Fremanezumab, a recombinant fully humanized immunoglobulin G2a (IgG2a) monoclonal antibody specific for calcitonin gene-related peptide (CGRP) ligand, is an antimigraine agent.1, 9
Preventive Treatment of Episodic Migraine
Fremanezumab-vfrm is used for the preventive treatment of episodic migraine in pediatric patients (6-17 years of age) who weigh at least 45 kg.1
Efficacy of fremanezumab for the preventive treatment of episodic migraine in pediatric patients 6 to 17 years of age was established in a multicenter, randomized, 3-month, double-blind, placebo-controlled study.1 Enrolled patients (n=235) had a history of episodic migraine (<15 headache days per month) and were randomly assigned to either fremanezumab or placebo subcutaneously as a once monthly injection.1 Fremanezumab dose was based on weight with patients weighing ≥45 kg administered 225 mg and those weighing <45 kg administered 120 mg.1 The primary end point was the mean change from baseline in the average number of migraine days during the 3-month treatment period.1
Of the 225 patients who completed the treatment period, fremanezumab was associated with a significant improvement in mean change from baseline in the average number of migraine days (-2.5 days for fremanezumab and -1.4 days for placebo).1 In addition, fremanezumab therapy was associated with a significant improvement in the proportion of patients experiencing ≥50% reduction in the monthly average number of migraine days (47.2% versus 27%) and the mean change from baseline in the monthly average number of days of use of any acute headache medication (-2.1 days versus -1.0 days).1
Fremanezumab-vfrm is administered by subcutaneous injection only.1 Fremanezumab-vfrm injection is commercially available in single-use prefilled syringes and auto-injectors containing 225 mg of the drug in 1.5 mL of solution.1 The drug may be administered by healthcare professionals, patients ≥13 years of age, and/or caregivers.1 A healthcare professional or adult caregiver must administer the drug to pediatric patients 6-12 years of age.1
Prior to use, patients and/or caregivers should receive proper training on how to prepare and administer fremanezumab-vfrm using the single-use prefilled syringes, including aseptic technique.1 The manufacturer's labeling should be consulted for detailed instructions regarding subcutaneous administration of the drug using the prefilled syringes or auto-injectors.1
Fremanezumab-vfrm should be administered subcutaneously into the abdomen, anterior thigh, or back of the upper arm; injections within 2 inches of the navel, knee, or groin should be avoided.1 Multiple injections of the drug (i.e., to administer a 675-mg dose) may be administered at the same body site, but not at the exact location of the previous injection.1 Fremanezumab-vfrm should not be administered concomitantly with other parenteral drugs at the same injection site.1 Injection into areas where the skin is tender, bruised, erythematous, or indurated should be avoided.1
Prefilled syringes and auto-injectors of fremanezumab-vfrm should be stored at 2-8°C in the original outer carton to protect from light.1 The syringes and auto-injectors may be stored at room temperature up to 30°C in the original carton for up to 7 days; the syringes and auto-injectors should not be returned to the refrigerator after storage at room temperature.1 If the syringes or auto-injectors are stored at room temperature for 7 days or more, they should be discarded.1 The prefilled syringes and auto-injectors should not be frozen, shaken, or exposed to extreme heat or direct sunlight.1
Prior to subcutaneous administration, prefilled syringes and auto-injectors of fremanezumab-vfrm should be removed from the refrigerator and allowed to sit at room temperature for 30 minutes protected from direct sunlight.1 Do not warm the syringes or auto-injectors by using a heat source (e.g., microwave, hot water).1 Prior to administration, the solution should be inspected visually for particulate matter and discoloration; the syringe or auto-injector should not be used if the solution is cloudy or discolored or contains particles.1 The prefilled syringes and auto-injectors are intended for single use only and should be discarded after use.1
Preventive Treatment of Migraine
For the preventive treatment of migraine in adults, the recommended dosage of fremanezumab-vfrm is 225 mg once monthly or 675 mg every 3 months (quarterly) by subcutaneous injection.1 The 675-mg dose should be administered as 3 consecutive subcutaneous injections of 225 mg each.1 There does not appear to be a need for dosage titration with fremanezumab-vfrm; therapy may be initiated with either the 225-mg monthly dose or the 675-mg quarterly dose.1, 12
When switching dosage regimens, the first dose of the new dosage regimen should be administered on the next scheduled date of administration.1
If a dose of fremanezumab-vfrm is missed, the missed dose should be administered as soon as possible.1 Subsequent doses may then be scheduled monthly (225-mg doses) or every 3 months (675-mg doses) from the date of the last administered dose.1
The risk of adverse drug interactions with fremanezumab appears to be minimal.1, 5, 6, 12 When initiating therapy with fremanezumab or another calcitonin gene-related peptide (CGRP) antagonist in a patient who is already receiving a preventive treatment for migraine, the American Headache Society (AHS) recommends adding the CGRP antagonist to the existing antimigraine regimen and not making other changes until the clinical efficacy of the CGRP antagonist is determined.12
Patients who respond to CGRP antagonist therapy usually respond following the first 3 subcutaneous injections.12 Therefore, the AHS recommends assessing the clinical efficacy of fremanezumab after 3 months (if using the monthly dosage regimen) or 6 months (if using the quarterly dosage regimen) of treatment and continuing therapy only if treatment benefits have been observed with the drug by that time.12
Preventive Treatment of Episodic Migraine
For the preventive treatment of episodic migraine in pediatric patients 6-17 years of age who weigh ≥45 kg, the recommended dosage is 225 mg once monthly.1
If a dose of fremanezumab-vfrm is missed, the missed dose should be administered as soon as possible.1 Subsequent doses may then be scheduled from the date of the last administered dose.1
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Hypersensitivity reactions, including rash, pruritus, drug hypersensitivity, and urticaria, have been reported in patients receiving fremanezumab in clinical trials.1 Most of the hypersensitivity reactions were mild to moderate in severity, but some led to discontinuance of the drug or required corticosteroid therapy.1 Most reactions occurred within hours to one month after administration.1 In the postmarketing setting, cases of anaphylaxis and angioedema have been reported.1
If a hypersensitivity reaction occurs during fremanezumab therapy, discontinuance of the drug should be considered and appropriate medical therapy initiated.1
The manufacturer states that the prefilled syringe and prefilled auto-injector are not made with natural rubber latex.1
In postmarketing experience, hypertension development and worsening of pre-existing hypertension have been reported following the use of fremanezumab.1 Some patients with new-onset hypertension had risk factors for development of elevated blood pressure.1 In addition, some cases required initiation of pharmacological treatment for hypertension and/or hospitalization; discontinuation of fremanezumab occurred in many cases.1 Hypertension may develop at any time during treatment with fremanezumab, but was most frequently reported within 7 days of therapy initiation.1 Patients treated with fremanezumab should be monitored for new-onset hypertension, or worsening of pre-existing hypertension.1 Discontinuation of fremanezumab may be warranted if an alternative etiology for hypertension is not identified or blood pressure is inadequately controlled.1
In postmarketing experience, Raynaud's phenomenon development and recurrence or worsening of pre-existing Raynaud's phenomenon have been reported following the use of fremanezumab.1 Symptom onset occurred a median of 71 days following dosing.1 Many cases involved serious outcomes, including hospitalizations and disability, generally related to debilitating pain.1 Discontinuation of therapy resulted in symptom resolution in most cases.1 Clinicians should discontinue fremanezumab if signs or symptoms of Raynaud's phenomenon develop, and patients should be evaluated if symptoms do not resolve.1 Patients with a history of Raynaud's phenomenon should be monitored for, and informed about the possibility of, worsening or recurrence of signs and symptoms.1
As with all therapeutic proteins, there is a potential for immunogenicity with fremanezumab therapy.1
In placebo-controlled clinical studies of 3 months' duration in adults, anti-fremanezumab antibodies were detected in 6 of 1701 patients (0.4%) who received the drug.1 Anti-fremanezumab antibodies with neutralizing activity were detected in one of these patients at day 84 of treatment.1 In an ongoing long-term, open-label study, anti-fremanezumab antibodies were detected in 30 of 1888 patients (1.6%); over half of these patients (about 57%) had anti-fremanezumab antibodies with neutralizing activity.1 Although these data do not demonstrate an effect of anti-fremanezumab antibody development on the efficacy or safety of fremanezumab, the data currently are too limited to make definitive conclusions.1
In a placebo-controlled study of 3 months' duration in pediatric patients with episodic migraine, anti-fremanezumab antibodies were detected in 2 of 123 patients (1.6%) who received the drug.1 One of these patients developed neutralizing antibodies at day 84.1 These data are too limited to make definitive conclusions on the impact of anti-fremanezumab antibodies on the efficacy, safety, or pharmacokinetics of the drug in pediatric patients.1
There are no adequate data to date on the developmental risk associated with the use of fremanezumab in pregnant women.1 The manufacturer states that the long elimination half-life of fremanezumab should be considered if the drug is used in women who are pregnant or plan to become pregnant during therapy.1 Animal studies in pregnant rats and rabbits administered fremanezumab subcutaneously at dosages resulting in systemic exposures up to approximately 2-3 times the exposure from the maximum recommended human dosage (675 mg) did not adversely affect the development of the offspring.1
The estimated rates of major birth defects and miscarriage among deliveries to women with migraine (2.2-2.9 and 17%, respectively) are similar to rates reported in women without migraine.1 Clinicians should be aware that published data suggest that women with migraine may be at increased risk of preeclampsia during pregnancy.1
A registry that monitors outcomes in women exposed to fremanezumab during pregnancy exists; enrollment in the registry can occur by calling 833-927-2605 or visiting [Web].1
It is not known whether fremanezumab is distributed into human milk.1 The effects of the drug on breast-fed infants and on milk production also are unknown.1 The manufacturer states that the developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for fremanezumab and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1
The safety and efficacy of fremanezumab were established for the preventive treatment of episodic migraine in pediatric patients 6-17 years of age weighing ≥45 kg in an adequate and well-controlled study.1 The safety and efficacy profile of the drug in these patients was similar to that observed in clinical trials of adults with migraine.1
Fremanezumab is not approved for pediatric patients who weigh <45 kg due to lack of an appropriate strength presentation.1 Fremanezumab is also not approved for use in pediatric patients <6 years of age and the safety and efficacy of the drug have not been established for the preventive treatment of chronic migraine in pediatric patients.1
The Pediatric and Adolescent Headache special interest group of the American Headache Society (AHS) recommends that CGRP antagonists (e.g., erenumab, fremanezumab, galcanezumab) should be considered mainly for use in postpubertal adolescents† with relatively frequent migraines (i.e., 8 or more headache days per month) who have moderate to severe disability associated with migraine (e.g., PedMIDAS score of 30 or more) and in whom at least 2 preventive therapies (including pharmacologic and nonpharmacologic therapies and dietary supplements) have failed.11 For younger pediatric patients† with severe chronic migraine that is refractory to multiple preventive therapies, these experts recommend that CGRP antagonists be considered only in carefully selected patients with close monitoring (e.g., pubertal status, bone health, linear growth, weight, body mass index [BMI], infectious complications).11
Clinical trials of fremanezumab did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently than younger adults.1
Hepatic impairment is not expected to substantially affect the pharmacokinetics of fremanezumab.1, 5 No clinically significant differences in fremanezumab pharmacokinetics were predicted based on mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment.1 The effect of severe hepatic impairment (Child-Pugh Class C) on fremanezumab pharmacokinetics is unknown.1
Because of its large molecular size, renal excretion of intact fremanezumab is unlikely.5 Therefore, renal impairment is not expected to substantially affect pharmacokinetics of the drug.1, 5
The most common adverse reactions (≥5% and incidence greater than placebo) with fremanezumab are injection site reactions.1
Formal drug interaction studies with fremanezumab have not been conducted to date.5 The risk of clinically important drug interactions with the drug appears to be minimal.1, 5, 6, 12 Fremanezumab is not metabolized by cytochrome P-450 (CYP) enzymes.1 In addition, fremanezumab, a monoclonal antibody, is unlikely to affect drug-metabolizing enzymes or drug transport systems.5 Therefore, pharmacokinetic interactions with drugs affecting or metabolized by CYP enzymes or substrates of various drug transport systems are not expected.1, 5
Population pharmacokinetic modeling suggests that other antimigraine agents, including acute (i.e., analgesics, selective serotonin type 1 [5-hydroxytryptamine type 1; 5-HT1] receptor agonists [triptans], ergotamine derivatives) and preventive agents, do not affect systemic exposure of fremanezumab.1
In post hoc analyses from 2 controlled studies evaluating fremanezumab as add-on preventive therapy in patients receiving stable dosages of preventive migraine treatments (e.g., β-adrenergic blocking agents, calcium-channel blocking agents, gabapentin, topiramate, valproate, tricyclic and other antidepressants), fremanezumab did not appear to adversely interact with other migraine preventive treatments and could be initiated without requiring other migraine preventive treatments to be gradually titrated then discontinued first.6
Fremanezumab is a fully humanized immunoglobulin G2a (IgG2a) delta/kappa monoclonal antibody that binds to the calcitonin gene-related peptide (CGRP) ligand and blocks its binding with the CGRP receptor.1, 9, 10 The drug is produced using recombinant DNA technology in Chinese hamster ovary cells.1
CGRP is a potent vasodilator and pain-signaling neuropeptide that has been associated with migraine pathophysiology.8, 9, 10, 18 CGRP and its receptors are located at sites that are relevant to migraine development such as the trigeminal neurons and are also widely distributed throughout the central and peripheral nervous systems as well as in nonneuronal tissues throughout the body.8, 9, 10, 11, 18
Increased serum CGRP concentrations have been observed in individuals during acute migraine attacks (with or without aura) and IV infusion of CGRP has been shown to induce migraines in patients with a history of migraines.8, 9, 10, 18 Fremanezumab binds to the CGRP ligand and blocks its interaction with the CGRP receptor.1, 9, 10 Because of its large molecular size, fremanezumab is unlikely to cross the blood-brain barrier and probably antagonizes CGRP function peripherally rather than centrally within the nervous system.11, 13, 18
The pharmacokinetics of fremanezumab in patients with migraine are similar to those reported in healthy individuals.5 Following single subcutaneous doses of 225, 675, or 900 mg in healthy adults, median time to peak plasma concentrations is 5-7 days.1, 7 Steady-state concentrations are achieved in approximately 6 months following multiple doses; median systemic accumulation is approximately 2.3- or 1.2-fold following 225-mg once-monthly or 675-mg quarterly dosage regimens, respectively.1 Pharmacokinetics of fremanezumab are dose proportional over a subcutaneous dose range of 225-900 mg.1 Antimigraine effects of CGRP antagonists, including fremanezumab, usually are evident following 1-3 monthly subcutaneous injections or 1-2 quarterly subcutaneous injections in responding patients.2, 3, 4, 12 Similar to other monoclonal antibodies, metabolism of fremanezumab is mediated by proteolytic degradation into small peptides and amino acids.1 The elimination half-life of the drug is approximately 31 days.1
The pharmacokinetics of fremanezumab-vfrm are not substantially affected by age, sex, race, body weight, or body mass index (BMI).1, 5, 7 Following administration of a 225 mg monthly dose in the pediatric population weighing ≥45 kg, exposure is similar to that seen in adults.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
1. Teva Pharmaceuticals USA, Inc. Ajovy® (fremanezumab-vfrm) injection, for subcutaneous use prescribing information. North Wales, PA; 2025 Aug.
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4. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761089Orig1s000: Summary review. From FDA website. [Web]
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9. Edvinsson L, Haanes KA, Warfvinge K et al. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol . 2018; 14:338-350. [PubMed 29691490]
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11. Szperka CL, VanderPluym J, Orr SL et al. Recommendations on the use of anti-CGRP monoclonal antibodies in children and adolescents. Headache . 2018; 58:1658-69. [PubMed 30324723]
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24. Charles AC, Digre KB, Goadsby PJ, et al. Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine: an American Headache Society position statement update. Headache. 2024;1-9. [Web]