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Fremanezumab-vfrm Injection

TABLE OF CONTENTS

1. DESCRIPTION 8. USE IN SPECIFIC POPULATIONS
2. INDICATIONS AND USAGE 10. MECHANISM OF ACTION
3. DOSAGE AND ADMINISTRATION 11. PHARMACODYNAMICS
4. CONTRAINDICATIONS 12. PHARMACOKINETICS
5. WARNINGS AND PRECAUTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING
6. ADVERSE REACTIONS  

 

1. DESCRIPTION

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.

Fremanezumab-vfrm injection is a sterile, preservative-free, clear to opalescent, colorless to slightly yellow solution for subcutaneous injection, supplied in a single-dose 225 mg/1.5 mL prefilled syringe.

Each prefilled syringe delivers 1.5 mL of solution containing 225 mg fremanezumab-vfrm, disodium ethylenediaminetetraacetic acid dihydrate (EDTA) (0.204 mg), L-histidine (0.815 mg), L-histidine hydrochloride monohydrate (3.93 mg), polysorbate-80 (0.3 mg), sucrose (99 mg), and Water for Injection, and has a pH of 5.5.

2. INDICATIONS AND USAGE

Fremanezumab-vfrm is indicated for the preventive treatment of migraine in adults.

3. DOSAGE AND ADMINISTRATION

3.1 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 injections 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.

3.2 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 [see Instructions for Use]:

• 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 [see How Supplied/Storage and Handling].

• Follow aseptic injection technique every time fremanezumab-vfrm is administered.

• Inspect fremanezumab-vfrm for particles or discoloration prior to administration [see Dosage Forms and Strengths]. 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.

4. CONTRAINDICATIONS

Fremanezumab-vfrm is contraindicated in patients with serious hypersensitivity to fremanezumab-vfrm or to any of the excipients [see Warnings and Precautions (5.1)].

5. WARNINGS AND PRECAUTIONS

5.1 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.

6. ADVERSE REACTIONS

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

• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]

6.1 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.

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 [see Clinical Studies]. 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-vfrm and At Least 2% Greater Than Placebo in Studies 1 and 2

a Injection site reactions include multiple related adverse event terms, such as injection site pain, induration, and erythema.

6.2 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.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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 [see Clinical Pharmacology]. 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

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.

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 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).

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

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

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.

10. 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.

11. PHARMACODYNAMICS

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

12. PHARMACOKINETICS

Absorption

After single subcutaneous (SC) administrations of 225 mg, 675 mg, and 900 mg fremanezumab-vfrm, median time to maximum concentrations (tmax) 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, ergots, and triptans) and preventive treatment of migraine were evaluated in a population PK model, and found not to influence fremanezumab exposure.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

AJOVY (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.

AJOVY is supplied as follows:

• NDC 51759-204-10: carton of one 225 mg/1.5 mL single-dose prefilled syringe

Storage and Handling:

• Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original outer carton to protect from light.

• If necessary, AJOVY 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, AJOVY must be used within 24 hours or discarded.

• Do not freeze.

• Do not expose to extreme heat or direct sunlight.

• Do not shake.

Rx only

Rev 09/18