AJOVY

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.

4 CONTRAINDICATIONS AJOVY is contraindicated in patients with serious hypersensitivity to fremanezumab-vfrm or to any of the excipients. Reactions have included anaphylaxis and angioedema [see Warnings and Precautions ( 5.1 )]. AJOVY is contraindicated in patients with serious hypersensitivity to fremanezumab-vfrm or to any of the excipients. ( 4 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Most reactions were reported from within hours to one month after administration. If hypersensitivity occurs, consider discontinuing AJOVY and institute appropriate therapy. ( 5.1 ) Hypertension: New-onset or worsening of pre-existing hypertension may occur. ( 5.2 ) Raynaud's Phenomenon: New-onset or worsening of pre-existing Raynaud’s phenomenon may occur. ( 5.3 ) 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. Cases of anaphylaxis and angioedema have been reported in the postmarketing setting. If a hypersensitivity reaction occurs, consider discontinuing AJOVY, and institute appropriate therapy [see Contraindications ( 4 )] . 5.2 Hypertension Development of hypertension and worsening of pre-existing hypertension have been reported following the use of CGRP antagonists, including AJOVY, 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. AJOVY was discontinued in many of the reported cases. Monitor patients treated with AJOVY for new-onset hypertension or worsening of pre-existing hypertension, and consider whether discontinuation of AJOVY is warranted if evaluation fails to establish an alternative etiology or blood pressure is inadequately controlled. 5.3 Raynaud's Phenomenon Development of Raynaud’s phenomenon and recurrence or worsening of pre-existing Raynaud’s phenomenon have been reported in the postmarketing setting following the use of CGRP antagonists, including AJOVY. 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. AJOVY should be discontinued if signs or symptoms of Raynaud’s phenomenon develop and patients should be evaluated by a healthcare provider if symptoms do not resolve. Patients with a history of Raynaud’s phenomenon should be monitored for, and informed about the possibility of, worsening or recurrence of signs and symptoms.

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 )]

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AJOVY 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 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 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 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).