Erenumab-Aooe

AIMOVIG is indicated for the preventive treatment of migraine in adults. AIMOVIG is a calcitonin gene-related peptide receptor antagonist indicated for the preventive treatment of migraine in adults. ( 1 )

For subcutaneous use only ( 2.1 , 2.2 ) Recommended dosage is 70 mg once monthly; some patients may benefit from a dosage of 140 mg once 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 Dosing The recommended dosage of AIMOVIG is 70 mg injected subcutaneously once monthly. Some patients may benefit from a dosage of 140 mg injected subcutaneously once monthly. If a dose of AIMOVIG is missed, administer as soon as possible. Thereafter, AIMOVIG can be scheduled monthly from the date of the last dose.

2.2 Important Administration Instructions AIMOVIG is for subcutaneous use only. AIMOVIG is intended for patient self-administration. Prior to use, provide proper training to patients and/or caregivers on how to prepare and administer AIMOVIG using the single-dose prefilled autoinjector or single-dose prefilled syringe, including aseptic technique [see Instructions for Use] : Prior to subcutaneous administration, allow AIMOVIG to sit at room temperature for at least 30 minutes protected from direct sunlight [see How Supplied/Storage and Handling (16.2) ]. This is important for administering the entire dose and helps minimize discomfort. Do not warm by using a heat source such as hot water or a microwave. Do not shake the product. Inspect visually for particulate matter and discoloration prior to administration [see Dosage Forms and Strengths (3) ] . Do not use if the solution is cloudy or discolored or contains flakes or particles. Administer AIMOVIG in the abdomen, thigh, or upper arm subcutaneously. Do not inject into areas where the skin is tender, bruised, red, or hard. Both prefilled autoinjector and prefilled syringe are single-dose and deliver the entire contents.

AIMOVIG is a sterile, clear to opalescent, colorless to light yellow solution available as follows: Injection: 70 mg/mL in a single-dose prefilled SureClick ® autoinjector Injection: 140 mg/mL in a single-dose prefilled SureClick ® autoinjector Injection: 70 mg/mL in a single-dose prefilled syringe Injection: 140 mg/mL in a single-dose prefilled syringe Injection: 70 mg/mL solution in a single-dose prefilled SureClick ® autoinjector ( 3 ) Injection: 140 mg/mL solution in a single-dose prefilled SureClick ® autoinjector ( 3 ) Injection: 70 mg/mL solution in a single-dose prefilled syringe ( 3 ) Injection: 140 mg/mL solution in a single-dose prefilled syringe ( 3 )

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

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: If a serious hypersensitivity reaction occurs, discontinue administration of AIMOVIG and initiate appropriate therapy. Hypersensitivity reactions can occur within hours to more than one week after administration. ( 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, angioedema, and anaphylaxis, have been reported with AIMOVIG in postmarketing experience. Most hypersensitivity reactions were not serious and occurred within hours of administration, although some occurred more than one week after administration. If a serious or severe hypersensitivity reaction occurs, discontinue administration of AIMOVIG and initiate appropriate therapy [see Contraindications (4) , and Patient Counseling Information (17) ] .

5.2 Constipation with Serious Complications Constipation with serious complications has been reported following the use of AIMOVIG in the postmarketing setting. There were cases 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 of AIMOVIG; however, patients have also presented with constipation later on in treatment. AIMOVIG was discontinued in most reported cases of constipation with serious complications. Constipation was one of the most common (up to 3%) adverse reactions reported in clinical studies [see Adverse Reactions (6.1) ] . Monitor patients treated with AIMOVIG for severe constipation and manage as clinically appropriate [see Patient Counseling Information (17) ] . The concurrent use of medications associated with decreased 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 AIMOVIG in the postmarketing setting. Many of the patients had pre-existing hypertension or risk factors for hypertension. There were cases requiring pharmacological treatment and, in some cases, hospitalization. Hypertension may occur at any time during treatment but was most frequently reported within seven days of dose administration. In the majority of the cases, the onset or worsening of hypertension was reported after the first dose. AIMOVIG was discontinued in many of the reported cases. Monitor patients treated with AIMOVIG for new-onset hypertension, or worsening of pre-existing hypertension, and consider whether discontinuation of AIMOVIG is warranted if evaluation fails to establish an alternative etiology.

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 AIMOVIG. 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. AIMOVIG 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 serious adverse reactions are described below and elsewhere in 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 in AIMOVIG clinical studies (occurring in at least 3% of treated patients and more often than placebo) are injection site reactions and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) 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. The safety of AIMOVIG has been evaluated in 2537 patients with migraine who received at least one dose of AIMOVIG, representing 3040.2 patient-years of exposure. Of these, 2271 patients were exposed to 70 mg or 140 mg once monthly for at least 6 months, 1305 patients were exposed for at least 12 months, and 216 patients were exposed through 5 years. In placebo-controlled clinical studies (Studies 1, 2, and 3) of 2184 patients, 787 patients received at least one dose of AIMOVIG 70 mg once monthly, 507 patients received at least one dose of AIMOVIG 140 mg once monthly, and 890 patients received placebo during 3 months or 6 months of double-blind treatment [see Clinical Studies (14) ] . Approximately 84% were female, 91% were white, and the mean age was 42 years at study entry. The most common adverse reactions (incidence ≥ 3% and more often than placebo) in the migraine studies were injection site reactions and constipation. Table 1 summarizes the adverse reactions that occurred during the first 3 months in the migraine studies (Studies 1, 2, and 3). Table 1: Adverse Reactions Occurring with an Incidence of at Least 2% for Either Dose of AIMOVIG and at Least 2% Greater than Placebo During the First 3 Months in Studies 1, 2, and 3 Adverse Reaction AIMOVIG 70 mg Once Monthly N = 787 % AIMOVIG 140 mg Once Monthly N = 507 % Placebo N = 890 % Injection site reactions Injection site reactions include multiple adverse reactions related terms, such as injection site pain and injection site erythema. , The rate of injection site reactions reported in Table 1 is with the prefilled syringe. 6 5 3 Constipation 1 3 1 Cramps, muscle spasms < 1 2 < 1 In Studies 1, 2, and 3, 1.3% of patients treated with AIMOVIG 70 mg or 140 mg discontinued double-blind treatment because of adverse events. The most frequent injection site reactions were injection site pain, injection site erythema, and injection site pruritus.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of AIMOVIG. 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: Hypersensitivity reactions, including rash, angioedema, and anaphylaxis [see Warnings and Precautions (5.1) ]. Gastrointestinal Disorders: Constipation with serious complications [see Warnings and Precautions (5.2) ] , oral mucosal ulceration . Skin and Subcutaneous Tissue Disorders: Rash, alopecia. 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 AIMOVIG during pregnancy. Patients should be encouraged to enroll by calling 1-833-244-4083 or visiting https://www.genesispregnancyregistry.com/. Risk Summary There are no adequate data on the developmental risk associated with the use of AIMOVIG in pregnant women. No adverse effects on offspring were observed when pregnant monkeys were administered erenumab-aooe throughout gestation [see Data ]. Serum erenumab-aooe exposures in pregnant monkeys were greater than those in humans at clinical doses. 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 In a study in which female monkeys were administered erenumab-aooe (0 or 50 mg/kg) twice weekly by subcutaneous injection throughout pregnancy (gestation day 20-22 to parturition), no adverse effects on offspring were observed. Serum erenumab-aooe exposures (AUC) in pregnant monkeys were approximately 20 times that in humans at a dose of 140 mg once monthly.

8.2 Lactation Risk Summary There are no data on the presence of erenumab-aooe 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 AIMOVIG and any potential adverse effects on the breastfed infant from AIMOVIG 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 AIMOVIG did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AIMOVIG during pregnancy. Patients should be encouraged to enroll by calling 1-833-244-4083 or visiting https://www.genesispregnancyregistry.com/. Risk Summary There are no adequate data on the developmental risk associated with the use of AIMOVIG in pregnant women. No adverse effects on offspring were observed when pregnant monkeys were administered erenumab-aooe throughout gestation [see Data ]. Serum erenumab-aooe exposures in pregnant monkeys were greater than those in humans at clinical doses. 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 In a study in which female monkeys were administered erenumab-aooe (0 or 50 mg/kg) twice weekly by subcutaneous injection throughout pregnancy (gestation day 20-22 to parturition), no adverse effects on offspring were observed. Serum erenumab-aooe exposures (AUC) in pregnant monkeys were approximately 20 times that in humans at a dose of 140 mg once monthly.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of AIMOVIG did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Erenumab-aooe is a human immunoglobulin G2 (IgG2) monoclonal antibody that has high affinity binding to the calcitonin gene-related peptide receptor. Erenumab-aooe is produced using recombinant DNA technology in Chinese hamster ovary (CHO) cells. It is composed of 2 heavy chains, each containing 456 amino acids, and 2 light chains of the lambda subclass, each containing 216 amino acids, with an approximate molecular weight of 150 kDa. AIMOVIG (erenumab-aooe) injection is supplied as a sterile, preservative-free, clear to opalescent, colorless to light yellow solution for subcutaneous administration. Each 1 mL 70 mg single-dose prefilled autoinjector and 70 mg single-dose prefilled glass syringe contains 70 mg erenumab-aooe, acetate (1.5 mg), polysorbate 80 (0.10 mg), and sucrose (73 mg). Each 1 mL 140 mg single-dose prefilled autoinjector and 140 mg single-dose prefilled glass syringe contains 140 mg erenumab-aooe, acetate (2.0 mg), polysorbate 80 (0.10 mg), and sucrose (65 mg). Enclosed within the autoinjector is a single-dose, prefilled glass syringe. The solution of AIMOVIG has a pH of 5.2.

Erenumab-aooe is a human monoclonal antibody that binds to the calcitonin gene-related peptide (CGRP) receptor and antagonizes CGRP receptor function.

In a randomized, double-blind, placebo-controlled study in healthy volunteers, concomitant administration of erenumab-aooe (140 mg intravenous, single-dose) with sumatriptan (12 mg subcutaneous, given as two 6 mg doses separated by one hour) had no effect on resting blood pressure compared with sumatriptan alone. AIMOVIG is for subcutaneous use only.

Erenumab-aooe exhibits non-linear kinetics as a result of binding to the CGRP receptor. The C max mean and AUC last mean following subcutaneous administration of a 70 mg once monthly and a 140 mg once monthly dose in healthy volunteers or migraine patients are included in Table 2. Less than 2-fold accumulation was observed in trough serum concentrations (C min ) for episodic and chronic migraine patients following subcutaneous administration of 70 mg once monthly and 140 mg once monthly doses (see Table 2 ). Serum trough concentrations approached steady state by 3 months of dosing. The effective half-life of erenumab-aooe is 28 days. Table 2: Pharmacokinetic Parameters of AIMOVIG AIMOVIG 70 mg Subcutaneously Once Monthly AIMOVIG 140 mg Subcutaneously Once Monthly C max mean (SD) SD = standard deviation , from a single-dose study 6.1 (2.1) mcg/mL 15.8 (4.8) mcg/mL AUC last mean (SD) , 159 (58) day*mcg/mL 505 (139) day*mcg/mL C min (SD) Episodic migraine 5.7 (3.1) mcg/mL 12.8 (6.5) mcg/mL Chronic migraine 6.2 (2.9) mcg/mL 14.9 (6.5) mcg/mL Absorption Following a single subcutaneous dose of 70 mg or 140 mg erenumab-aooe administered to healthy adults, median peak serum concentrations were attained in approximately 6 days, and estimated absolute bioavailability was 82%. Distribution Following a single 140 mg intravenous dose, the mean (SD) volume of distribution during the terminal phase (V z ) was estimated to be 3.86 (0.77) L. Metabolism and Excretion Two elimination phases were observed for erenumab-aooe. At low concentrations, the elimination is predominantly through saturable binding to target (CGRP receptor), while at higher concentrations the elimination of erenumab-aooe is largely through a non-specific, non-saturable proteolytic pathway. Specific Populations The pharmacokinetics of erenumab-aooe were not affected by age, gender, race, or subtypes of migraine spectrum (episodic or chronic migraine) based on population pharmacokinetics analysis . Patients with Renal or Hepatic Impairment Population pharmacokinetic analysis of integrated data from the AIMOVIG clinical studies did not reveal a difference in the pharmacokinetics of erenumab-aooe in patients with mild or moderate renal impairment relative to those with normal renal function. Patients with severe renal impairment (eGFR < 30 mL/min/1.73 m 2 ) have not been studied. No dedicated clinical studies were conducted to evaluate the effect of hepatic impairment or renal impairment on the pharmacokinetics of erenumab-aooe. Renal or hepatic impairment is not expected to affect pharmacokinetics of erenumab-aooe. Drug Interaction Studies P450 Enzymes Erenumab-aooe is not metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely. Oral Contraceptives In an open-label drug interaction study in healthy female volunteers, erenumab-aooe (140 mg subcutaneous, single-dose) did not affect the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate. Sumatriptan In a study in healthy volunteers, concomitant administration of erenumab-aooe with sumatriptan had no effect on the pharmacokinetics of sumatriptan [see Clinical Pharmacology (12.2) ] .

, Mutagenesis, Impairment of Fertility Carcinogenesis The carcinogenic potential of erenumab-aooe has not been assessed. Mutagenesis Genetic toxicology studies of erenumab-aooe have not been conducted. Impairment of Fertility Mating studies have not been conducted on erenumab-aooe. No histopathological changes in male or female reproductive organs were observed in monkeys administered erenumab-aooe (0, 25, or 150 mg/kg) by subcutaneous injection twice weekly for up to 6 months. Serum erenumab-aooe exposures (AUC) at the higher dose tested were more than 100 times that in humans at a dose of 140 mg once monthly.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Information on Preparation and Administration Provide guidance to patients and caregivers on proper subcutaneous administration technique, including aseptic technique, and how to use the single-dose prefilled autoinjector or single-dose prefilled syringe [see Dosage and Administration (2.2) ] . Instruct patients and/or caregivers to read and follow the Instructions for Use each time they use AIMOVIG. Advise patients to let AIMOVIG sit at room temperature for at least 30 minutes prior to administration [see Dosage and Administration (2.2) ] . Hypersensitivity Reactions Advise patients to seek immediate medical attention if they experience any symptoms of serious or severe hypersensitivity reactions [see Warnings and Precautions (5.1) ] . Constipation with Serious Complications Advise patients that constipation with serious complications can occur with AIMOVIG and that they should contact their healthcare providers if they experience severe constipation [see Warnings and Precautions (5.2) ] . Hypertension Advise patients that development of hypertension and worsening of pre-existing hypertension can occur with AIMOVIG and that they should contact their healthcare providers if they experience elevation in their blood pressure [see Warnings and Precautions (5.3) ] . Pregnancy Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AIMOVIG during pregnancy [see Use in Specific Populations (8.1) ]. Raynaud's Phenomenon Inform patients that Raynaud's phenomenon can develop or worsen with AIMOVIG. Advise patients to discontinue AIMOVIG and contact their healthcare provider if they experience signs or symptoms of Raynaud's phenomenon [see Warnings and Precautions (5.4) ] .

Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until time of use. If removed from the refrigerator, AIMOVIG should be kept at room temperature (up to 25°C [77°F]) in the original carton and must be used within 7 days. Throw away AIMOVIG that has been left at room temperature for more than 7 days. Do not freeze. Do not shake.