Clinical Information
Gen. Code and Des.
78897 fremanezumab-vfrm SUBCUT SYRINGE 225 MG/1.5
GCN and Des.
45306 fremanezumab-vfrm SUBCUT SYRINGE 225 MG/1.5
Strength
225MG
Dose Form
SYRINGE (ML)
Product Category
RX Pharmaceuticals
Fine Line Class
850085008510 All Rx Products
DEA Class
NC
OMP Family
AHFS Class
28321200 CALCITONIN GENE-RELATED PEPTIDE ANTAG.
Active Ingredients
17742 fremanezumab-vfrm
Inactive Ingredients
2551 polysorbates 9005645
2598 sucrose 57501
3785 edetic acid 60004
AJOVY is the only anti-CGRP treatment for the prevention of migraine with quarterly (225 mg x 3) and monthly (225 mg) dosing options.
Important Safety Information
Contraindications: AJOVY is contraindicated in patients with serious hypersensitivity to fremanezumab-vfrm or to any of the excipients.
Hypersensitivity Reactions: Hypersensitivity reactions, including rash, pruritus, drug hypersensitivity, and urticaria were reported with AJOVY 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 AJOVY and institute appropriate therapy.
Adverse Reactions: The most common adverse reactions (≥5% and greater than placebo) were injection site reactions.
Indication
AJOVY is indicated for the preventive treatment of migraine in adults.
HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use AJOVY safely and effectively. See full prescribing information for AJOVY. AJOVYTM (fremanezumab-vfrm) injection, for subcutaneous use Initial U.S. Approval: 2018 INDICATIONS AND USAGE AJOVY is a calcitonin gene-related peptide antagonist indicated for the preventive treatment of migraine in adults. (1) DOSAGE AND ADMINISTRATION � For subcutaneous use only. (2.1, 2.2) � Two subcutaneous dosing options of AJOVY are available to administer the recommended dosage: ◦ 225 mg monthly, or ◦ 675 mg every 3 months (quarterly) (2.1) � The 675 mg quarterly dosage is administered as three consecutive injections of 225 mg each. (2.1) � Administer in the abdomen, thigh, or upper arm subcutaneously. (2.2) � See Dosage and Administration for important administration instructions. (2.2)
DOSAGE FORMS AND STRENGTHS Injection: 225 mg/1.5 mL solution in a single-dose prefilled syringe. (3) CONTRAINDICATIONS AJOVY is contraindicated in patients with serious hypersensitivity to fremanezumabvfrm or to any of the excipients. (4) WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: If hypersensitivity occurs, consider discontinuing AJOVY and institute appropriate therapy. (5.1) ADVERSE REACTIONS The most common adverse reactions (≥5% and greater than placebo) were injection site reactions. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 9/2018
FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage 2.2 Important Administration Instructions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Immunogenicity 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use
11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE AJOVY is indicated for the preventive treatment of migraine in adults. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage Two subcutaneous dosing options of AJOVY 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 AJOVY is missed, administer as soon as possible. Thereafter, AJOVY can be scheduled from the date of the last dose. 2.2 Important Administration Instructions AJOVY is for subcutaneous use only. AJOVY 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 AJOVY prefilled syringe, including aseptic technique [see Instructions for Use]: � Remove AJOVY from the refrigerator. Prior to use, allow AJOVY 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 AJOVY if it has been at room temperature for 24 hours or longer [see How Supplied/ Storage and Handling (16.2)]. � Follow aseptic injection technique every time AJOVY is administered. � Inspect AJOVY for particles or discoloration prior to administration [see Dosage Forms and Strengths (3)]. Do not use if the solution is cloudy, discolored, or contains particles. � Administer AJOVY 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 AJOVY with other injectable drugs at the same injection site. 3 DOSAGE FORMS AND STRENGTHS AJOVY is a sterile, clear to opalescent, colorless to slightly yellow solution, available as follows: � Injection: 225 mg/1.5 mL single-dose prefilled syringe 4 CONTRAINDICATIONS AJOVY is contraindicated in patients with serious hypersensitivity to fremanezumabvfrm 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 AJOVY 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 AJOVY, 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 AJOVY was evaluated in 2512 patients with migraine who received at least 1 dose of AJOVY, representing 1279 patient-years of exposure. Of these, 1730 patients were exposed to AJOVY 225 mg monthly or AJOVY 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 AJOVY 225 mg monthly for 12 weeks (with or without a loading dose of 675 mg), and 663 patients received AJOVY 675 mg quarterly for 12 weeks [see Clinical Studies (14)]. 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 AJOVY and At Least 2% Greater Than Placebo in Studies 1 and 2 Adverse Reaction AJOVY 225 mg Monthly (n=290) % AJOVY 675 mg Quarterly (n=667) % Placebo Monthly (n=668) % Injection site reactionsa 43 45 38 a Injection site reactions include multiple related adverse event terms, such as injection site pain, induration, and erythema.
2
AJOVYTM (fremanezumab-vfrm) injection AJOVYTM (fremanezumab-vfrm) injection 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 AJOVY 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 AJOVY in specific assays. In 3-month placebo-controlled studies, treatment-emergent ADA responses were observed in 6 out of 1701 (0.4%) AJOVY-treated patients. One of the 6 patients developed anti-AJOVY 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 AJOVY 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 AJOVY in pregnant women. AJOVY has a long half-life [see Clinical Pharmacology (12.3)]. This should be taken into consideration for women who are pregnant or plan to become pregnant while using AJOVY. 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 AJOVY and any potential adverse effects on the breastfed infant from AJOVY 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 AJOVY did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 11 DESCRIPTION Fremanezumab-vfrm is a fully humanized IgG2Da/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. AJOVY (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 fremanezumabvfrm, 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. 12 CLINICAL PHARMACOLOGY 12.1 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. 12.2 Pharmacodynamics The relationship between the pharmacodynamic activity and the mechanism(s) by which fremanezumab-vfrm exerts its clinical effects is unknown. 12.3 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. Fremanezumabvfrm 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 AJOVY. 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 AJOVY 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 NONCLINICAL TOXICOLOGY 13.1 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. 14 CLINICAL STUDIES The efficacy of AJOVY 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 injections of either AJOVY 675 mg every three months (quarterly), AJOVY 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 doubleblind 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 AJOVY demonstrated statistically significant improvements for efficacy endpoints compared to placebo over the
