Highlights

See Patient counseling information and medication guide available in the DAILYMED drug label information.

Indications and usage

Fremanezumab is indicated for:

Dosage and administration

Recommended dosage

Adults. The recommended dosage in adults for the preventive treatment of migraine is administered by subcutaneous injection as one of the following options:

When switching dosage options, administer the first dose of the new regimen on the next scheduled date of administration.

Pediatric patients who are 6 to 17 years of age and who weigh 45 kg or more. The recommended dosage for the preventive treatment of episodic migraine in pediatric patients who are 6 to 17 years of age and who weigh 45 kg or more is administered by subcutaneous injection as follows:

Fremanezumab is not approved in pediatric patients weighing less than 45 kg because of the lack of an appropriate strength presentation.

Missed dose. If a dose of fremanezumab is missed, administer as soon as possible. Thereafter, fremanezumab can be scheduled from the date of the last dose.

Important administration instructions

Fremanezumab is for subcutaneous use only.

Fremanezumab may be administered by healthcare providers, patients 13 years of age and older, or caregivers. In pediatric patients 6 to 12 years of age, fremanezumab must be administered by a healthcare provider or adult caregiver. Before use, provide proper training to patients or caregivers on the preparation and administration of fremanezumab prefilled syringe, including aseptic technique:

Dosage forms and strengths

Fremanezumab is a sterile, clear to opalescent, colorless to slightly yellow solution, available as follows:

Contraindications

Fremanezumab is contraindicated in patients with serious hypersensitivity to fremanezumab-vfrm or to any of the excipients. Reactions have included anaphylaxis and angioedema.

Warnings and precautions

Hypersensitivity reactions

Hypersensitivity reactions, including rash, pruritus, drug hypersensitivity, and urticaria, were reported with fremanezumab 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 1 month after administration. Cases of anaphylaxis and angioedema have been reported in the postmarketing setting.

If a hypersensitivity reaction occurs, consider discontinuing fremanezumab, and institute appropriate therapy.

Hypertension

Development of hypertension and worsening of pre-existing hypertension have been reported following the use of CGRP antagonists, including fremanezumab, in the postmarketing setting. Some of the patients who developed new-onset hypertension had risk factors for hypertension. There were cases requiring initiation of pharmacological treatment for hypertension and, in some cases, hospitalization. Hypertension may occur at any time during treatment, but was most frequently reported within 7 days of therapy initiation. Fremanezumab was discontinued in many of the reported cases.

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

Raynaud phenomenon

Development of Raynaud phenomenon and recurrence or worsening of pre-existing Raynaud phenomenon have been reported in the postmarketing setting following the use of CGRP antagonists, including fremanezumab. In reported cases with monoclonal antibody CGRP antagonists, symptom onset occurred a median of 71 days following dosing. Many of the cases reported serious outcomes, including hospitalizations and disability, generally related to debilitating pain.

In most reported cases, discontinuation of the CGRP antagonist resulted in resolution of symptoms.

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

Adverse reactions

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

Clinical trials experience

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.

Adults. The safety of fremanezumab was evaluated in 2512 patients with migraine who received at least one dose of fremanezumab, representing 1279 patient-years of exposure. Of these, 1730 patients were exposed to fremanezumab 225 mg monthly or fremanezumab 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 225 mg monthly for 12 weeks (with or without a loading dose of 675 mg), and 663 patients received fremanezumab 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.

Table 1. Adverse Reactions Occurring with an Incidence of At Least 2% for Either Dosing Regimen of Fremanezumab and At Least 2% Greater Than Placebo in Studies 1 and 2

Pediatric patients 6 to 17 years of age. The safety of fremanezumab was evaluated in 225 pediatric patients 6 to 17 years of age with episodic migraine who received at least one dose of fremanezumab. Of these patients, 209 received fremanezumab monthly for at least 6 months, and 100 received fremanezumab for at least 12 months. In the placebo-controlled trial (Study 3), 123 pediatric patients with episodic migraine were treated with fremanezumab. The most common adverse reactions of fremanezumab observed in Study 3 were injection site reactions. Hypersensitivity reactions were also observed. Overall, the safety profile in pediatric patients is similar to the known safety profile in adults.

Postmarketing experience

The following adverse reactions have been identified during postapproval use of fremanezumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders. Anaphylactic reactions and angioedema.

Vascular disorders. Hypertension, Raynaud phenomenon.

Use in specific populations

Pregnancy

Pregnancy exposure registry. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to fremanezumab during pregnancy. Healthcare providers are encouraged to register pregnant patients, or pregnant women may enroll themselves in the registry by calling 1-833-927-2605 or visiting www.tevamigrainepregnancyregistry.com.

Risk summary. There are no adequate data on the developmental risk associated with the use of fremanezumab in pregnant women. Fremanezumab has a long half-life. This should be taken into consideration for women who are pregnant or plan to become pregnant while using fremanezumab. 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The estimated rate of major birth defects (2.2% to 2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.

Clinical considerations.

Disease-associated maternal or embryo/fetal risk. Published data have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy.

Data.

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 two 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 three 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 two times that in humans (675 mg).

Lactation

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 and any potential adverse effects on the breastfed infant from fremanezumab or from the underlying maternal condition.

Pediatric use

Episodic migraine. The safety and effectiveness of fremanezumab have been established in an adequate and well-controlled study for the preventive treatment of episodic migraine in pediatric patients who are 6 to 17 years of age and who weigh 45 kg or more (Study 3). The safety and efficacy profile of fremanezumab in these patients was similar to the safety and efficacy profile seen in clinical trials in adults with migraine.

Fremanezumab is not approved in pediatric patients weighing less than 45 kg because of the lack of an appropriate strength presentation.

The safety and effectiveness of fremanezumab for the preventive treatment of episodic migraine in pediatric patients younger than 6 years of age have not been established.

Chronic migraine. The safety and effectiveness of fremanezumab for the preventive treatment of chronic migraine in pediatric patients have not been established.

Juvenile animal toxicity data. Subcutaneous administration of fremanezumab-vfrm (0, 50, 150, or 450 mg/kg) to juvenile rats once weekly from postnatal day (PND) 28 to PND 63 resulted in no adverse effects on growth, sexual maturation, or neurobehavioral or reproductive function. The highest dose tested was associated with plasma drug exposures (AUC) approximately 58 times that in pediatric patients at the recommended human dose (225 mg), when calculated on a monthly basis.

Geriatric use

Clinical studies of fremanezumab did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Clinical pharmacology

Mechanism of action

Fremanezumab-vfrm is a humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP) ligand and blocks its binding to the receptor.

Pharmacodynamics

The relationship between the pharmacodynamic activity and the mechanism(s) by which fremanezumab-vfrm exerts its clinical effects is unknown.

Pharmacokinetics

Absorption. After single subcutaneous administrations of 225 mg, 675 mg, and 900 mg fremanezumab-vfrm, median time to maximum concentrations (t_max) was 5 to 7 days. Dose-proportionality, based on population PK, was observed between 225 and 900 mg. The geometric mean (%CV) for fremanezumab-vfrm maximum concentration (C_max) was 29.7 (13.7%) µg/mL and total systemic exposure (AUC_0-inf) was 42.5 (17.5%) h*mg/mL following administration of 225 mg fremanezumab-vfrm. The geometric mean (%CV) for fremanezumab-vfrm maximum concentration (C_max) was 104.8 (28.8%) µg/mL, and total systemic exposure (AUC_0-inf) was 132.8 (31.7%) h*mg/mL following administration of 675 mg fremanezumab-vfrm. Steady state was achieved by approximately 168 days (approximately 6 months) following 225 mg subcutaneous monthly and 675 mg subcutaneous 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. No clinically significant differences in fremanezumab-vfrm pharmacokinetics were predicted based on race (White, Black, Asian, and other races), sex, mild hepatic impairment (Child-Pugh Class A), and moderate hepatic impairment (Child-Pugh Class B). The effect of severe hepatic impairment (Child-Pugh Class C) on fremanezumab-vfrm pharmacokinetics is unknown.

Pediatric patients. Following subcutaneous administration of 225 mg fremanezumab monthly in the pediatric population weighing 45 kg or more, the predicted steady state fremanezumab-vfrm exposures (maximum plasma concentration [C_max], area under the plasma concentration-time curve [AUC]) are similar to those of adults.

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, ergots, and triptans) and preventive treatment of migraine were evaluated in a population PK model, and found not to influence fremanezumab exposure.

Immunogenicity

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

In 3-month, placebo-controlled studies in adult patients, treatment-emergent anti-drug antibodies were observed in 0.4% (six of 1701) fremanezumab-treated patients. One of the six patients developed anti-fremanezumab neutralizing antibodies at Day 84. In the long-term, open-label study, anti-drug antibodies were detected in 1.6% of patients (30 out of 1888). Out of 30 anti-drug antibody-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 efficacy or safety of fremanezumab in these patients, available data are too limited to make definitive conclusions.

In the 3-month, placebo-controlled study in pediatric patients with episodic migraine, treatment-emergent anti-drug antibody responses were observed in two of 123 (1.6%) fremanezumab-treated patients. One of the two patients developed anti-fremanezumab-vfrm neutralizing antibodies at Day 84. The available data are too limited to make definitive conclusions about the impact of the development of anti-fremanezumab-vfrm antibodies on the pharmacokinetics, efficacy, or safety of fremanezumab in pediatric patients.

Nonclinical toxicology

Carcinogenesis, mutagenesis, and 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 before 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 two times that in humans at a dose of 675 mg.

Clinical studies

Adults. The efficacy of fremanezumab was evaluated as a preventive treatment of episodic or chronic migraine in adult patients 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 fewer than 15 headache days per month). All patients were randomized (1:1:1) to receive subcutaneous injections of either fremanezumab 675 mg every 3 months (quarterly), fremanezumab 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 demonstrated statistically significant improvements for efficacy endpoints compared to placebo over the 3-month period.

See Table 3 and Figures 1 and 2 in the DAILYMED drug label information for more information.

Chronic migraine. 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 injections of either fremanezumab 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 treatment demonstrated statistically significant improvement for key efficacy outcomes compared to placebo, as summarized in Table 4.

See Table 4 and Figures 3 and 4 in the DAILYMED drug label information for more information.

Pediatric patients 6 to 17 years of age. The efficacy of fremanezumab for the preventive treatment of episodic migraine in pediatric patients 6 to 17 years of age was evaluated in a multicenter, randomized, 3-month, double-blind, placebo-controlled study (Study 3).

Episodic migraine. Study 3 (NCT 04458857) included pediatric patients 6 to 17 years of age with a history of episodic migraine (patients with <15 headache days per month). All patients were randomized (1:1) to receive monthly subcutaneous injections of either fremanezumab or placebo, over a 3-month period. Patients who weighed 45 kg or more received fremanezumab 225 mg and patients who weighed less than 45 kg received fremanezumab 120 mg. Patients were allowed to use acute headache treatments during the study. A subset of patients (21%) was allowed to use up to two additional concomitant preventive medications. The study excluded patients with clinically significant cardiovascular disease.

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 monthly average number of headache days of at least moderate severity during the 3-month treatment period.

In Study 3, a total of 235 patients (130 females, 105 males) were randomized. A total of 225 patients completed the 3-month, double-blind treatment period.

Fremanezumab demonstrated statistically significant improvements for efficacy endpoints compared to placebo over the 3-month period, as summarized in Table 5.

See Table 5 and Figure 5 in the DAILYMED drug label information for more information.

How supplied/storage and handling

How supplied

Fremanezumab (fremanezumab-vfrm) injection is a sterile, preservative-free, clear to opalescent, colorless to slightly yellow solution for subcutaneous administration.

Fremanezumab is not made with natural rubber latex.

Fremanezumab is supplied as follows:

Prefilled autoinjector.

Prefilled syringe.

Storage and handling

Patient counseling information

Advise the patient or caregiver to read the FDA-approved patient labeling.

Information on preparation and administration. Instruct patients who are 13 years and older or caregivers on proper subcutaneous administration technique, including aseptic technique, and how to use the single-dose prefilled syringe. Instruct patients or caregivers to read and follow the Instructions for Use each time they use fremanezumab.

Instruct patients who are prescribed the regimen of 675 mg every 3 months to administer the dosage as three consecutive subcutaneous injections 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 if signs or symptoms of hypersensitivity reactions occur and to seek immediate medical attention if they experience serious or severe hypersensitivity reactions.

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

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

Pregnancy. Advise women that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to fremanezumab during pregnancy.

Medication guide

See the Medication guide section of the DAILYMED drug label information.

Acknowledgement

This article was excerpted from U.S. FDA Drug Labeling information available on the DailyMed website.