View source for Fremanezumab-vfrm

{{DrugProjectFormSinglePage
|authorTag={{ZL}}
|genericName=fremanezumab-vfrm
|aOrAn=a
|drugClass=[[calcitonin gene-related peptide]] antagonist
|indication=[[migraine]] in adults
|indicationType=preventive treatment
|hasBlackBoxWarning=
|blackBoxWarningTitle=
|blackBoxWarningBody=
|fdaLIADAdult=
Indication
*Fremanezumab-vfrm is indicated for the preventive treatment of [[migraine]] in adults.
Dosage
*Two [[subcutaneous]] dosing options of fremanezumab-vfrm are available to administer the recommended dosage:
**225 mg monthly, or
**675 mg every 3 months (quarterly), which is administered as three consecutive [[subcutaneous]] injections of 225 mg each.
|offLabelAdultGuideSupport=
There is limited information regarding fremanezumab-vfrm Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
|offLabelAdultNoGuideSupport=
There is limited information regarding fremanezumab-vfrm Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
|fdaLIADPed=
Safety and effectiveness in pediatric patients have not been established.
|offLabelPedGuideSupport=
There is limited information regarding fremanezumab-vfrm Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
|offLabelPedNoGuideSupport=
There is limited information regarding fremanezumab-vfrm Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
|contraindications=
*Fremanezumab-vfrm is contraindicated in patients with serious [[hypersensitivity]] to fremanezumab-vfrm or to any of the excipients.
|warnings=
=====Hypersensitivity Reactions=====
*[[Hypersensitivity reactions]], including [[rash]], [[pruritus]], [[drug hypersensitivity]], and [[urticaria]], were reported with fremanezumab-vfrm in clinical trials. Most reactions were mild to moderate, but some led to discontinuation or required [[corticosteroid]] treatment. Most reactions were reported from within hours to one month after administration.
*If a [[hypersensitivity reaction]] occurs, consider discontinuing fremanezumab-vfrm, and institute appropriate therapy.
|adverseReactions=[[injection site reactions]]
|clinicalTrials=
*Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates observed in clinical practice.
*The safety of fremanezumab-vfrm was evaluated in 2512 patients with [[migraine]] who received at least 1 dose of fremanezumab-vfrm, representing 1279 patient-years of exposure. Of these, 1730 patients were exposed to fremanezumab-vfrm 225 mg monthly or fremanezumab-vfrm 675 mg quarterly for at least 6 months, 775 patients for at least 12 months, and 138 patients for at least 15 months. In placebo-controlled clinical trials (Studies 1 and 2), 662 patients received fremanezumab-vfrm 225 mg monthly for 12 weeks (with or without a loading dose of 675 mg), and 663 patients received fremanezumab-vfrm 675 mg quarterly for 12 weeks. In the controlled trials, 87% of patients were female, 80% were White, and the mean age was 41 years.
*The most common adverse reactions in the clinical trials for the preventive treatment of [[migraine]] (incidence at least 5% and greater than placebo) were [[injection site reactions]]. The adverse reactions that most commonly led to discontinuations were [[injection site reactions]] (1%). Table 1 summarizes adverse reactions reported in the 3-month placebo-controlled studies (Study 1 and Study 2), and the 1-month follow-up period after those studies.
[[File:FremanezumabTable1.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]
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===Immunogenicity===
*As with all therapeutic proteins, there is a potential for [[immunogenicity]]. The detection of [[antibody]] formation is highly dependent on 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 fremanezumab-vfrm in the studies described below with the incidence of antibodies in other studies to other products may be misleading. Clinical immunogenicity of fremanezumab-vfrm was monitored by analyzing anti-drug antibodies (ADA) and neutralizing antibodies in drug-treated patients. The data reflect the percentage of patients whose test results were positive for antibodies to fremanezumab-vfrm in specific assays.
*In 3-month placebo-controlled studies, treatment-emergent ADA responses were observed in 6 out of 1701 (0.4%) fremanezumab-vfrm-treated patients. One of the 6 patients developed anti-fremanezumab-vfrm neutralizing [[antibodies]] at Day 84. In the ongoing long-term open-label study, ADA were detected in 1.6% of patients (30 out of 1888). Out of 30 ADA-positive patients, 17 had a neutralizing activity in their post-dose samples. Although these data do not demonstrate an impact of anti-fremanezumab-vfrm antibody development on the efficacy or safety of fremanezumab-vfrm in these patients, the available data are too limited to make definitive conclusions.
|postmarketing=
|drugInteractions=
|FDAPregCat=
|useInPregnancyFDA=
Risk Summary
*There are no adequate data on the developmental risk associated with the use of fremanezumab-vfrm in pregnant women. Fremanezumab-vfrm has a long half-life. This should be taken into consideration for women who are pregnant or plan to become pregnant while using fremanezumab-vfrm. Administration of fremanezumab-vfrm to rats and rabbits during the period of [[organogenesis]] or to rats throughout [[pregnancy]] and lactation at doses resulting in plasma levels greater than those expected clinically did not result in adverse effects on development [see Animal Data]. 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]].
Clinical Considerations <br>
''Disease-Associated Maternal and/or Embryo/Fetal Risk''
*Published data have suggested that women with [[migraine]] may be at increased risk of [[preeclampsia]] during [[pregnancy]].
Animal Data
*When fremanezumab-vfrm (0, 50, 100, or 200 mg/kg) was administered to male and female rats by weekly [[subcutaneous injection]] prior to and during mating and continuing in females throughout [[organogenesis]], no adverse embryofetal effects were observed. The highest dose tested was associated with plasma exposures (AUC) approximately 2 times that in humans at a dose of 675 mg.
*Administration of fremanezumab-vfrm (0, 10, 50, or 100 mg/kg) weekly by [[subcutaneous injection]] to pregnant rabbits throughout the period of [[organogenesis]] produced no adverse effects on embryofetal development. The highest dose tested was associated with plasma AUC approximately 3 times that in humans (675 mg).
*Administration of fremanezumab-vfrm (0, 50, 100, or 200 mg/kg) weekly by [[subcutaneous injection]] to female rats throughout [[pregnancy]] and lactation resulted in no adverse effects on pre- and postnatal development. The highest dose tested was associated with plasma AUC approximately 2 times that in humans (675 mg).
|AUSPregCat=
|useInPregnancyAUS=
|useInLaborDelivery=
|useInNursing=
Risk Summary
*There are no data on the presence of fremanezumab-vfrm 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 fremanezumab-vfrm and any potential adverse effects on the breastfed infant from fremanezumab-vfrm or from the underlying maternal condition.
|useInPed=
*Safety and effectiveness in pediatric patients have not been established.
|useInGeri=
*Clinical studies of fremanezumab-vfrm did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
|useInGender=
|useInRace=
|useInRenalImpair=
|useInHepaticImpair=
|useInReproPotential=
|useInImmunocomp=
|othersTitle=
|useInOthers=
|administration=
=====Recommended Dosage=====
*Two [[subcutaneous]] dosing options of fremanezumab-vfrm are available to administer the recommended dosage:
**225 mg monthly, or
**675 mg every 3 months (quarterly), which is administered as three consecutive [[subcutaneous injection]]s of 225 mg each.
*When switching dosage options, administer the first dose of the new regimen on the next scheduled date of administration. If a dose of fremanezumab-vfrm is missed, administer as soon as possible. Thereafter, fremanezumab-vfrm can be scheduled from the date of the last dose.
=====Important Administration Instructions=====
*Fremanezumab-vfrm is for [[subcutaneous]] use only.
*Fremanezumab-vfrm may be administered by healthcare professionals, patients, and/or caregivers. Prior to use, provide proper training to patients and/or caregivers on the preparation and administration of fremanezumab-vfrm prefilled syringe, including [[aseptic technique]]:
**Remove fremanezumab-vfrm from the refrigerator. Prior to use, allow fremanezumab-vfrm to sit at room temperature for 30 minutes protected from direct sunlight. Do not warm by using a heat source such as hot water or a microwave. Do not use fremanezumab-vfrm if it has been at room temperature for 24 hours or longer.
**Follow aseptic injection technique every time fremanezumab-vfrm is administered.
**Inspect fremanezumab-vfrm for particles or discoloration prior to administration. Do not use if the solution is cloudy, discolored, or contains particles.
**Administer fremanezumab-vfrm by [[subcutaneous injection]] into areas of the abdomen, thigh, or upper arm that are not tender, bruised, red, or indurated. For multiple injections, you may use the same body site, but not the exact location of the previous injection.
**Do not co-administer fremanezumab-vfrm with other injectable drugs at the same injection site.
|monitoring=
|IVCompat=
|overdose=
|drugBox=
{{drugbox2
| type              = mab
| image             = 
| alt               = 
| mab_type          = mab
| source            = zu
| target            = [[Calcitonin gene-related peptide|CGRP]] α, β
<!-- Clinical data -->
| pronounce         =
| tradename         = Ajovy
| Drugs.com         = {{drugs.com|monograph|Fremanezumab-vfrm}}
| MedlinePlus       = a618053
| pregnancy_AU      = <!-- A/B1/B2/B3/C/D/X -->
| pregnancy_US      = <!-- A/B/C/D/X -->
| pregnancy_category=  
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->
| legal_AU_comment =
| legal_BR =  <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->
| legal_BR_comment =
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM -->
| legal_US = Rx-only
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_NZ = <!--Class A, B, C -->
| legal_status      = 
| routes_of_administration = [[Subcutaneous injection]]
| class             = [[Calcitonin gene-related peptide antagonist]]
<!-- Pharmacokinetic data -->
| bioavailability   = 55–66%
| protein_bound     = 
| metabolism        = [[Proteolysis]]
| metabolites       = 
| onset             = 
| elimination_half-life = 30–31 days (estimated)
| duration_of_action= 
| excretion         = [[Kidney]]
<!-- Identifiers -->
| CAS_number        = 1655501-53-3
| ATC_prefix        = N02
| ATC_suffix        = CX09
| PubChem           = 
| DrugBank          = DB14041
| UNII              = PF8K38CG54
| KEGG              = D11055
| synonyms          = TEV-48125
| ChemSpiderID      = none

| C=6470 | H=9952 | N=1716 | O=2016 | S=46
}}
|mechAction=
*Fremanezumab-vfrm is a humanized [[monoclonal antibody]] that binds to [[calcitonin gene-related peptide]] (CGRP) [[ligand]] and blocks its binding to the receptor.
|structure=
*Fremanezumab-vfrm is a fully humanized IgG2Δa/kappa [[monoclonal antibody]] specific for [[calcitonin gene-related peptide]] (CGRP) [[ligand]]. Fremanezumab-vfrm is produced by [[recombinant DNA technology]] in Chinese hamster ovary (CHO) cells. The [[antibody]] consists of 1324 [[amino acids]] and has a molecular weight of approximately 148 kDa.
|PD=
*The relationship between the pharmacodynamic activity and the mechanism(s) by which fremanezumab-vfrm exerts its clinical effects is unknown.
|PK=
Absorption
*After single [[subcutaneous]] (SC) administrations of 225 mg, 675 mg, and 900 mg fremanezumab-vfrm, median time to maximum concentrations (t<sub>max</sub>) was 5 to 7 days. Dose-proportionality, based on population PK, was observed between 225 mg to 900 mg. Steady state was achieved by approximately 168 days (about 6 months) following 225 mg SC monthly and 675 mg SC quarterly dosing regimens. Median accumulation ratio, based on once-monthly and once-quarterly dosing regimens, is approximately 2.3 and 1.2, respectively.
Distribution
*Fremanezumab-vfrm has an apparent volume of distribution of approximately 6 liters, suggesting minimal distribution to the extravascular tissues.
Metabolism
*Similar to other [[monoclonal antibodies]], fremanezumab-vfrm is degraded by enzymatic [[proteolysis]] into small [[peptides]] and [[amino acids]].
Elimination
*Fremanezumab-vfrm apparent clearance was approximately 0.141 L/day. Fremanezumab-vfrm was estimated to have a half-life of approximately 31 days.
Specific Populations
*A population PK analysis assessing effects of age, race, sex, and weight was conducted on data from 2287 subjects. No dose adjustments are recommended for fremanezumab-vfrm.
Patients with Hepatic or Renal Impairment
*[[Hepatic]]/[[renal impairment]] is not expected to affect the pharmacokinetics of fremanezumab. A population PK analysis of integrated data from the fremanezumab-vfrm clinical studies did not reveal a difference in the pharmacokinetics of fremanezumab in patients with mild [[hepatic impairment]], relative to those with normal hepatic function. There were only 4 patients with moderate hepatic impairment, and no patient with severe hepatic impairment in fremanezumab clinical studies. No dedicated hepatic/renal impairment studies were conducted to assess the effect of hepatic or [[renal impairment]] on the pharmacokinetics of fremanezumab.
Drug Interactions
*Fremanezumab is not metabolized by [[cytochrome P450]] [[enzymes]]; therefore, interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely. Additionally, the effects of medications for the acute treatment (specifically [[analgesics]], [[ergot]]s, and [[triptans]]) and preventive treatment of [[migraine]] were evaluated in a population PK model, and found not to influence fremanezumab exposure.
|nonClinToxic=
=====Carcinogenesis, Mutagenesis, Impairment of Fertility=====
Carcinogenesis
*Carcinogenicity studies of fremanezumab-vfrm were not conducted.
Mutagenesis
*Genetic toxicology studies of fremanezumab-vfrm were not conducted.
Impairment of Fertility
*When fremanezumab-vfrm (0, 50, 100, or 200 mg/kg) was administered to male and female rats by weekly [[subcutaneous injection]] prior to and during mating and continuing in females throughout [[organogenesis]], no adverse effects on male or female [[fertility]] were observed. The highest dose tested was associated with plasma exposures (AUC) approximately 2 times that in humans at a dose of 675 mg.
|clinicalStudies=
*The efficacy of fremanezumab-vfrm was evaluated as a preventive treatment of episodic or chronic [[migraine]] in two multicenter, randomized, 3-month, double-blind, placebo-controlled studies (Study 1 and Study 2, respectively).
''Episodic Migraine''
*Study 1 (NCT 02629861) included adults with a history of episodic [[migraine]] (patients with <15 [[headache]] days per month). All patients were randomized (1:1:1) to receive [[subcutaneous injection]]s of either fremanezumab-vfrm 675 mg every three months (quarterly), fremanezumab-vfrm 225 mg monthly, or placebo monthly, over a 3-month treatment period. Patients were allowed to use acute [[headache]] treatments during the study. A subset of patients (21%) was allowed to use one additional concomitant preventive medication.
*The study excluded patients with a history of significant [[cardiovascular disease]], vascular [[ischemia]], or [[thrombotic]] events, such as [[cerebrovascular accident]], [[transient ischemic attacks]], [[deep vein thrombosis]], or [[pulmonary embolism]].
*The primary efficacy endpoint was the mean change from baseline in the monthly average number of [[migraine]] days during the 3-month treatment period. Secondary endpoints included the proportion of patients reaching at least a 50% reduction in monthly average number of [[migraine]] days during the 3-month treatment period, the mean change from baseline in the monthly average number of days of use of any acute [[headache]] medication during the 3-month treatment period, and the mean change from baseline in the number of [[migraine]] days during the first month of the treatment period.
*In Study 1, a total of 875 patients (742 females, 133 males), ranging in age from 18 to 70 years, were randomized. A total of 791 patients completed the 3-month double-blind phase. The mean [[migraine]] frequency at baseline was approximately 9 [[migraine]] days per month, and was similar across treatment groups.
*Both monthly and quarterly dosing regimens of fremanezumab-vfrm demonstrated statistically significant improvements for efficacy endpoints compared to placebo over the 3-month period, as summarized in Table 2.
[[File:FremanezumabTable2.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]
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*Figure 1 displays the mean change from baseline in the average monthly number of [[migraine]] days in Study 1.
[[File:FremanezumabFigure1.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]
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*Figure 2 shows the distribution of change from baseline in mean monthly [[migraine]] days in bins of 2 days by treatment group in Study 1. A treatment benefit over placebo for both doses of fremanezumab-vfrm is seen across a range of changes from baseline in monthly [[migraine]] days.
[[File:FremanezumabFigure2.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]
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*Study 2 (NCT 02621931) included adults with a history of chronic [[migraine]] (patients with ≥15 [[headache]] days per month). All patients were randomized (1:1:1) to receive [[subcutaneous injection]]s of either fremanezumab-vfrm 675 mg starting dose followed by 225 mg monthly, 675 mg every 3 months (quarterly), or placebo monthly, over a 3-month treatment period. Patients were allowed to use acute headache treatments during the study. A subset of patients (21%) was allowed to use one additional concomitant, preventive medication.
*The study excluded patients with a history of significant [[cardiovascular disease]], vascular [[ischemia]], or [[thrombotic]] events, such as [[cerebrovascular accident]], [[transient ischemic attacks]], [[deep vein thrombosis]], or [[pulmonary embolism]].
*The primary efficacy endpoint was the mean change from baseline in the monthly average number of [[headache]] days of at least moderate severity during the 3-month treatment period. The secondary endpoints were the mean change from baseline in the monthly average number of [[migraine]] days during the 3-month treatment period, the proportion of patients reaching at least 50% reduction in the monthly average number of headache days of at least moderate severity during the 3-month treatment period, the mean change from baseline in the monthly average number of days of use of any acute headache medication during the 3-month treatment period, and the mean change from baseline in the number of headache days of at least moderate severity during the first month of treatment.
*In Study 2, a total of 1130 patients (991 females, 139 males), ranging in age from 18 to 70 years, were randomized. A total of 1034 patients completed the 3-month double-blind phase.
*Both monthly and quarterly dosing regimens of fremanezumab-vfrm treatment demonstrated statistically significant improvement for key efficacy outcomes compared to placebo, as summarized in Table 3.
[[File:FremanezumabTable3.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]
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*Figure 3 displays the mean change from baseline in the average monthly number of [[headache]] days of at least moderate severity in Study 2.
[[File:FremanezumabFigure3.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]
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*Figure 4 shows the distribution of change from baseline in monthly [[headache]] days of at least moderate severity at month 3 in bins of 3 days by treatment group. A treatment benefit over placebo for both dosing regimens of fremanezumab-vfrm is seen across a range of changes from baseline in headache days.
[[File:FremanezumabFigure4.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]
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|howSupplied=
*Fremanezumab-vfrm injection is a sterile, preservative-free, clear to opalescent, colorless to slightly yellow solution for [[subcutaneous]] administration.
*The prefilled syringe cap is not made with natural rubber latex.
*Fremanezumab-vfrm is supplied as follows:
**NDC 51759-204-10: carton of one 225 mg/1.5 mL single-dose prefilled syringe
|NDC=
|storage=
*Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original outer carton to protect from light.
*If necessary, fremanezumab-vfrm may be kept in the original carton at room temperature up to 25°C (77°F) for a maximum of 24 hours. After removal from the refrigerator, fremanezumab-vfrm must be used within 24 hours or discarded.
*Do not freeze.
*Do not expose to extreme heat or direct sunlight.
*Do not shake.
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|packLabel=
[[File:FremanezumabLabel1.jpeg|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]
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[[File:FremanezumabLabel2.jpeg|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]
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|fdaPatientInfo=
Information on Preparation and Administration
*Provide guidance to patients and caregivers on proper [[subcutaneous]] administration technique, including [[aseptic technique]], and how to use the single-dose prefilled syringe. Instruct patients and/or caregivers to read and follow the Instructions for Use each time they use fremanezumab-vfrm.
*Instruct patients prescribed the regimen of 675 mg every 3 months to administer the dosage as three consecutive [[subcutaneous injection]]s of 225 mg each.
Hypersensitivity Reactions
*Inform patients about the signs and symptoms of [[hypersensitivity reactions]] and that these reactions can occur up to 1 month after administration. Advise patients to contact their healthcare provider immediately if signs or symptoms of hypersensitivity reactions occur.
=====Medication Guide=====
[[File:FremanezumabMedGuide.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]
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=====Instructions for Use=====
[[File:FremanezumabInstruct.png|600px|thumbnail|left|This image is provided by the National Library of Medicine.]]
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|nlmPatientInfo=
|alcohol=
|brandNames=[[Ajovy]]
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