Fremanezumab

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 )

AJOVY is a sterile, clear to opalescent, colorless to slightly yellow solution, available as follows: Injection: 225 mg/1.5 mL single-dose prefilled autoinjector Injection: 225 mg/1.5 mL single-dose prefilled syringe Injection: 225 mg/1.5 mL solution in a single-dose prefilled autoinjector. ( 3 ) Injection: 225 mg/1.5 mL solution in a single-dose prefilled syringe. ( 3 )

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 )

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 ) Constipation with Serious Complications: Serious complications of constipation may occur. ( 5.2 ) Hypertension: New-onset or worsening of pre-existing hypertension may occur. ( 5.3 ) Raynaud's Phenomenon: New-onset or worsening of pre-existing Raynaud’s phenomenon may occur. ( 5.4 )

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 Constipation with Serious Complications Constipation with serious complications has been reported following the use of monoclonal antibody CGRP antagonists, including AJOVY, in the postmarketing setting. There were cases with monoclonal antibody CGRP antagonists that required hospitalization, including cases where surgery was necessary. In a majority of these cases, the onset of constipation was reported after the first dose; however, patients have also presented with constipation later in treatment. The monoclonal antibody CGRP antagonist was discontinued in many of the reported cases of constipation with serious complications. Monitor patients treated with AJOVY for severe constipation and manage as clinically appropriate [see Patient Counseling Information (17)] . The concurrent use of medications that reduce gastrointestinal motility may increase the risk for more severe constipation and the potential for constipation-related complications.

5.3 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.

5.4 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.

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 )] Constipation with Serious Complications [see Warnings and Precautions ( 5.2 )] Hypertension [see Warnings and Precautions ( 5.3 )] Raynaud’s Phenomenon [see Warnings and Precautions ( 5.4 )] 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. Gastrointestinal Disorders: Constipation [see Warnings and Precautions ( 5.2 )] Immune System Disorders : Anaphylactic reactions and angioedema [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] Vascular Disorders : Hypertension [see Warnings and Precautions ( 5.3 )] , Raynaud’s phenomenon [see Warnings and Precautions ( 5.4 )]

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).

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 Episodic Migraine The safety and effectiveness of AJOVY 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 AJOVY in these patients was similar to the safety and efficacy profile seen in clinical trials in adults with migraine [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), and Clinical Studies ( 14 )]. AJOVY 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 AJOVY 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 AJOVY 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.

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.

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