Fremanezumab-Vfrm

1 INDICATIONS AND USAGE AJOVY is indicated for: the preventive treatment of migraine in adults, and the preventive treatment of episodic migraine in pediatric patients who are 6 to 17 years of age and who weigh 45 kg or more. AJOVY is a calcitonin gene-related peptide antagonist indicated for: the preventive treatment of migraine in adults, and the preventive treatment of episodic migraine in pediatric patients who are 6 to 17 years of age and who weigh 45 kg or more. ( 1 )

2 DOSAGE AND ADMINISTRATION For subcutaneous use only. Recommended dosage: Adults : Two subcutaneous dosing options of AJOVY are available to administer the recommended dosage; 225 mg monthly or 675 mg every 3 months (quarterly). The 675 mg quarterly dosage is administered as three consecutive injections of 225 mg each. ( 2.1 ) Pediatric patients 6 to 17 years of age and who weigh 45 kg or more : 225 mg monthly ( 2.1 ) Administer in the abdomen, thigh, or upper arm subcutaneously. ( 2.2 ) See Dosage and Administration for important administration instructions. ( 2.2 ) 2.1 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: 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. 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: 225 mg monthly. AJOVY is not approved in pediatric patients weighing less than 45 kg because of the lack of an appropriate strength presentation [see Clinical Studies (14) and How Supplied/Storage and Handling (16.1)] . Missed Dose 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 providers, patients 13 years of age and older, and/or caregivers. In pediatric patients 6 to 12 years of age, AJOVY must be administered by a healthcare provider or adult caregiver. 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 7 days 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.

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 )] Hypertension [see Warnings and Precautions ( 5.2 )] Raynaud’s Phenomenon [see Warnings and Precautions ( 5.3 )] 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 . 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. Adults 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 reactions a 43 45 38 a Injection site reactions include multiple related adverse event terms, such as injection site pain, induration, and erythema. Pediatric Patients 6 to 17 Years of Age The safety of AJOVY was evaluated in 225 pediatric patients 6 to 17 years of age with episodic migraine who received at least one dose of AJOVY. Of these patients, 209 received AJOVY monthly for at least 6 months and 100 received AJOVY for at least 12 months. In the placebo-controlled trial (Study 3), 123 pediatric patients with episodic migraine were treated with AJOVY [see Clinical Studies (14)] . The most common adverse reactions of AJOVY 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of AJOVY. 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 [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] Vascular Disorders : Hypertension [see Warnings and Precautions ( 5.2 )] , Raynaud’s phenomenon [see Warnings and Precautions ( 5.3 )]

12.3 Pharmacokinetics Absorption After single subcutaneous (SC) 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 mg to 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 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 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 AJOVY 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.