AHFS Class:

• Calcitonin Gene-related Peptide (CGRP) Antagonists 28:32.12

Generic Name(s):

• Fremanezumab-vfrm

Fremanezumab, a recombinant fully humanized immunoglobulin G_2a (IgG_2a) monoclonal antibody specific for calcitonin gene-related peptide (CGRP) ligand, is an antimigraine agent.1,9

Preventive Treatment of Migraine

Fremanezumab-vfrm is used for the preventive treatment of migraine in adults.1,2,3 In clinical studies, fremanezumab prophylaxis substantially reduced the monthly average number of migraine or headache days and acute antimigraine agent- or headache medication-use days in patients with episodic or chronic migraine compared with placebo.1,2,3

Clinical Experience

Efficacy and safety of fremanezumab for the preventive treatment of migraine have been established in 2 randomized, double-blind, placebo-controlled, multicenter studies (studies 1 and 2) in adults with a history of migraine according to the International Classification of Headache Disorders, third edition, beta version (ICHD-3 beta) diagnostic criteria.1,2,3 Study 1 included patients with episodic migraine (fewer than 15 headache days per month with at least 4 days fulfilling ICHD-3 beta criteria for migraine with or without aura, probable migraine, or use of selective serotonin type 1 [5-hydroxytryptamine type 1; 5-HT₁] receptor agonists [triptans] or ergotamine derivatives) and study 2 included patients with chronic migraine (at least 15 headache days per month with at least 8 days fulfilling ICHD-3 beta criteria for migraine with or without aura or use of triptans or ergotamine derivatives).1,2,3

Patients in both clinical studies received treatment with fremanezumab or placebo; concomitant use of a single preventive antimigraine agent (e.g., β-adrenergic blocking agents, tricyclic antidepressants, anticonvulsants) was permitted in a subset of 21% of patients in both studies.1,2,3 In addition, patients were allowed to use acute antimigraine agents and headache medication during both studies.1,2,3 The median age of patients in these studies was 41-43 years; the majority of patients were female (85-88%) and Caucasian (77-84%).1,2,3,4 The studies excluded patients with a history of clinically important cardiovascular disease, vascular ischemia, or thromboembolic events.1,4

In study 1, patients with a history of episodic migraine were randomized to receive subcutaneous injections of fremanezumab-vfrm 225 mg once monthly, a single fremanezumab-vfrm 675-mg dose (to represent an intended quarterly, or every 3 month, dose), or placebo once monthly for 3 months.1,2 The primary efficacy end point was the mean change from baseline in the monthly average number of migraine days over the 3-month treatment period after the first dose.1,2 Secondary end points included the proportion of patients achieving at least a 50% reduction in the monthly average number of migraine days over the 3-month treatment period, the mean change from baseline in the monthly average number of acute headache medication-use days over the 3-month period, and the mean change from baseline in the number of migraine days during the first month of treatment.1,2 A total of 875 patients underwent randomization and 791 (90%) of those patients completed the study.1,2

Results of study 1 showed that fremanezumab treatment substantially reduced monthly migraine days compared with placebo; from a mean baseline of approximately 9 migraine days per month, treatment with fremanezumab-vfrm 225 mg monthly or 675 mg quarterly reduced monthly migraine days by 3.7 or 3.4 days, respectively, compared with a reduction of 2.2 days with placebo.1,2 Treatment benefit with both dosages of fremanezumab-vfrm was observed by the first month of treatment and continued throughout the 3-month treatment period.2,4 At least a 50% reduction in the monthly average number of migraine days was achieved in a substantially greater proportion of patients receiving fremanezumab-vfrm 225 mg monthly or 675 mg quarterly (47.7 or 44.4%, respectively) compared with those receiving placebo (27.9%), and the mean number of acute headache medication-use days per month was reduced by 3 or 2.9 days in patients who received fremanezumab-vfrm 225 mg monthly or 675 mg quarterly, respectively, compared with 1.6 days in placebo recipients.1,2

In study 2, 1130 patients with a history of chronic migraine were randomized to receive subcutaneous injections of fremanezumab-vfrm 225 mg once monthly (with an initial 675-mg loading dose), a single fremanezumab-vfrm 675-mg dose (to represent an intended quarterly, or every 3 month, dose), or placebo once monthly for 3 months.1,3 The primary efficacy end point was the mean change from baseline in the monthly average number of headache days of at least moderate severity over the 3-month treatment period.1,3 Secondary end points included the mean change from baseline in the monthly average number of migraine days over the 3-month treatment period, the proportion of patients achieving at least a 50% reduction in the monthly average number of headache days of at least moderate severity over the 3-month treatment period, the mean change from baseline in the monthly average number of acute headache medication-use days over 3 months, and the mean change from baseline in the number of headache days of at least moderate severity during the first month of treatment.1,3

Results of study 2 showed that from a mean baseline frequency of approximately 13 headache days per month, treatment with fremanezumab-vfrm 225 mg monthly or 675 mg quarterly reduced the monthly average number of headache days of at least moderate severity by 4.6 or 4.3 days, respectively, compared with a reduction of 2.5 days with placebo.1,3 Treatment benefit with both dosages of fremanezumab-vfrm was observed by the first month of treatment and continued throughout the 3-month treatment period.3,4 In addition, monthly migraine days were reduced by approximately 5 days in patients receiving either dosage of fremanezumab-vfrm compared with 3.2 days in patients receiving placebo.1,3 At least a 50% reduction in monthly average number of headache days of at least moderate severity was achieved in a substantially greater proportion of patients receiving fremanezumab-vfrm 225 mg monthly or 675 mg quarterly (40.8 or 37.6%, respectively) compared with those receiving placebo (18.1%), and the mean number of acute headache medication-use days per month was reduced by 4.2 or 3.7 days in patients who received fremanezumab-vfrm 225 mg monthly or 675 mg quarterly, respectively, compared with 1.9 days in placebo recipients.1,3

Clinical Perspective

The American Headache Society (AHS) has published expert consensus statements on integrating new migraine treatments into clinical practice over the last years.12,23,24 AHS states that fremanezumab and other anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies offer a number of advantages over some oral migraine preventive therapies, including no need for dosage escalation, rapid onset of therapeutic activity (within days to weeks), demonstrated efficacy after failure of prior preventive treatments or in combination with oral preventive treatments, minimal risk of adverse drug interactions, and favorable overall tolerability profiles.12,23 In 2024, AHS stated that CGRP-targeting therapies should be considered as a first-line approach for migraine prevention along with previous first-line treatments, without a requirement for prior failure of other migraine preventive drug classes.24 AHS noted that the cumulative evidence for the efficacy, safety, and tolerability of CGRP-targeting therapies is significantly greater than that for any established migraine preventive therapy.24

Similar to other commercially available antimigraine agents, fremanezumab is unlikely to achieve complete migraine freedom, but substantial reductions in migraine frequency were observed in controlled clinical trials.1,2,3,4

Administration

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 or caregivers and/or self-administered .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

Dosage

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

Special Populations

Hepatic Impairment

The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1

Renal Impairment

The manufacturer makes no specific dosage recommendations for patients with renal impairment.1

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.1

Contraindications

• Serious hypersensitivity to fremanezumab or to any excipients in the formulation.1

Warnings/Precautions

Hypersensitivity Reactions

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

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity with fremanezumab therapy.1 In placebo-controlled clinical studies of 3 months' duration, 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 available 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

Specific Populations

Pregnancy

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

Lactation

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

Pediatric Use

The manufacturer states that the safety and efficacy of fremanezumab have not been established in pediatric patients.1

Pending further clinical experience with the use of calcitonin gene-related peptide (CGRP) antagonists in pediatric patients, 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

Geriatric Use

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

Hepatic impairment is not expected to substantially affect the pharmacokinetics of fremanezumab.1,5 Formal pharmacokinetic studies of fremanezumab have not been conducted in patients with hepatic impairment.1 Population pharmacokinetic analysis from clinical studies with the drug did not reveal a difference in the pharmacokinetics of fremanezumab in patients with mild hepatic impairment compared with those with normal hepatic function.1 Only 4 patients with moderate hepatic impairment and no patients with severe hepatic impairment were enrolled in clinical studies with the drug.1

Renal Impairment

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 Formal pharmacokinetic studies of fremanezumab have not been conducted in patients with renal impairment.1

Common Adverse Effects

Adverse effects reported in ≥5% of patients receiving fremanezumab-vfrm for preventive treatment of migraine in clinical studies and more frequently than with placebo include injection site reactions (e.g., pain, induration, erythema),1,2,3 most of which were mild to moderate in severity and self-limited.2,3,4

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

Antimigraine Agents

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

Description

Fremanezumab is a fully humanized immunoglobulin G_2a (IgG_2a) 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 (including between Japanese and Caucasian healthy individuals), body weight, or body mass index (BMI).1,5,7

Advice to Patients

• Advise patients and/or caregivers to read the manufacturer's patient information and to read and follow the instructions for use each time they use fremanezumab.1
• Provide guidance to patients and/or caregivers on proper subcutaneous administration of fremanezumab-vfrm, including the use of aseptic technique and how to use the single-dose prefilled syringes or auto-injectors.1
• Inform patients receiving the 675-mg dose that the dose should be administered as 3 consecutive injections of 225 mg each.1
• If a dose is missed, administer the missed dose as soon as possible.1 Schedule subsequent doses monthly or quarterly from the date of the last administered dose.1
• Inform patients of possible signs and symptoms of hypersensitivity reactions (e.g., rash, pruritus, urticaria), which can occur within hours and up to 1 month after administration of fremanezumab.1 Patients should immediately contact their healthcare provider if signs or symptoms of a hypersensitivity reaction occur.1
• Inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise women that there is a pregnancy exposure registry that monitors outcomes in women exposed to fremanezumab during pregnancy.1
• Inform patients of other precautionary information.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.

1. Teva Pharmaceuticals USA, Inc. Ajovy^® (fremanezumab-vfrm) injection, for subcutaneous use prescribing information. North Wales, PA; 2022 Oct.

2. Dodick DW, Silberstein SD, Bigal ME et al. Effect of Fremanezumab Compared With Placebo for Prevention of Episodic Migraine: A Randomized Clinical Trial. JAMA . 2018; 319:1999-2008. [PubMed 29800211]

3. Silberstein SD, Dodick DW, Bigal ME et al. Fremanezumab for the Preventive Treatment of Chronic Migraine. N Engl J Med . 2017; 377:2113-2122. [PubMed 29171818]

4. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761089Orig1s000: Summary review. From FDA website. [Web]

5. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761089Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. [Web]

6. Cohen JM, Dodick DW, Yang R et al. Fremanezumab as Add-On Treatment for Patients Treated With Other Migraine Preventive Medicines. Headache . 2017; 57:1375-84. [PubMed 28862758]

7. Cohen-Barak O, Weiss S, Rasamoelisolo M et al. A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects. Cephalalgia . 2018; 38:1960-71. [PubMed 29667896]

8. Shi L, Lehto SG, Zhu DX et al. Pharmacologic Characterization of AMG 334, a Potent and Selective Human Monoclonal Antibody against the Calcitonin Gene-Related Peptide Receptor. J Pharmacol Exp Ther . 2016; 356:223-31. [PubMed 26559125]

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]

10. Schuster NM, Rapoport AM. Calcitonin Gene-Related Peptide-Targeted Therapies for Migraine and Cluster Headache: A Review. Clin Neuropharmacol . 2017 Jul/Aug; 40:169-174. [PubMed 28644160]

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]

12. American Headache Society. The American Headache Society position statement on integrating new migraine treatments into clinical practice. Headache . 2019; 59:1-18. [PubMed 30536394]

13. Raffaelli B, Reuter U. The biology of monoclonal antibodies: focus on calcitonin gene-related peptide for prophylactic migraine therapy. Neurotherapeutics . 2018; 15:324-35. [PubMed 29616494]

18. Edvinsson L. The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine. Headache . 2017; 57:47-55. [PubMed 28485848]

23. Ailani J, Burch RC, Robbins MS et al. The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache . 2021; 61:1021-1039. [PubMed 34160823]

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]