanezumab-gnlm steady-state concentration after the first dose. A dose of 300 mg monthly would achieve steady-state concentration after the fourth dose. The time to maximum concentration is 5 days, and the elimination half-life is 27 days.<br />
*There was no difference in pharmacokinetic parameters between healthy volunteers, patients with episodic or chronic [[migraine]], and patients with episodic [[cluster headache]].<br />
Absorption<br />
*Following a [[subcutaneous]] dose of galcanezumab-gnlm, the time to maximum concentration was about 5 days.<br />
*Injection site location did not significantly influence the absorption of galcanezumab-gnlm.<br />
Distribution<br />
*The apparent volume of distribution (V/F) of galcanezumab-gnlm was 7.3 L (34% Inter Individual Variability [IIV]).<br />
Metabolism and Elimination<br />
*Galcanezumab-gnlm is expected to be degraded into small [[peptide]]s and [[amino acids]] via catabolic pathways in the same manner as endogenous [[IgG]].<br />
*The apparent clearance (CL/F) of galcanezumab-gnlm was 0.008 L/h and the elimination half-life of galcanezumab was approximately 27 days.<br />
Specific Populations <br><br />
''Age, Sex, Weight, Race, Ethnicity''<br />
*The pharmacokinetics of galcanezumab-gnlm were not affected by age, sex, race, subtypes of [[migraine]] spectrum (episodic or chronic [[migraine]]), or [[headache]] diagnosis ([[migraine]] vs. episodic [[cluster headache]]) based on a population pharmacokinetics analysis. Body weight has no clinically relevant effect on the pharmacokinetics of galcanezumab-gnlm.<br />
''Patients with Renal or Hepatic Impairment''<br />
*[[Renal]] and [[hepatic impairment]] are not expected to affect the pharmacokinetics of galcanezumab-gnlm. Population pharmacokinetic analysis of integrated data from the galcanezumab-gnlm clinical studies revealed that [[creatinine]] clearance did not affect the pharmacokinetics of galcanezumab-gnlm in patients with mild or moderate [[renal impairment]]. Patients with severe renal impairment (creatinine clearance <30 mL/min) have not been studied. Based on a population PK analysis, [[bilirubin]] concentration did not significantly influence the CL/F of galcanezumab-gnlm.<br />
*No dedicated clinical studies were conducted to evaluate the effect of [[hepatic impairment]] or [[renal impairment]] on the pharmacokinetics of galcanezumab-gnlm.<br />
Drug Interaction Studies<br />
''P450 Enzymes''<br />
*Galcanezumab-gnlm is not metabolized by [[cytochrome P450]] enzymes; therefore, interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.<br />
|nonClinToxic=<br />
=====Carcinogenesis, Mutagenesis, Impairment of Fertility=====<br />
Carcinogenesis<br />
*The carcinogenic potential of galcanezumab-gnlm has not been assessed.<br />
Mutagenesis<br />
*Genetic toxicology studies of galcanezumab-gnlm have not been conducted.<br />
Impairment of Fertility<br />
*When galcanezumab-gnlm (0, 30, or 250 mg/kg) was administered to male rats by [[subcutaneous injection]] prior to and during mating, no adverse effects on [[fertility]] was observed. The higher dose tested was associated with a plasma exposure (C<sub>ave, ss</sub>) 8 or 4 times that in humans at the recommended human dose (RHD) for [[migraine]] (120 mg) or episodic [[cluster headache]] (300 mg), respectively. When galcanezumab-gnlm was administered to female rats by subcutaneous injection in two studies (0, 30, or 100 mg/kg; 0 or 250 mg/kg) prior to and during mating and continuing throughout [[organogenesis]], no adverse effects on fertility were observed. The highest dose tested (250 mg/kg) was associated with a plasma Cave, ss 38 or 18 times that in humans at 120 mg or 300 mg, respectively.<br />
|clinicalStudies=<br />
=====Migraine=====<br />
*The efficacy of galcanezumab-gnlm was evaluated as a preventive treatment of episodic or chronic [[migraine]] in three multicenter, randomized, double-blind, placebo-controlled studies: two 6-month studies in patients with episodic [[migraine]] (Studies 1 and 2) and one 3-month study in patients with chronic [[migraine]] (Study 3).<br />
Episodic Migraine<br />
*Study 1 (NCT02614183) and Study 2 (NCT02614196) included adults with a history of episodic [[migraine]] (4 to 14 [[migraine]] days per month). All patients were randomized in a 1:1:2 ratio to receive once-monthly [[subcutaneous injection]]s of galcanezumab-gnlm 120 mg, galcanezumab-gnlm 240 mg, or placebo. All patients in the 120 mg galcanezumab-gnlm group received an initial 240 mg loading dose. Patients were allowed to use acute [[headache]] treatments, including [[migraine]]-specific medications (i.e., [[triptans]], [[ergotamine]] derivatives), [[NSAID]]s, and [[acetaminophen]] during the study.<br />
*The studies excluded patients on any other [[migraine]] preventive treatment, patients with medication overuse [[headache]], patients with [[ECG]] abnormalities compatible with an acute cardiovascular event and patients with a history of [[stroke]], [[myocardial infarction]], [[unstable angina]], [[percutaneous coronary intervention]], [[coronary artery bypass grafting]], [[deep vein thrombosis]], or [[pulmonary embolism]] within 6 months of screening.<br />
*The primary efficacy endpoint for Studies 1 and 2 was the mean change from baseline in the number of monthly [[migraine]] [[headache]] days over the 6-month treatment period. Key secondary endpoints included response rates (the mean percentages of patients reaching at least 50%, 75%, and 100% reduction from baseline in the number of monthly [[migraine]] headache days over the 6-month treatment period), the mean change from baseline in the number of monthly [[migraine]] headache days with use of any acute headache medication during the 6-month treatment period, and the impact of [[migraine]] on daily activities, as assessed by the mean change from baseline in the average Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) Role Function-Restrictive domain score during the last 3 months of treatment (Months 4 to 6). Scores are scaled from 0 to 100, with higher scores indicating less impact of [[migraine]] on daily activities.<br />
*In Study 1, a total of 858 patients (718 females, 140 males) ranging in age from 18 to 65 years, were randomized. A total of 703 patients completed the 6-month double-blind phase. In Study 2, a total of 915 patients (781 female, 134 male) ranging in age from 18 to 65 years, were randomized. A total of 785 patients completed the 6-month double-blind phase. In Study 1 and Study 2, the mean [[migraine]] frequency at baseline was approximately 9 [[migraine]] days per month, and was similar across treatment groups.<br />
*Galcanezumab-gnlm 120 mg demonstrated statistically significant improvements for efficacy endpoints compared to placebo over the 6-month period, as summarized in TABLE 2. Galcanezumab-gnlm treatment with the 240 mg once-monthly dose showed no additional benefit over the galcanezumab-gnlm 120 mg once-monthly dose.<br />
[[File:GalcanezumabTable2.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
[[File:GalcanezumabFigure1.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
[[File:GalcanezumabFigure2.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
*FIGURE 3 shows the distribution of change from baseline in the mean number of monthly [[migraine]] headache days in bins of 2 days, by treatment group, in Study 1. A treatment benefit over placebo for galcanezumab-gnlm is seen across a range of changes from baseline in monthly [[migraine]] headache days.<br />
[[File:GalcanezumabFigure3.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
*FIGURE 4 shows the distribution of change from baseline in the mean number of monthly [[migraine]] headache days in bins of 2 days, by treatment group, in Study 2. A treatment benefit over placebo for galcanezumab-gnlm is seen across a range of changes from baseline in monthly [[migraine]] headache days.<br />
[[File:GalcanezumabFigure4.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
Chronic Migraine<br />
*Study 3 (NCT02614261) included adults with a history of chronic [[migraine]] (≥15 headache days per month with ≥8 [[migraine]] days per month). All patients were randomized in a 1:1:2 ratio to receive once-monthly [[subcutaneous injection]]s of galcanezumab-gnlm 120 mg, galcanezumab-gnlm 240 mg, or placebo over a 3-month treatment period. All patients in the 120 mg galcanezumab-gnlm group received an initial 240 mg [[loading dose]].<br />
*Patients were allowed to use acute headache treatments including [[migraine]]-specific medications (i.e., [[triptans]], [[ergotamine]] derivatives), [[NSAID]]s, and [[acetaminophen]]. A subset of patients (15%) was allowed to use one concomitant [[migraine]] preventive medication. Patients with medication overuse headache were allowed to enroll.<br />
*The study excluded patients with [[ECG]] abnormalities compatible with an acute cardiovascular event, and patients with a history of [[stroke]], [[myocardial infarction]], [[unstable angina]], [[percutaneous coronary intervention]], [[coronary artery bypass grafting]], [[deep vein thrombosis]], or [[pulmonary embolism]] within 6 months of screening.<br />
*The primary endpoint was the mean change from baseline in the number of monthly [[migraine]] headache days over the 3-month treatment period. The secondary endpoints were response rates (the mean percentages of patients reaching at least 50%, 75% and 100% reduction from baseline in the number of monthly [[migraine]] headache days over the 3-month treatment period), the mean change from baseline in the number of monthly [[migraine]] headache days with use of any acute headache medication during the 3-month treatment period, and the impact of [[migraine]] on daily activities as assessed by the mean change from baseline in the MSQ v2.1 Role Function-Restrictive domain score at Month 3. Scores are scaled from 0 to 100, with higher scores indicating less impact of [[migraine]] on daily activities.<br />
*In Study 3, a total of 1113 patients (946 female, 167 male) ranging in age from 18 to 65 years, were randomized. A total of 1037 patients completed the 3-month double-blind phase. The mean number of monthly [[migraine]] headache days at baseline was approximately 19.<br />
*Galcanezumab-gnlm 120 mg demonstrated statistically significant improvement for the mean change from baseline in the number of monthly [[migraine]] headache days over the 3-month treatment period, and in the mean percentage of patients reaching at least 50% reduction from baseline in the number of monthly [[migraine]] headache days over the 3-month treatment period, as summarized in TABLE 3. Galcanezumab-gnlm treatment with the 240 mg once-monthly dose showed no additional benefit over the galcanezumab-gnlm 120 mg once-monthly dose.<br />
[[File:GalcanezumabTable3.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
*Study 3 utilized a sequential testing procedure to control the Type-I error rate for the multiple secondary endpoints. Once a secondary endpoint failed to reach the required level for statistical significance, formal hypothesis testing was terminated for subsequent endpoints, and p-values were considered nominal only. In Study 3, galcanezumab-gnlm 120 mg was not significantly better than placebo for the proportion of patients with ≥75% or 100% reduction in [[migraine]] headache days. Patients treated with galcanezumab-gnlm 120 mg showed a nominally greater reduction in the number of monthly [[migraine]] headache days that acute medication was taken (-4.7 for galcanezumab-gnlm 120 mg vs. -2.2 for placebo; nominal p-value <0.001), and the mean change from baseline in the MSQ Role Function-Restrictive Domain score at Month 3 was nominally greater in patients treated with galcanezumab-gnlm 120 mg than in patients on placebo (21.8 for galcanezumab-gnlm 120 mg vs. 16.8 for placebo; nominal p-value <0.001).<br />
[[File:GalcanezumabFigure5.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
*FIGURE 6 shows the distribution of change from baseline in the mean number of monthly [[migraine]] headache days for the 3-month study period in bins of 3 days by treatment group. A treatment benefit over placebo for galcanezumab-gnlm is seen across a range of changes from baseline in monthly [[migraine]] headache days.<br />
[[File:GalcanezumabFigure6.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
=====Episodic Cluster Headache=====<br />
*The efficacy of galcanezumab-gnlm was evaluated for the treatment of episodic [[cluster headache]] in a randomized, 8-week, double-blind, placebo-controlled study (Study 4).<br />
*Study 4 (NCT02397473) included adults who met the International Classification of Headache Disorders 3rd edition (beta version) diagnostic criteria for episodic [[cluster headache]] and had a maximum of 8 attacks per day, a minimum of one attack every other day, and at least 4 attacks during the prospective 7-day baseline period. All patients were randomized in a 1:1 ratio to receive once-monthly [[subcutaneous injection]]s of galcanezumab-gnlm 300 mg or placebo. Patients were allowed to use certain specified acute/abortive [[cluster headache]] treatments, including [[triptans]], [[oxygen]], [[acetaminophen]], and [[NSAID]]s during the study.<br />
*The study excluded patients on other treatments intended to reduce the frequency of [[cluster headache]] attacks; patients with [[medication overuse headache]]; patients with [[ECG]] abnormalities compatible with an acute cardiovascular event or conduction delay; and patients with a history of [[myocardial infarction]], [[unstable angina]], [[percutaneous coronary intervention]], [[coronary artery bypass grafting]], [[deep vein thrombosis]], or [[pulmonary embolism]] within 6 months of screening. In addition, patients with any history of [[stroke]], intracranial or [[carotid]] [[aneurysm]], [[intracranial hemorrhage]], or [[vasospastic angina]]; clinical evidence of [[peripheral vascular disease]]; or diagnosis of Raynaud’s disease were excluded.<br />
*The primary efficacy endpoint for Study 4 was the mean change from baseline in weekly [[cluster headache]] attack frequency across Weeks 1 to 3. A secondary endpoint was the percentage of patients who achieved a response (defined as a reduction from baseline of 50% or greater in the weekly [[cluster headache]] attack frequency) at Week 3.<br />
*In Study 4, a total of 106 patients (88 males, 18 females) ranging in age from 19 to 65 years were randomized and treated. A total of 90 patients completed the 8-week double-blind phase. In the prospective baseline phase, the mean number of weekly [[cluster headache]] attacks was 17.5, and was similar across treatment groups.<br />
*Galcanezumab-gnlm 300 mg demonstrated statistically significant improvements for efficacy endpoints compared to placebo, as summarized in TABLE 4.<br />
[[File:GalcanezumabTable4.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
[[File:GalcanezumabFigure7.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
*FIGURE 8 shows the distribution of the average percent change from baseline in weekly [[cluster headache]] attack frequency across Weeks 1 to 3 in bins of 25%, by treatment group, in Study 4.<br />
[[File:GalcanezumabFigure8.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
|howSupplied=<br />
*Galcanezumab-gnlm injection is a sterile, preservative-free, clear to opalescent, colorless to slightly yellow to slightly brown solution for [[subcutaneous]] administration.<br />
*Galcanezumab-gnlm is not made with natural rubber latex.<br />
*Galcanezumab-gnlm is supplied as follows:<br />
[[File:GalcanezumabSupplied.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
|NDC=<br />
|storage=<br />
*Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect galcanezumab-gnlm from light until use.<br />
*Do not freeze.<br />
*Do not shake.<br />
*Galcanezumab-gnlm may be stored out of refrigeration in the original carton at temperatures up to 30°C (86°F) for up to 7 days. Once stored out of refrigeration, do not place back in the refrigerator.<br />
*If these conditions are exceeded, galcanezumab-gnlm must be discarded.<br />
*Discard the galcanezumab-gnlm single-dose prefilled pen or syringe after use in a puncture-resistant container.<br />
|manBy= <br />
|distBy=<br />
|drugImages=<br />
|packLabel=<br />
[[File:GalcanezumabLabel1.jpeg|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
[[File:GalcanezumabLabel2.jpeg|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
[[File:GalcanezumabLabel3.jpeg|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
|fdaPatientInfo=<br />
*Instructions on Self-Administration: Provide guidance to patients and/or caregivers on proper [[subcutaneous injection]] technique, including [[aseptic technique]], and how to use the prefilled pen or prefilled syringe correctly [see Instructions for Use]. Instruct patients and/or caregivers to read and follow the Instructions for Use each time they use galcanezumab-gnlm.<br />
*Hypersensitivity Reactions: Advise patients to seek immediate medical attention if they experience any symptoms of serious or severe [[hypersensitivity reactions]].<br />
*For more information go to www.EMGALITY.com or call 1-833-EMGALITY (1-833-364-2548).<br />
=====Patient Package Insert=====<br />
[[File:GalcanezumabMedGuide.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
=====Instructions for Use=====<br />
[[File:GalcanezumabInstruct1.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
[[File:GalcanezumabInstruct2.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
[[File:GalcanezumabInstruct3.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
|nlmPatientInfo=<br />
|alcohol=<br />
|brandNames=[[Emgality]]<br />
|lookAlike=<br />
|drugShortage=<br />
|price=<br />
}}</div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:GalcanezumabLabel3.jpeg&diff=1577638File:GalcanezumabLabel3.jpeg2019-07-31T15:12:00Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:GalcanezumabLabel2.jpeg&diff=1577637File:GalcanezumabLabel2.jpeg2019-07-31T15:11:27Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:GalcanezumabLabel1.jpeg&diff=1577636File:GalcanezumabLabel1.jpeg2019-07-31T15:10:36Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:GalcanezumabInstruct3.png&diff=1577635File:GalcanezumabInstruct3.png2019-07-31T15:09:51Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:GalcanezumabInstruct2.png&diff=1577634File:GalcanezumabInstruct2.png2019-07-31T15:08:40Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:GalcanezumabInstruct1.png&diff=1577633File:GalcanezumabInstruct1.png2019-07-31T15:07:40Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:GalcanezumabMedGuide.png&diff=1577631File:GalcanezumabMedGuide.png2019-07-31T15:06:24Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:GalcanezumabSupplied.png&diff=1577630File:GalcanezumabSupplied.png2019-07-31T15:05:26Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:GalcanezumabFigure8.png&diff=1577629File:GalcanezumabFigure8.png2019-07-31T15:04:20Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:GalcanezumabFigure7.png&diff=1577626File:GalcanezumabFigure7.png2019-07-31T15:03:40Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:GalcanezumabFigure6.png&diff=1577625File:GalcanezumabFigure6.png2019-07-31T15:03:04Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:GalcanezumabFigure5.png&diff=1577623File:GalcanezumabFigure5.png2019-07-31T15:02:29Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:GalcanezumabFigure4.png&diff=1577622File:GalcanezumabFigure4.png2019-07-31T15:01:50Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:GalcanezumabFigure3.png&diff=1577621File:GalcanezumabFigure3.png2019-07-31T15:01:14Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:GalcanezumabFigure2.png&diff=1577620File:GalcanezumabFigure2.png2019-07-31T15:00:28Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:GalcanezumabFigure1.png&diff=1577618File:GalcanezumabFigure1.png2019-07-31T14:59:57Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:GalcanezumabTable4.png&diff=1577617File:GalcanezumabTable4.png2019-07-31T14:58:30Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:GalcanezumabTable3.png&diff=1577614File:GalcanezumabTable3.png2019-07-31T14:57:39Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:GalcanezumabTable2.png&diff=1577613File:GalcanezumabTable2.png2019-07-31T14:56:59Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=File:GalcanezumabTable1.png&diff=1577612File:GalcanezumabTable1.png2019-07-31T14:56:23Z<p>Zach Leibowitz: </p>
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<div></div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=Copiktra&diff=1577406Copiktra2019-07-30T16:24:09Z<p>Zach Leibowitz: ←Redirected page to Duvelisib</p>
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<div>#redirect[[Duvelisib]]</div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=Duvelisib&diff=1577405Duvelisib2019-07-30T16:23:34Z<p>Zach Leibowitz: Created page with "{{DrugProjectFormSinglePage |authorTag={{ZL}} |genericName=duvelisib |aOrAn=a |drugClass=kinase inhibitor |indication=adult patients with: *Relapsed or refractory chroni..."</p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{ZL}}<br />
|genericName=duvelisib<br />
|aOrAn=a<br />
|drugClass=[[kinase inhibitor]]<br />
|indication=adult patients with:<br />
*Relapsed or refractory [[chronic lymphocytic leukemia]] ([[CLL]]) or [[small lymphocytic lymphoma]] ([[SLL]]) after at least two prior therapies.<br />
*Relapsed or refractory [[follicular lymphoma]] ([[FL]]) after at least two prior systemic therapies<br />
|indicationType=treatment<br />
|hasBlackBoxWarning=yes<br />
|blackBoxWarningTitle=FATAL AND SERIOUS TOXICITIES: INFECTIONS, DIARRHEA OR COLITIS, CUTANEOUS REACTIONS, AND PNEUMONITIS<br />
|blackBoxWarningBody=<br />
<br><br />
*Fatal and/or serious infections occurred in 31% of duvelisib-treated patients. Monitor for signs and symptoms of infection. Withhold duvelisib if infection is suspected.<br />
*Fatal and/or serious diarrhea or colitis occurred in 18% of duvelisib-treated patients. Monitor for the development of severe diarrhea or colitis. Withhold duvelisib.<br />
*Fatal and/or serious cutaneous reactions occurred in 5% of duvelisib-treated patients. Withhold duvelisib.<br />
*Fatal and/or serious pneumonitis occurred in 5% of duvelisib-treated patients. Monitor for pulmonary symptoms and interstitial infiltrates. Withhold duvelisib.<br />
|fdaLIADAdult=<br />
=====Indication=====<br />
[[Chronic Lymphocytic Leukemia]] ([[CLL]])/[[Small Lymphocytic Lymphoma]] ([[SLL]])<br />
*Duvelisib is indicated for the treatment of adult patients with relapsed or refractory [[CLL]] or [[SLL]] after at least two prior therapies.<br />
[[Follicular Lymphoma]] ([[FL]])<br />
*Duvelisib is indicated for the treatment of adult patients with relapsed or refractory [[FL]] after at least two prior systemic therapies.<br />
*This indication is approved under accelerated approval based on overall response rate (ORR); continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.<br />
=====Dosage=====<br />
*25 mg orally, twice daily. Modify dosage for toxicity.<br />
|offLabelAdultGuideSupport=<br />
There is limited information regarding duvelisib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.<br />
|offLabelAdultNoGuideSupport=<br />
There is limited information regarding duvelisib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.<br />
|fdaLIADPed=<br />
Safety and effectiveness of duvelisib have not been established in pediatric patients.<br />
|offLabelPedGuideSupport=<br />
There is limited information regarding duvelisib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.<br />
|offLabelPedNoGuideSupport=<br />
There is limited information regarding duvelisib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.<br />
|contraindications=<br />
None.<br />
|warnings=<br />
=====Infections=====<br />
*Serious, including fatal (18/442; 4%), [[infections]] occurred in 31% of patients receiving duvelisib 25 mg BID (N = 442). The most common serious infections were [[pneumonia]], [[sepsis]], and [[lower respiratory infections]]. Median time to onset of any grade infection was 3 months (range: 1 day to 32 months), with 75% of cases occurring within 6 months.<br />
*Treat [[infections]] prior to initiation of duvelisib. Advise patients to report any new or worsening signs and symptoms of infection. For grade 3 or higher infection, withhold duvelisib until infection has resolved. Resume duvelisib at the same or reduced dose.<br />
*Serious, including fatal, ‘’[[Pneumocystis jirovecii]]’’ [[pneumonia]] (PJP) occurred in 1% of patients taking duvelisib. Provide [[prophylaxis]] for PJP during treatment with duvelisib. Following completion of duvelisib treatment, continue PJP prophylaxis until the absolute CD4+ [[T cell]] count is greater than 200 cells/µL. Withhold duvelisib in patients with suspected PJP of any grade, and permanently discontinue if PJP is confirmed.<br />
*[[CMV]] reactivation/infection occurred in 1% of patients taking duvelisib. Consider prophylactic [[antivirals]] during duvelisib treatment to prevent CMV infection including CMV reactivation. For clinical CMV infection or [[viremia]], withhold duvelisib until infection or viremia resolves. If duvelisib is resumed, administer the same or reduced dose and monitor patients for CMV reactivation by [[PCR]] or antigen test at least monthly.<br />
=====Diarrhea or Colitis=====<br />
*Serious, including fatal (1/442; <1%), [[diarrhea]] or [[colitis]] occurred in 18% of patients receiving duvelisib 25 mg BID (N = 442). The median time to onset of any grade diarrhea or colitis was 4 months (range: 1 day to 33 months), with 75% of cases occurring by 8 months. The median event duration was 0.5 months (range: 1 day to 29 months; 75th percentile: 1 month).<br />
*Advise patients to report any new or worsening [[diarrhea]]. For non-infectious diarrhea or [[colitis]], follow the guidelines below:<br />
*For patients presenting with mild or moderate [[diarrhea]] (Grade 1-2) (i.e. up to 6 stools per day over baseline) or asymptomatic (Grade 1) [[colitis]], initiate supportive care with [[antidiarrheal]] agents as appropriate, continue duvelisib at the current dose, and monitor the patient at least weekly until the event resolves. If the diarrhea is unresponsive to antidiarrheal therapy, withhold duvelisib and initiate supportive therapy with enteric acting steroids (e.g. [[budesonide]]). Monitor the patient at least weekly. Upon resolution of the diarrhea, consider restarting duvelisib at a reduced dose.<br />
*For patients presenting with [[abdominal pain]], stool with mucus or blood, change in bowel habits, peritoneal signs, or with severe [[diarrhea]] (Grade 3) (i.e. > 6 stools per day over baseline) withhold duvelisib and initiate supportive therapy with enteric acting steroids (e.g. [[budesonide]]) or systemic steroids. A diagnostic work-up to determine etiology, including [[colonoscopy]], should be performed. Monitor at least weekly. Upon resolution of the [[diarrhea]] or [[colitis]], restart duvelisib at a reduced dose. For recurrent Grade 3 diarrhea or recurrent colitis of any grade, discontinue duvelisib. Discontinue duvelisib for life-threatening diarrhea or colitis.<br />
=====Cutaneous Reactions=====<br />
*Serious, including fatal (2/442; < 1%), [[cutaneous]] reactions occurred in 5% of patients receiving duvelisib 25 mg BID (N = 442). Fatal cases included drug reaction with [[eosinophilia]] and systemic symptoms ([[DRESS]]) and [[toxic epidermal necrolysis]] (TEN). Median time to onset of any grade cutaneous reaction was 3 months (range: 1 day to 29 months, 75th percentile: 6 months), with a median event duration of 1 month (range: 1 day to 37 months, 75th percentile: 2 months).<br />
*Presenting features for the serious events were primarily described as pruritic, [[erythematous]], or maculo-papular. Less common presenting features include [[exanthem]], [[desquamation]], [[erythroderma]], skin [[exfoliation]], [[keratinocyte]] [[necrosis]], and papular [[rash]]. Advise patients to report any new or worsening [[cutaneous]] reactions. Review all concomitant medications and discontinue any medications potentially contributing to the event. For patients presenting with mild or moderate (Grade 1-2) cutaneous reactions, continue duvelisib at the current dose, initiate supportive care with [[emollients]], anti-histamines (for [[pruritus]]), or topical [[steroids]], and monitor the patient closely. Withhold duvelisib for severe (Grade 3) cutaneous reaction until resolution. Initiate supportive care with steroids (topical or systemic) or anti-histamines (for pruritus). Monitor at least weekly until resolved. Upon resolution of the event, restart duvelisib at a reduced dose. Discontinue duvelisib if severe cutaneous reaction does not improve, worsens, or recurs. For life-threatening cutaneous reactions, discontinue duvelisib. In patients with [[SJS]], [[TEN]], or [[DRESS]] of any grade, discontinue duvelisib.<br />
=====Pneumonitis=====<br />
*Serious, including fatal (1/442; < 1%), [[pneumonitis]] without an apparent infectious cause occurred in 5% of patients receiving duvelisib 25 mg BID (N = 442). Median time to onset of any grade pneumonitis was 4 months (range: 9 days to 27 months), with 75% of cases occurring within 9 months). The median event duration was 1 month, with 75% of cases resolving by 2 months.<br />
*Withhold duvelisib in patients who present with new or progressive pulmonary signs and symptoms such as [[cough]], [[dyspnea]], [[hypoxia]], interstitial infiltrates on a radiologic exam, or a decline by more than 5% in oxygen saturation and evaluate for etiology. If the [[pneumonitis]] is infectious, patients may be restarted on duvelisib at the previous dose once the infection, pulmonary signs and symptoms resolve. For moderate non-infectious pneumonitis (Grade 2), treat with systemic [[corticosteroids]], and resume duvelisib at a reduced dose upon resolution. If non-infectious pneumonitis recurs or does not respond to steroid therapy, discontinue duvelisib. For severe or life-threatening non-infectious pneumonitis, discontinue duvelisib and treat with systemic steroids.<br />
=====Hepatotoxicity=====<br />
*Grade 3 and 4 ALT and/or AST elevation developed in 8% and 2%, respectively, in patients receiving duvelisib 25 mg BID (N = 442). Two percent of patients had both an [[ALT]] or [[AST]] greater than 3 x ULN and total [[bilirubin]] greater than 2 x ULN. Median time to onset of any grade [[transaminase]] elevation was 2 months (range: 3 days to 26 months), with a median event duration of 1 month (range: 1 day to 16 months).<br />
*Monitor hepatic function during treatment with duvelisib. For Grade 2 [[ALT]]/[[AST]] elevation (greater than 3 to 5 × ULN), maintain duvelisib dose and monitor at least weekly until return to less than 3 × ULN. For Grade 3 ALT/AST elevation (greater than 5 to 20 × ULN), withhold duvelisib and monitor at least weekly until return to less than 3 × ULN. Resume duvelisib at the same dose (first occurrence) or at a reduced dose for subsequent occurrence. For grade 4 ALT/AST elevation (greater than 20 × ULN) discontinue duvelisib.<br />
=====Neutropenia=====<br />
*Grade 3 or 4 [[neutropenia]] occurred in 42% of patients receiving duvelisib 25 mg BID (N = 442), with Grade 4 neutropenia occurring in 24% of all patients. The median time to onset of Grade ≥ 3 neutropenia was 2 months (range: 3 days to 31 months), with 75% of cases occurring within 4 months.<br />
*Monitor [[neutrophil]] counts at least every 2 weeks for the first 2 months of duvelisib therapy, and at least weekly in patients with neutrophil counts < 1.0 Gi/L (Grade 3-4). Withhold duvelisib in patients presenting with neutrophil counts < 0.5 Gi/L (Grade 4). Monitor until [[ANC]] is > 0.5 Gi/L, resume duvelisib at same dose for the first occurrence or a reduced dose for subsequent occurrence.<br />
=====Embryo-Fetal Toxicity=====<br />
*Based on findings in animals and its mechanism of action, duvelisib can cause fetal harm when administered to a [[pregnant]] woman. In animal reproduction studies, administration of duvelisib to pregnant rats and rabbits during [[organogenesis]] caused adverse developmental outcomes including embryo-fetal mortality (resorptions, post-implantation loss, and decreased viable fetuses), alterations to growth (lower fetal weights) and structural abnormalities (malformations) at maternal doses approximately 10 times and 39 times the maximum recommended human dose (MRHD) of 25 mg BID in rats and rabbits, respectively. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose.<br />
|adverseReactions=[[diarrhea]] or [[colitis]], [[neutropenia]], [[rash]], [[fatigue]], [[pyrexia]], [[cough]], [[nausea]], [[upper respiratory infection]], [[pneumonia]], [[musculoskeletal pain]], and [[anemia]]<br />
|clinicalTrials=<br />
*Because clinical trials are conducted under widely variable conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with rates in clinical trials of another drug and may not reflect the rates observed in practice.<br />
Summary of Clinical Trial Experience in [[B-cell]] Malignancies<br />
*The data described below reflect exposure to duvelisib in two single-arm, open-label clinical trials, one open-label extension clinical trial, and one randomized, open-label, actively controlled clinical trial totaling 442 patients with previously treated hematologic malignancies primarily including [[CLL]]/[[SLL]] (69%) and [[FL]] (22%). Patients were treated with duvelisib 25 mg BID until unacceptable toxicity or progressive disease. The median duration of exposure was 9 months (range: 0.1 to 53 months), with 36% (160/442) of patients having at least 12 months of exposure.<br />
*For the 442 patients, the median age was 67 years (range: 30 to 90 years), 65% were male, 92% were White, and 93% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Patients had a median of 2 prior therapies. The trials required [[hepatic transaminases]] at least ≤ 3 times upper limit of normal (ULN), total [[bilirubin]] ≤ 1.5 times ULN, and [[serum creatinine]] ≤ 1.5 times ULN. Patients were excluded for prior exposure to a [[PI3K]] inhibitor within 4 weeks.<br />
*Fatal adverse reactions within 30 days of the last dose occurred in 36 patients (8%) treated with duvelisib 25 mg BID.<br />
*Serious adverse reactions were reported in 289 patients (65%). The most frequent serious adverse reactions that occurred were [[infection]] (31%), [[diarrhea]] or [[colitis]] (18%), [[pneumonia]] (17%), [[rash]] (5%), and [[pneumonitis]] (5%).<br />
*Adverse reactions resulted in treatment discontinuation in 156 patients (35%), most often due to [[diarrhea]] or [[colitis]], [[infection]], and [[rash]]. Duvelisib was dose reduced in 104 patients (24%) due to adverse reactions, most often due to diarrhea or colitis and [[transaminase]] elevation. The median time to first dose modification or discontinuation was 4 months (range: 0.1 to 27 months), with 75% of patients having their first dose modification or discontinuation within 7 months.<br />
Common Adverse Reactions<br />
*TABLE 3 summarizes common adverse reactions in patients receiving duvelisib 25 mg BID, and TABLE 4 summarizes the treatment-emergent laboratory abnormalities. The most common adverse reactions (reported in ≥ 20% of patients) were [[diarrhea]] or [[colitis]], [[neutropenia]], [[rash]], [[fatigue]], [[pyrexia]], [[cough]], [[nausea]], [[upper respiratory infection]], [[pneumonia]], [[musculoskeletal pain]], and [[anemia]].<br />
[[File:DuvelisibTable3.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
*Grade 4 adverse reactions occurring in ≥ 2% of recipients of duvelisib included [[neutropenia]] (18%), [[thrombocytopenia]] (6%), [[sepsis]] (3%), [[hypokalemia]] and increased [[lipase]] (2% each), and [[pneumonia]] and [[pneumonitis]] (2% each).<br />
[[File:DuvelisibTable4.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
*Grade 4 laboratory abnormalities developing in ≥ 2% of patients included [[neutropenia]] (24%), [[thrombocytopenia]] (7%), [[lipase]] increase (4%), [[lymphocytopenia]] (3%), and [[leukopenia]] (2%).<br />
Summary of Clinical Trial Experience in [[CLL]]/[[SLL]] <br><br />
Study 1<br />
*The safety data below reflects exposure in a randomized, open-label, actively controlled clinical trial for adult patients with [[CLL]] or [[SLL]] who received at least one prior therapy. Of 313 patients treated, 158 received duvelisib monotherapy and 155 received ofatumumab. The 442-patient safety analysis above includes patients from Study 1.<br />
*Duvelisib was administered at 25 mg BID in 28-day treatment cycles until unacceptable toxicity or progressive disease. The comparator group received 12 doses of ofatumumab with an initial dose of 300 mg intravenous (IV) on Day 1 followed a week later by 7 weekly doses of 2000 mg IV, followed 4 weeks later by 2000 mg IV every 4 weeks for 4 doses.<br />
*In the total study population, the median age was 69 years (range: 39 to 90 years), 60% were male, 92% were White, and 91% had an ECOG performance status of 0 to 1. Patients had a median of 2 prior therapies, with 61% of patients having received 2 or more prior therapies. The trial required a [[hemoglobin]] ≥ 8 g/dL and [[platelets]] ≥ 10,000 µL with or without transfusion support, [[hepatic transaminases]] ≤ 3 times upper limit of normal (ULN), total [[bilirubin]] ≤ 1.5 times ULN, and [[serum creatinine]] ≤ 2 times ULN. The trial excluded patients with prior autologous transplant within 6 months or allogeneic transplant, prior exposure to a [[PI3K]] inhibitor or a Bruton’s [[tyrosine]] [[kinase]] (BTK) inhibitor, and uncontrolled [[autoimmune hemolytic anemia]] or [[idiopathic thrombocytopenic purpura]].<br />
*During randomized treatment, the median duration of exposure to duvelisib was 11.6 months with 72% (114/158) exposed for ≥ 6 months and 49% (77/158) exposed for ≥ 1 year. The median duration of exposure to [[ofatumumab]] was 5.3 months, with 77% (120/155) receiving at least 10 of 12 doses.<br />
*Fatal adverse reactions within 30 days of the last dose occurred in 12% (19/158) of patients treated with duvelisib and in 4% (7/155) of patients treated with [[ofatumumab]].<br />
*Serious adverse reactions were reported in 73% (115/158) of patients treated with duvelisib and most often involved infection (38% of patients; 60/158) and [[diarrhea]] or [[colitis]] (23% of patients; 36/158).<br />
*Duvelisib was discontinued in 57 patients (36%), most often due to [[diarrhea]] or [[colitis]], [[infection]], and [[rash]]. Duvelisib was dose reduced in 46 patients (29%) due to adverse reactions, most often due to diarrhea or colitis and rash.<br />
Common Adverse Reactions<br />
*TABLE 5 summarizes selected adverse reactions in Study 1, and TABLE 6 summarizes treatment-emergent laboratory abnormalities. The most common adverse reactions with duvelisib (reported in ≥ 20% of patients) were [[diarrhea]] or [[colitis]], [[neutropenia]], [[pyrexia]], [[upper respiratory tract infection]], [[pneumonia]], [[rash]], [[fatigue]], [[nausea]], [[anemia]] and [[cough]].<br />
[[File:DuvelisibTable5.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
[[File:DuvelisibTable6.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
*Grade 4 laboratory abnormalities that developed in ≥ 2% of duvelisib treated patients included [[neutropenia]] (32%), [[thrombocytopenia]] (6%), [[lymphopenia]] (3%), and [[hypokalemia]] (2%).<br />
*The data above are not an adequate basis for comparison of rates between the study drug and the active control.<br />
Summary of Clinical Trial Experience in [[FL]]<br />
*The data described below reflect the exposure to duvelisib 25 mg BID in 96 patients with relapsed or refractory [[FL]]. These patients were included in the 442-patient safety analysis presented above. The median duration of treatment was 24 weeks, with 46% of patients exposed for ≥ 6 months and 19% exposed for ≥ 1 year.<br />
*The median age was 64 years (range: 30 to 82 years), and 93% had an ECOG performance status of 0 to 1. Patients had a median of 3 prior systemic therapies.<br />
*Serious adverse reactions were reported in 58% and most often involved [[diarrhea]] or [[colitis]], [[pneumonia]], [[renal insufficiency]], [[rash]], and [[sepsis]]. The most common adverse reactions (≥ 20% of patients) were diarrhea or colitis, [[nausea]], [[fatigue]], [[musculoskeletal pain]], rash, [[neutropenia]], [[cough]], [[anemia]], [[pyrexia]], [[headache]], [[mucositis]], [[abdominal pain]], [[vomiting]], [[transaminase]] elevation, and [[thrombocytopenia]].<br />
*Adverse reactions resulted in duvelisib discontinuation in 29% of patients, most often due to [[diarrhea]] or [[colitis]] and [[rash]]. Duvelisib was dose reduced in 23% due to adverse reactions, most often due to [[transaminase]] elevation, diarrhea or colitis, [[lipase]] increased, and [[infection]].<br />
|postmarketing=<br />
|drugInteractions=<br />
=====Effects of Other Drugs on Duvelisib=====<br />
CYP3A Inducers<br />
*Co-administration with a strong [[CYP3A]] inducer decreases duvelisib area under the curve (AUC), which may reduce duvelisib efficacy. Avoid co-administration of duvelisib with strong [[CYP3A4]] inducers.<br />
CYP3A Inhibitors<br />
*Co-administration with a strong [[CYP3A]] inhibitor increases duvelisib AUC, which may increase the risk of duvelisib toxicities. Reduce duvelisib dose to 15 mg BID when co-administered with a strong [[CYP3A4]] inhibitor.<br />
=====Effects of Duvelisib on Other Drugs=====<br />
CYP3A Substrates<br />
*Co-administration with duvelisib increases AUC of a sensitive [[CYP3A4]] substrate which may increase the risk of toxicities of these drugs. Consider reducing the dose of the sensitive CYP3A4 substrate and monitor for signs of toxicities of the co-administered sensitive [[CYP3A]] substrate.<br />
|FDAPregCat=<br />
|useInPregnancyFDA=<br />
Risk Summary<br />
*Based on findings from animal studies and the mechanism of action, duvelisib can cause fetal harm when administered to a [[pregnant]] woman.<br />
*There are no available data in [[pregnant]] women to inform the drug-associated risk. In animal reproduction studies, administration of duvelisib to pregnant rats and rabbits during [[organogenesis]] caused adverse developmental outcomes including embryo-fetal mortality (resorptions, post-implantation loss, and decreased viable fetuses), alterations to growth (lower fetal weights) and structural abnormalities (malformations) at maternal doses 10 times and 39 times the MRHD of 25 mg BID in rats and rabbits, respectively.<br />
*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.<br />
Animal Data<br />
*In an embryo-fetal development study in rats, pregnant animals received daily oral doses of duvelisib of 0, 10, 50, 150 and 275 mg/kg/day during the period of [[organogenesis]]. Administration of duvelisib at doses ≥ 50 mg/kg/day resulted in adverse developmental outcomes including reduced fetal weights and external abnormalities (bent tail and fetal [[anasarca]]), and doses ≥ 150 mg/kg/day resulted in maternal toxicity including mortality and no live fetuses (100% resorption) in surviving dams. In another study in pregnant rats receiving oral doses of duvelisib up to 35 mg/kg/day during the period of organogenesis, no maternal or embryo-fetal effects were observed. The dose of 50 mg/kg/day in rats is approximately 10 times the MRHD of 25 mg BID.<br />
*In an embryo-fetal development study in rabbits, [[pregnant]] animals received daily oral doses of duvelisib of 0, 25, 100, and 200 mg/kg/day during the period of [[organogenesis]]. Administration of duvelisib at doses ≥ 100 mg/kg/day resulted in maternal toxicity (body weight losses or lower mean body weights and increased mortality) and adverse developmental outcomes (increased resorptions and post-implantation loss, abortion, and decreased numbers of viable fetuses). In another study in pregnant rabbits receiving oral doses of duvelisib up to 75 mg/kg/day, no maternal or embryo-fetal effects were observed. The dose of 100 mg/kg/day in rabbits is approximately 39 times the MRHD of 25 mg BID.<br />
|AUSPregCat=<br />
|useInPregnancyAUS=<br />
|useInLaborDelivery=<br />
|useInNursing=<br />
Risk Summary<br />
*There are no data on the presence of duvelisib and/or its metabolites in human milk, the effects on the breastfed child, or on milk production. Because of the potential for serious adverse reactions from duvelisib in a breastfed child, advise lactating women not to breastfeed while taking duvelisib and for at least 1 month after the last dose.<br />
|useInPed=<br />
*Safety and effectiveness of duvelisib have not been established in pediatric patients. Pediatric studies have not been conducted.<br />
|useInGeri=<br />
*Clinical trials of duvelisib included 270 patients (61%) that were 65 years of age and older and 104 (24%) that were 75 years of age and older. No major differences in efficacy or safety were observed between patients less than 65 years of age and patients 65 years of age and older.<br />
|useInGender=<br />
|useInRace=<br />
|useInRenalImpair=<br />
|useInHepaticImpair=<br />
|useInReproPotential=<br />
''Pregnancy Testing''<br />
*Duvelisib can cause fetal harm when administered to a pregnant woman. Conduct [[pregnancy]] testing before initiation of duvelisib treatment.<br />
''[[Contraception]]'' <br><br />
Females<br />
*Based on animal studies, duvelisib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective [[contraception]] during treatment with duvelisib and for at least 1 month after the last dose.<br />
Males<br />
*Advise male patients with female partners of reproductive potential to use effective contraception during treatment with duvelisib and for at least 1 month after the last dose.<br />
''[[Infertility]]''<br />
*Based on testicular findings in animals, male [[fertility]] may be impaired by treatment with duvelisib. There are no data on the effect of duvelisib on human fertility.<br />
|useInImmunocomp=<br />
|othersTitle=<br />
|useInOthers=<br />
|administration=<br />
=====Dosing=====<br />
*The recommended dose of duvelisib is 25 mg administered as oral capsules twice daily (BID) with or without food. A cycle consists of 28 days. The capsules should be swallowed whole. Advise patients not to open, break, or chew the capsules.<br />
*Advise patients that if a dose is missed by fewer than 6 hours, to take the missed dose right away and take the next dose as usual. If a dose is missed by more than 6 hours, advise patients to wait and take the next dose at the usual time.<br />
=====Recommended Prophylaxis=====<br />
*Provide [[prophylaxis]] for ‘’[[Pneumocystis jirovecii]]’’ (PJP) during treatment with duvelisib. Following completion of duvelisib treatment, continue PJP prophylaxis until the absolute CD4+ [[T cell]] count is greater than 200 cells/µL.<br />
*Withhold duvelisib in patients with suspected PJP of any grade, and discontinue if PJP is confirmed.<br />
*Consider prophylactic [[antivirals]] during duvelisib treatment to prevent [[cytomegalovirus]] (CMV) infection including CMV reactivation.<br />
=====Dose Modifications for Adverse Reactions=====<br />
*Manage toxicities per TABLE 1 with dose reduction, treatment hold, or discontinuation of duvelisib.<br />
[[File:DuvelisibTable1.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
*Recommended dose modification levels for duvelisib are presented in TABLE 2.<br />
[[File:DuvelisibTable2.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
=====Dose Modification for Concomitant Use with CYP3A4 Inhibitors=====<br />
*Reduce duvelisib dose to 15 mg twice daily when co-administered with strong [[CYP3A4]] inhibitors (e.g. [[ketoconazole]]).<br />
|monitoring=<br />
|IVCompat=<br />
|overdose=<br />
|drugBox=<br />
{{drugbox2<br />
| IUPAC_name = 8-Chloro-2-phenyl-3-[(1''S'')-1-(3''H''-purin-6-ylamino)ethyl]-1(2''H'')-isoquinolinone<br />
| type = <!-- single chemical drug; default --><br />
| image = DuvelisibStructure.png<br />
| width = 175<br />
| pronounce = {{respell|doo|VE|li|SIB}}<br />
<br />
<!-- Clinical data --><br />
| tradename = Copiktra<br />
| Drugs.com = {{drugs.com|monograph|duvelisib}}<br />
| MedlinePlus = a618056<br />
| license_US = Duvelisib<br />
| pregnancy_AU = <!-- A/B1/B2/B3/C/D/X --><br />
| pregnancy_AU_comment = <br />
| pregnancy_US = <br />
| pregnancy_category = <br />
| routes_of_administration = By mouth ([[Capsule (pharmacy)|capsules]])<br />
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--><br />
| legal_AU_comment =<br />
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII --><br />
| legal_DE = <!-- Anlage I, II, III --><br />
| legal_NZ = <!-- Class A, B, C --><br />
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C --><br />
| legal_US = Rx-only<br />
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV--><br />
<br />
<!-- Pharmacokinetic data --><br />
| bioavailability =<br />
| protein_bound =<br />
| metabolism = mainly metabolized by CYP3A4<ref>{{cite web|title=Full prescribing information: duvelisib (duvelisib)|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211155s000lbl.pdf|website=U.S. Food and Drug Administration |accessdate=23 October 2018}}</ref><br />
| metabolites =<br />
| onset = 1-2 hours after initial administration<br />
| elimination_half-life = 5.2 to 10.9 hours<br />
| duration_of_action = <br />
| excretion = Feces (79%), urine (14%)<br />
<br />
<!-- Identifiers --><br />
| CAS_number = 1201438-56-3<br />
| class = [[Phosphoinositide 3-kinase inhibitor|PI3-Kinase inhibitor]]<br />
| DrugBank = DB11952<br />
| ChemSpiderID = 57251273<br />
| ATCvet = <br />
| ATC_prefix = none<br />
| ATC_suffix = <br />
| UNII = 610V23S0JI<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}} <br />
| ChEMBL = CHEMBL3039502<br />
| PubChem = 50905713<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D10555<br />
<br />
<!-- Chemical data --><br />
| chemical_formula = C<sub>22</sub>H<sub>17</sub>ClN<sub>6</sub>O<br />
| molecular_weight = 416.86 g/mol<br />
| smiles = C[C@@H](C1=CC2=C(C(=CC=C2)Cl)C(=O)N1C3=CC=CC=C3)NC4=NC=NC5=C4NC=N5<br />
| StdInChIKey = SJVQHLPISAIATJ-ZDUSSCGKSA-N<br />
}}<br />
|mechAction=<br />
Duvelisib is an inhibitor of [[PI3K]] with inhibitory activity predominantly against PI3K-δ and PI3K-γ isoforms expressed in normal and malignant [[B-cells]]. Duvelisib induced growth inhibition and reduced viability in cell lines derived from malignant B-cells and in primary [[CLL]] tumor cells. Duvelisib inhibits several key cell-signaling pathways, including B-cell receptor signaling and CXCR12-mediated chemotaxis of malignant B-cells. Additionally, duvelisib inhibits CXCL12-induced [[T cell]] migration and M-CSF and IL-4 driven M2 polarization of [[macrophages]].<br />
|structure=<br />
*Duvelisib is a white-to-off-white crystalline solid with the empirical formula C<sub>22</sub>H<sub>17</sub>ClN<sub>6</sub>O•H<sub>2</sub>O and a molecular weight of 434.88 g/mol.<br />
[[File:DuvelisibStructure.jpeg|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
|PD=<br />
*At the recommended dose of 25 mg BID, reductions in levels of phosphorylated [[AKT]] (a downstream marker for [[PI3K]] inhibition) were observed in patients treated with duvelisib.<br />
Cardiac Electrophysiology<br />
*The effect of multiple doses of duvelisib 25 and 75 mg BID on the [[QTc interval]] was evaluated in patients with previously treated hematologic malignancies. Increases of > 20 ms in the QTc interval were not observed.<br />
|PK=<br />
*Duvelisib exposure increased in a dose-proportional manner over a dose range of 8 mg to 75 mg twice daily (0.3 to 3 times the recommended dosage).<br />
*At steady state following 25 mg BID administration of duvelisib in patients, the geometric mean (CV%) maximum concentration (C<sub>max</sub>) was 1.5 (64%) µg/mL and AUC was 7.9 (77%) µg•h/mL.<br />
Absorption<br />
*The absolute bioavailability of 25 mg duvelisib after a single oral dose in healthy volunteers was 42%. The median time to peak concentration (T<sub>max</sub>) was observed at 1 to 2 hours in patients.<br />
Effect of Food<br />
*Duvelisib may be administered without regard to food. The administration of a single dose of duvelisib with a high-fat meal (fat accounted for approximately 50% of the total caloric content of the meal) decreased C<sub>max</sub> by approximately 37% and decreased the AUC by approximately 6%, relative to fasting conditions.<br />
Distribution<br />
*Protein binding of duvelisib is greater than 98% with no concentration dependence. The mean blood-to-plasma ratio was 0.5. The geometric mean (CV%) apparent volume of distribution at steady state (V<sub>ss</sub>/F) is 28.5 L (62%). Duvelisib is a substrate of [[P-glycoprotein]] (P-gp) and BCRP in vitro.<br />
Elimination<br />
*The geometric mean (CV%) apparent systemic clearance at steady-state is 4.2 L/hr (56%) in patients with [[lymphoma]] or [[leukemia]]. The geometric mean (CV%) terminal elimination half-life of duvelisib is 4.7 hours (57%).<br />
Metabolism<br />
*Duvelisib is primarily metabolized by [[cytochrome P450]] [[CYP3A4]].<br />
Excretion<br />
*Following a single 25 mg oral dose of radiolabeled duvelisib, 79% of the radioactivity was excreted in feces (11% unchanged) and 14% was excreted in the urine (< 1% unchanged).<br />
Specific Populations<br />
*Age (18 to 90 years), sex, race, [[renal impairment]] ([[creatinine]] clearance 23 to 80 mL/ min), [[hepatic impairment]] (Child Pugh Class A, B, and C) and body weight (40 to 154 kg) had no clinically significant effect on the exposure of duvelisib.<br />
Drug Interaction Studies <br><br />
''Strong and Moderate CYP3A Inhibitors''<br />
*Co-administration of strong [[CYP3A]] inhibitor [[ketoconazole]] (at 200 mg BID for 5 days), a strong inhibitor of [[CYP3A4]], with a single oral 10 mg dose of duvelisib in healthy adults (n= 16) increased duvelisib C<sub>max</sub> by 1.7-fold and AUC by 4-fold. Based on physiologically-based pharmacokinetic (PBPK) modeling and simulation, the increase in exposure to duvelisib is estimated to be ~2-fold at steady state when concomitantly used with strong CYP3A4 inhibitors such as ketoconazole. PBPK modeling and simulation estimated no effect on duvelisib exposures from concomitantly used mild or moderate CYP3A4 inhibitors.<br />
''Strong and Moderate CYP3A4 Inducers''<br />
*Co-administration of 600 mg once daily [[rifampin]], a strong [[CYP3A]] inducer, for 7 days with a single oral 25 mg duvelisib dose in healthy adults (N = 13) decreased duvelisib C<sub>max</sub> by 66% and AUC by 82%.<br />
*The effect of moderate [[CYP3A4]] induction has not been studied.<br />
''CYP3A4 Substrates''<br />
*Co-administration of multiple doses of duvelisib 25 mg BID for 5 days with single oral 2 mg [[midazolam]], a sensitive [[CYP3A4]] substrate, in healthy adults (N = 14), increased in the midazolam AUC by 4.3-fold and C<sub>max</sub> by 2.2-fold.<br />
''In Vitro Studies''<br />
*Duvelisib is a substrate of [[P-glycoprotein]] (P-gp) and [[breast cancer]]-resistant protein (BCRP).<br />
*Duvelisib does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BCRP, or P-gp.<br />
|nonClinToxic=<br />
=====Carcinogenesis, Mutagenesis, Impairment of Fertility=====<br />
*Carcinogenicity studies have not been conducted with duvelisib.<br />
*Duvelisib did not cause genetic damage in in vitro or in vivo assays.<br />
*[[Fertility]] studies with duvelisib were not conducted. Histological findings in male and female rats were observed in the repeat dose toxicity studies and included [[testis]] (seminiferous [[epithelial]] [[atrophy]], decreased weight, soft testes), and [[epididymis]] (small size, [[oligo]]/[[aspermia]]) in males and [[ovary]] (decreased weight) and [[uterus]] (atrophy) in females.<br />
|clinicalStudies=<br />
=====Efficacy in Relapsed or Refractory [[CLL]]/[[SLL]]=====<br />
Study 1<br />
*A randomized, multicenter, open-label trial (Study 1; NCT02004522) compared duvelisib versus ofatumumab in 319 adult patients with [[CLL]] (N = 312) or [[SLL]] (N = 7) after at least one prior therapy. The trial excluded patients with prior autologous transplant within 6 months or allogeneic transplant, prior exposure to a [[PI3K]] inhibitor or a Bruton’s [[tyrosine kinase]] (BTK) inhibitor. The trial required [[hepatic transaminases]] ≤ 3 times upper limit of normal (ULN), total [[bilirubin]] ≤ 1.5 times ULN, and [[serum creatinine]] ≤ 2 times ULN.<br />
*The study randomized patients with a 1:1 ratio to receive either duvelisib 25 mg BID until disease progression or unacceptable toxicity or [[ofatumumab]] for 7 cycles. Ofatumumab was administered intravenously at an initial dose of 300 mg, followed one week later by 2000 mg once weekly for 7 doses, and then 2000 mg once every 4 weeks for 4 additional doses.<br />
*The approval of duvelisib was based on efficacy and safety analysis of patients with at least 2 prior lines of therapy, where the benefit:risk appeared greater in this more heavily pretreated population compared to the overall trial population.<br />
*In this subset (95 randomized to duvelisib, 101 to [[ofatumumab]]), the median patient age was 69 years (range: 40 to 90 years), 59% were male, and 88% had an ECOG performance status of 0 or 1. Forty-six percent received 2 prior lines of therapy, and 54% received 3 or more prior lines. At baseline, 52% of patients had at least one tumor ≥ 5 cm, and 22% of patients had a documented 17p deletion.<br />
*During randomized treatment, the median duration of exposure to duvelisib was 13 months (range: 0.2 to 37), with 80% of patients receiving at least 6 months and 52% receiving at least 12 months of duvelisib. The median duration of exposure to [[ofatumumab]] was 5 months (range: < 0.1 to 6).<br />
*Efficacy was based on progression-free survival (PFS) as assessed by an Independent Review Committee (IRC). Other efficacy measures included overall response rate. Efficacy of duvelisib compared to [[ofatumumab]] specifically in patients treated with at least two prior therapies is presented in TABLE 8 and FIGURE 1.<br />
[[File:DuvelisibTable8.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
[[File:DuvelisibFigure1.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
=====Efficacy in Relapsed or Refractory [[FL]]=====<br />
Study 2<br />
*Efficacy of duvelisib in patients with previously treated [[FL]] is based on a single-arm, multicenter trial (Study 2; NCT02204982). In this study, duvelisib 25 mg BID was administered in patients with [[FL]] (N = 83) who were refractory to [[rituximab]] and to either [[chemotherapy]] or [[radioimmunotherapy]]. Refractory disease was defined as less than a partial remission or relapse within 6 months after the last dose. The trial excluded patients with Grade 3b [[FL]], large cell transformation, prior allogeneic transplant, and prior exposure to a [[PI3K]] inhibitor or to a Bruton’s [[tyrosine]] [[kinase inhibitor]].<br />
*The median age was 64 years (range: 30 to 82 years), 68% were male, and 37% had bulky disease assessed at baseline (target lesion ≥ 5 cm). Patients had a median of 3 prior lines of therapy (range: 1 to 10), with 94% being refractory to their last therapy and 81% being refractory to 2 or more prior lines of therapy. Most patients (93%) had an ECOG performance status of 0 or 1.<br />
*The median duration of exposure to duvelisib was 5 months (range: 0.4 to 24), with 41% of patients receiving at least 6 months and 10% receiving at least 12 months of duvelisib.<br />
*Efficacy was based on overall response rate and duration of response as assessed by an IRC (TABLE 9).<br />
[[File:DuvelisibTable9.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
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|howSupplied=<br />
*Duvelisib capsules are supplied as follows:<br />
[[File:DuvelisibSupplied.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
|NDC=<br />
|storage=<br />
*Store at 20° to 25°C (68° to 77°F), with excursions permitted at 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Retain in original package until dispensing. Dispense blister packs in original container.<br />
|manBy= <br />
|distBy=<br />
|drugImages=<br />
|packLabel=<br />
[[File:DuvelisibLabel1.jpeg|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
[[File:DuvelisibLabel2.jpeg|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
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[[File:DuvelisibLabel3.jpeg|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
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[[File:DuvelisibLabel4.jpeg|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
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[[File:DuvelisibLabel5.jpeg|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
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[[File:DuvelisibLabel6.jpeg|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
{{clear}}<br />
|fdaPatientInfo=<br />
*Advise the patient to read the FDA-approved patient labeling (MEDICATION GUIDE).<br />
*Physicians and healthcare professionals are advised to discuss the following with patients prior to treatment with duvelisib:<br />
Infections<br />
*Advise patients that duvelisib can cause serious [[infections]] that may be fatal. Advise patients to immediately report symptoms of infection (e.g. [[fever]], [[chills]]).<br />
Diarrhea or Colitis<br />
*Advise patients that duvelisib can cause serious [[diarrhea]] or [[colitis]] (inflammation of the gut) that may be fatal, and to notify their healthcare provider immediately about any new or worsening diarrhea, stool with mucus or blood, or [[abdominal pain]].<br />
Cutaneous Reactions<br />
*Advise patients that duvelisib can cause a serious [[skin rash]] that may be fatal, and to notify their healthcare provider immediately if they develop a new or worsening skin rash.<br />
Pneumonitis<br />
*Advise patients that duvelisib may cause [[pneumonitis]] (inflammation of the lungs) that may be fatal, and to report any new or worsening respiratory symptoms including [[cough]] or [[difficulty breathing]].<br />
Hepatotoxicity<br />
*Advise patients that duvelisib may cause significant elevations in [[liver enzymes]], and that monitoring of liver tests is needed. Advise patients to report symptoms of liver dysfunction including [[jaundice]] (yellow eyes or yellow skin), [[abdominal pain]], [[bruising]], or bleeding.<br />
Neutropenia<br />
*Advise patients of the need for periodic monitoring of [[blood counts]]. Advise patients to notify their healthcare provider immediately if they develop a [[fever]] or any sign of [[infection]].<br />
Embryo-Fetal Toxicity<br />
*Advise females to inform their healthcare provider if they are [[pregnant]] or become pregnant. Inform female patients of the risk to a fetus.<br />
*Advise females of reproductive potential to use effective [[contraception]] during treatment and for at least 1 month after receiving the last dose of duvelisib.<br />
*Advise males with female partners of reproductive potential to use effective [[contraception]] during treatment with duvelisib and for at least 1 month after the last dose.<br />
Lactation<br />
*Advise lactating women not to breastfeed during treatment with duvelisib and for at least 1 month after the last dose.<br />
*Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products, before and during treatment with duvelisib.<br />
Instructions for Taking Duvelisib<br />
*Advise patients to take duvelisib exactly as prescribed. Duvelisib may be taken with or without food; the capsules should be swallowed whole.<br />
*Advise patients that if a dose is missed by fewer than 6 hours, to take the missed dose right away and take the next dose as usual. If a dose is missed by more than 6 hours, advise patients to wait and take the next dose at the usual time.<br />
=====Medication Guide=====<br />
[[File:DuvelisibMedGuide.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]<br />
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|nlmPatientInfo=<br />
|alcohol=<br />
|brandNames=[[Copiktra]]<br />
|lookAlike=<br />
|drugShortage=<br />
|price=<br />
}}</div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=Small_Lymphocytic_Lymphoma&diff=1577403Small Lymphocytic Lymphoma2019-07-30T16:17:44Z<p>Zach Leibowitz: ←Redirected page to Small cell lymphoma</p>
<hr />
<div>#redirect[[Small cell lymphoma]]</div>Zach Leibowitzhttps://www.wikidoc.org/index.php?title=Bipolar_disorder_historical_perspective&diff=1577397Bipolar disorder historical perspective2019-07-30T15:43:27Z<p>Zach Leibowitz: </p>
<hr />
<div>__NOTOC__<br />
{{Bipolar disorder}}<br />
{{CMG}}<br />
==Overview==<br />
<br />
* The connection between mania and melancholia dates back to the 2nd Century CE.<br />
** Soranus of Ephesus (98-177 CE), a Greek physician, characterized mania and melancholia as separate illnesses.<br />
* German [[psychiatrist]] [[Emil Kraepelin]] ([[1856]]-[[1926]]) examined and classified the natural course of patients with untreated bipolar disorder years prior to the discovery of [[mood stabilizer]]s.<br />
** In 1902, Kraepelin created the term ''manic depressive psychosis'' to describe these patients.<br />
* In 1957, Karl Leonhard, a German psychiatrist, coined the terms ''bipolar'' and ''unipolar'' to describe subclassifications of manic depressive psychosis (bipolar disorder).<br />
** ''Bipolar'' was used to describe cases with manic episodes.<br />
** ''Unipolar'' was used to describe cases characterized by the presence of depressive episodes and the lack of manic episodes.<br />
<br />
==Historical Perspective==<br />
<br />
* Humans have experienced cycles of varying moods and energy levels for thousands of years.<br />
* The terms ''melancholia'' and ''mania'' originated in Ancient Greece.<br />
** ''Melancholia'' originates from the Greek words ''melas'' and ''chole,'' meaning "black" and "bile" or "gall"<ref name="Liddell 1980">{{cite book|author = [[Henry George Liddell|Liddell, Henry George]] and [[Robert Scott (philologist)|Robert Scott]] | year = 1980 | title = [[A Greek-English Lexicon]] (Abridged Edition) | publisher = [[Oxford University Press]] | location = United Kingdom | id = ISBN 0-19-910207-4}}</ref> respectively.<br />
** ''Mania'' originates from the Greek words ''ania'' and ''manos,'' meaning "to produce great mental anguish" and "relaxed or loose" respectively.<br />
* Both mania and melancholia were thought to arise from imbalances in the body's humors. Mania was thought to result from excess amounts of yellow bile, while melancholia was thought to result from excess black bile.<br />
* The connection between mania and melancholia dates back to the 2nd Century CE.<sup>[http://www.k12academics.com/bipolar_history.htm]</sup><br />
** Soranus of Ephesus (98-177 CE), a Greek physician, characterized mania and melancholia as separate illnesses<sup>[http://assets.cambridge.org/97805218/35176/excerpt/9780521835176_excerpt.pdf]</sup> during a period where many viewed melancholia as a type of mania.<br />
** Aretaeus of Cappadocia, a medical philosopher who lived between the years 30 and 150 CE, is credited with the earliest accounts of a connection between melancholia and mania. Aretaeus wrote many texts that survive today in which he described manic-depressive disease that he believed originated in black bile.<br />
* Early Chinese authors established clear classification of bipolar disorder as a mental illness. For example, author and encyclopedist Gao Lian (c. 1583) described the disorder in ''Eight Treatises on the Nurturing of Life.''<sup>[http://www.nmh.gov.tw/nmh_web/english_version/exhibition/exhibition_s0703.cfm]</sup><br />
* The modern psychiatric understanding of manic-depressive illness is often traced to the 1850s.<br />
** On January 31, 1854, French psychologist Jules Baillarger presented a description of a biphasic mental illness characterized by alternating periods of mania and depression to the French Imperial Academy of Medicine. Baillarger termed the illness "folie à double forme" (dual-form insanity).<br />
* German psychiatrist Emil Kraepelin (1856-1926) examined and classified the natural course of patients with untreated bipolar disorder years prior to the discovery of mood stabilizers.<br />
** In 1902, Kraepelin created the term manic depressive psychosis to describe these patients.<br />
** He observed that periods of acute illness (manic or depressive) were often preceded and followed by symptom-free periods in which patients were able to function normally.<ref>[[Emil Kraepelin|Kraepelin, Emil]] (1921) ''Manic-depressive Insanity and Paranoia'' ISBN 0-405-07441-7 </ref><br />
* Following the Second World War, Australian psychiatrist Dr. John Cade conducted research on the effectiveness of different compounds in treating veterans with manic-depressive illness. Through his research, Dr. Cade found that lithium carbonate was effective at treating manic-depressive illness<ref>{{cite journal <br />
| title = Lithium salts in the treatment of psychotic excitement<br />
| author = Cade J. F. J.<br />
| journal = Medical Journal of Australia<br />
| year = 1949<br />
| volume = 2 <br />
| issue = <br />
| pages = 349–352<br />
| url = http://www.who.int/docstore/bulletin/pdf/2000/issue4/classics.pdf}}</ref>. Lithium was not widely used as a treatment immediately following Dr. Cade's discovery as many held fears of its toxicity. However, following the use of lithium in the treatment of manic-depressive disorder in some hospitals beginning in the 1950s and reports of the benefits of lithium treatment in medical journals in the 1960s, the Food and Drug Administration approved the use of lithium as a treatment for manic-depressive illness in 1970<ref>{{cite journal <br />
| title =Lithium treatment for bipolar disorder<br />
| author = P. B. Mitchell, D. Hadzi-Pavlovic<br />
| journal = Bulletin of the World Health Organization<br />
| year = 2000<br />
| volume = 78 <br />
| issue =4<br />
| pages = 515-519<br />
| url = http://www.who.int/docstore/bulletin/pdf/2000/issue4/classics.pdf}}</ref>.<br />
* In 1952, the phrase "manic-depressive ''reaction''" was included in the first American Psychiatric Association Diagnostic Manual, demonstrating the belief that the disease was a result of a reaction of biogenetic factors to social/environmental factors.<ref>Goodwin & Jamison. p60-61</ref><br />
* In 1957, Karl Leonhard, a German psychiatrist, coined the terms ''bipolar'' and ''unipolar'' to describe subclassifications of manic depressive psychosis (bipolar disorder).<ref>Goodwin & Jamison. p62</ref><br />
**''Bipolar'' was used to describe cases with manic episodes.<br />
**''Unipolar'' was used to describe cases characterized by the presence of depressive episodes and the lack of manic episodes.<br />
* In 1968, ICD-8 and DSM-II both called the condition "manic-depressive ''illness,"'' demonstrating the increasing biological thinking surrounding the condition.<ref>Goodwin & Jamison. p88</ref><br />
* The current term for the condition, bipolar disorder, recently became popular, though some prefer the old nosology and claim that "manic-depressive illness" better described the multifaceted illness.<br />
<br />
==References==<br />
<br />
{{reflist|2}}<br />
{{WH}}<br />
{{WS}}</div>Zach Leibowitz