` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`
`AIMOVIG safely and effectively. See full prescribing information for
`AIMOVIG.
`
`AIMOVIGTM (erenumab-aooe) injection, for subcutaneous use
`Initial U.S. Approval: 2018
`
`----------------------------INDICATIONS AND USAGE--------------------------
`AIMOVIG is a calcitonin gene-related peptide receptor antagonist indicated
`
`for the preventive treatment of migraine in adults (1)
`
`
`---------------------------DOSAGE AND ADMINISTRATION------------------
` 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)
` The 140 mg dose is administered once monthly as two consecutive
`
`injections of 70 mg each (2.1)
`
`
` The needle shield within the white cap of the prefilled autoinjector and the
`
`
`gray needle cap of the prefilled syringe contain dry natural rubber (a
`
`derivative of latex), which may cause allergic reactions in individuals
`sensitive to latex (2.2)
` Administer in the abdomen, thigh, or upper arm subcutaneously (2.2)
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`2
`
`2.1 Recommended Dosing
`
`Important Administration Instructions
`2.2
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
`ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`6.2
`Immunogenicity
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Lactation
`8.4
`Pediatric Use
`8.5 Geriatric Use
`
`3
`4
`6
`
`8
`
`
`
`
`
`
`
`
`
`
`
` See Dosage and Administration for important administration instructions
`
`(2.2)
`-----------------------DOSAGE FORMS AND STRENGTHS------------------
` Injection: 70 mg/mL solution in a single-dose prefilled SureClick®
`
`
`autoinjector (3)
` Injection: 70 mg/mL solution in a single-dose prefilled syringe (3)
`
`------------------------------CONTRAINDICATIONS----------------------------
`None (4)
`------------------------------ADVERSE REACTIONS-----------------------------
`
`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.
`See 17 for PATIENT COUNSELING INFORMATION and
`
`FDA-approved Patient Labeling.
`
`
`Revised: 5/2018
`
`
`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
`
`
`
`
`
`Reference ID: 4264882
`
`
`
`
`Page 1 of 14
`
`1
`
`EX2238
`Eli Lilly & Co. v. Teva Pharms. Int'l GMBH
`IPR2018-01425
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`1
`
`INDICATIONS AND USAGE
`
`
`AIMOVIG is indicated for the preventive treatment of migraine in adults.
`
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`
`Recommended Dosing
`2.1
`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, which is administered as two
`consecutive subcutaneous injections of 70 mg each.
`
`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.
`
`
`Important Administration Instructions
`2.2
`AIMOVIG is for subcutaneous use only.
`
`The needle shield within the white cap of the AIMOVIG prefilled autoinjector and gray needle cap of the
`AIMOVIG prefilled syringe contain dry natural rubber (a derivative of latex), which may cause allergic
`reactions in individuals sensitive to latex.
`
`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)]. 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.
`
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`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: 70 mg/mL in a single-dose prefilled syringe
`
`
`
`4
`
`CONTRAINDICATIONS
`
`
`None.
`
`
`
`Reference ID: 4264882
`
`
`
`
`Page 2 of 14
`
`2
`
`
`
`
`
`6
`
`
`
` ADVERSE REACTIONS
`
`
`Clinical Trials Experience
`6.1
`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 2,537 patients with migraine who received at least one dose of
`AIMOVIG, representing 2,310 patient-years of exposure. Of these, 2,057 patients were exposed to 70 mg or
`140 mg once monthly for at least 6 months, 1,198 patients were exposed for at least 12 months, and 287 patients
`were exposed for at least 18 months.
`
`In placebo-controlled clinical studies (Studies 1, 2, and 3) of 2,184 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
`
`AIMOVIG
`
`AIMOVIG
`Placebo
`70 mg Once Monthly
`
`
`
`140 mg Once Monthly
`N = 787
`N = 890
`N = 507
`%
`%
`%
`3
`Injection site reactionsa
`6
`5
`1
`1
`3
`Constipation
`< 1
`
`< 1
`2
`Cramps, muscle spasms
`aInjection site reactions include multiple adverse reactions related terms, such as injection site pain and injection site erythema.
`
`
`Adverse Reaction
`
`In Studies 1, 2, and 3, 1.3% of patients treated with AIMOVIG 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
`
`Immunogenicity
`
`As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation,
`including neutralizing antibodies, is highly dependent on the 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 erenumab-aooe in the studies described below with the incidence of antibodies in other studies or to other
`products may be misleading.
`
`The immunogenicity of AIMOVIG has been evaluated using an immunoassay for the detection of binding
`anti-erenumab-aooe antibodies. For patients whose sera tested positive in the screening immunoassay, an in
`vitro biological assay was performed to detect neutralizing antibodies.
`
`
`
`Reference ID: 4264882
`
`
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`Page 3 of 14
`
`3
`
`
`
`
`In controlled studies with AIMOVIG, the incidence of anti-erenumab-aooe antibody development was
`6.2% (48/778) in patients receiving AIMOVIG 70 mg once monthly (2 of whom had in vitro neutralizing
`activity) and 2.6% (13/504) in patients receiving AIMOVIG 140 mg once monthly (none of whom had in vitro
`
`neutralizing activity). The neutralizing anti-erenumab-aooe antibody positive rate may be underestimated
`because of limitations of the assay. Although these data do not demonstrate an impact of anti-erenumab-aooe
`antibody development on the efficacy or safety of AIMOVIG in these patients, the available data are too limited
`to make definitive conclusions.
`
`
`
`8
`
`
`8.1
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`
`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 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.
`
`
`
`Reference ID: 4264882
`
`
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`Page 4 of 14
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`4
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`
`
`
`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.
`
`
`DESCRIPTION
`11
`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 single-dose prefilled autoinjector and
`single-dose prefilled glass syringe contains 70 mg erenumab-aooe, acetate (1.5 mg), polysorbate 80 (0.10 mg),
`
`and sucrose (73 mg). Enclosed within the autoinjector is a single-dose, prefilled glass syringe. The solution of
`AIMOVIG has a pH of 5.2.
`
`
`12
`
`CLINICAL PHARMACOLOGY
`
`
`
`
`12.1 Mechanism of Action
`Erenumab-aooe is a human monoclonal antibody that binds to the calcitonin gene-related peptide (CGRP)
`receptor and antagonizes CGRP receptor function.
`
`
`12.2 Pharmacodynamics
`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.
`
`
`12.3 Pharmacokinetics
`Erenumab-aooe exhibits non-linear kinetics as a result of binding to the CGRP receptor. The Cmax mean and
`AUClast 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 (Cmin) 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.
`
`
`
`Reference ID: 4264882
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`Page 5 of 14
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`5
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`
`
`Table 2: Pharmacokinetic Parameters of AIMOVIG
`AIMOVIG 70 mg
`AIMOVIG 140 mg
`
`Subcutaneously Once Monthly
`Subcutaneously Once Monthly
`
`
` 6.1 (2.1) mcg/mL
` 15.8 (4.8) mcg/mL
` 505 (139) day*mcg/mL
`159 (58) day*mcg/mL
`
`
`
`
`
`5.7 (3.1) mcg/mL
`
`6.2 (2.9) mcg/mL
`
`
`12.8 (6.5) mcg/mL
`
`14.9 (6.5) mcg/mL
`
`Cmax mean (SD)a,b
`
`AUClast mean (SD)a,b
`
`
` Cmin (SD)
`Episodic migraine
`
`Chronic migraine
`a SD = standard deviation
`
`b from a single-dose study
`
` 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
`(Vz) 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 m2) 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)].
`
`
`
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`Reference ID: 4264882
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`Page 6 of 14
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`6
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`
`13
`
`
`
` NONCLINICAL TOXICOLOGY
`
`
`
`
` 13.1 Carcinogenesis, 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.
`
`
`
`CLINICAL STUDIES
`14
`The efficacy of AIMOVIG was evaluated as a preventive treatment of episodic or chronic migraine in three
`randomized, double-blind, placebo-controlled studies: two studies in patients with episodic migraine (4 to 14
`migraine days per month) (Study 1 and Study 2) and one study in patients with chronic migraine (≥ 15 headache
`days per month with ≥ 8 migraine days per month) (Study 3). The studies enrolled patients with a history of
`migraine, with or without aura, according to the International Classification of Headache Disorders (ICHD-III)
`diagnostic criteria.
`Episodic Migraine
`Study 1 (NCT 02456740) was a randomized, multi-center, 6-month, placebo-controlled, double-blind study
`evaluating AIMOVIG for the preventive treatment of episodic migraine. A total of 955 patients with a history of
`
`episodic migraine were randomized to receive either AIMOVIG 70 mg (N = 317), AIMOVIG 140 mg
`(N = 319), or placebo (N = 319) by subcutaneous injection once monthly (QM) for 6 months. Patients were
`allowed to use acute headache treatments including migraine-specific medications (i.e., triptans, ergotamine
`derivatives) and NSAIDs during the study.
`The study excluded patients with medication overuse headache as well as patients with myocardial infarction,
`stroke, transient ischemic attacks, unstable angina, coronary artery bypass surgery, or other revascularization
`procedures within 12 months prior to screening.
`
`The primary efficacy endpoint was the change from baseline in mean monthly migraine days over months 4 to
`6. Secondary endpoints included the achievement of a ≥ 50% reduction from baseline in mean monthly
`migraine days over months 4 to 6 (“≥ 50% MMD responders”), the change from baseline in mean monthly
`acute migraine-specific medication days over months 4 to 6, and the change from baseline in mean Migraine
`Physical Function Impact Diary (MPFID) over months 4 to 6. The MPFID measures the impact of migraine on
`everyday activities (EA) and physical impairment (PI) using an electronic diary administered daily. Monthly
`
`MPFID scores are averaged over 28 days, including days with and without migraine; scores are scaled from 0 to
`100. Higher scores indicate worse impact on EA and PI. Reductions from baseline in MPFID scores indicate
`improvement.
`A total of 858 (90%) patients completed the 6-month double-blind study. Patients had a median age of 42 years
`(range: 18 to 65 years), 85% were female, and 89% were white. Three percent of patients were taking
`
`concomitant preventive treatments for migraine. The mean migraine frequency at baseline was approximately 8
`migraine days per month and was similar across treatment groups.
`
`AIMOVIG treatment demonstrated statistically significant improvements for key efficacy endpoints compared
`to placebo, as summarized in Table 3.
`
`
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`Reference ID: 4264882
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`Page 7 of 14
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`7
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`
`
`Table 3: Efficacy Endpoints Over Months 4 to 6 in Study 1
`
`
` AIMOVIG
`AIMOVIG
`
`70 mg Once Monthly
`
`140 mg Once Monthly
`N = 312
`N = 318
`
`
`-3.2
`
`-1.4
`< 0.001
`
`
`Monthly Migraine Days (MMD)
`
`
`Change from baseline
`Difference from placebo
`p-value
`
`≥ 50% MMD responders
`
`
`
`% Responders
`43.3%
`
`Difference from placebo
`16.7%
`Odds ratio relative to placebo
`2.1
`p-value
`< 0.001
`Monthly acute migraine-specific medication days
`
`
`
`-1.1
`Change from baseline
`
`Difference from placebo
`-0.9
`p-value
`< 0.001
`
`
`-3.7
`
`-1.9
`< 0.001
`
`
`50.0%
`
`23.4%
`2.8
`< 0.001
`
`
`-1.6
`
`-1.4
`< 0.001
`
`Placebo
`
`N = 316
`
`
`-1.8
`
`
`
`
`26.6%
`
`
`
`
`
`-0.2
`
`
`
`
`Figure 1: Change from Baseline in Monthly Migraine Days in Study 1a
`
`
`
` a Least-square means and 95% confidence intervals are presented.
`
`
`
`
`
`Figure 2 shows the distribution of change from baseline in mean monthly migraine days over months 4 to 6 in
`bins of 2 days by treatment group. A treatment benefit over placebo for both doses of AIMOVIG is seen across
`a range of changes from baseline in monthly migraine days.
`
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`
`
`Figure 2: Distribution of Change from Baseline in Mean Monthly Migraine Days over Months 4 to 6 by
`
`Treatment Group in Study 1
`
`
`Figure excludes patients with missing data.
`
`
`
`Compared to placebo, patients treated with AIMOVIG 70 mg once monthly and 140 mg once monthly showed
`greater reductions from baseline in mean monthly MPFID everyday activity scores averaged over months 4 to 6
`[difference from placebo: -2.2 for AIMOVIG 70 mg and -2.6 for AIMOVIG 140 mg; p-value < 0.001 for both],
`
`and in mean monthly MPFID physical impairment scores averaged over months 4 to 6 [difference from
`placebo: -1.9 for AIMOVIG 70 mg and -2.4 for AIMOVIG 140 mg; p-value < 0.001 for both].
`
`Study 2 (NCT 02483585) was a randomized, multi-center, 3-month, placebo-controlled, double-blind study
`evaluating AIMOVIG for the preventive treatment of episodic migraine. A total of 577 patients with a history of
`episodic migraine were randomized to receive either AIMOVIG 70 mg (N = 286) or placebo (N = 291) by
`subcutaneous injection once monthly for 3 months. Patients were allowed to use acute headache treatments
`including migraine-specific medications (i.e., triptans, ergotamine derivatives) and NSAIDs during the study.
`
`The study excluded patients with medication overuse headache as well as patients with myocardial infarction,
`stroke, transient ischemic attacks, unstable angina, coronary artery bypass surgery, or other revascularization
`procedures within 12 months prior to screening.
`
`The primary efficacy endpoint was the change from baseline in monthly migraine days at month 3. Secondary
`endpoints included the achievement of a ≥ 50% reduction from baseline in monthly migraine days (“≥ 50%
`MMD responders”), the change from baseline in monthly acute migraine-specific medication days at month 3,
`
`and the proportion of patients with at least a 5-point score reduction from baseline in MPFID at month 3.
`
`A total of 546 (95%) patients completed the 3-month double-blind study. Patients had a median age of 43 years
`(range: 18 to 65 years), 85% were female, and 90% were white. Six to seven percent of patients were taking
`concomitant preventive migraine treatment. The mean migraine frequency at baseline was approximately 8
`migraine days per month and was similar between treatment groups.
`
`AIMOVIG treatment demonstrated statistically significant improvements for key efficacy endpoints compared
`to placebo, as summarized in Table 4.
`
`
`
`Reference ID: 4264882
`
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`Page 9 of 14
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`9
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`
`
`Table 4: Efficacy Endpoints at Month 3 for Study 2
`
` AIMOVIG
`70 mg Once Monthly
`N = 282
`
`
`Monthly Migraine Days (MMD)
`
`
`Change from baseline
`Difference from placebo
`p-value
`
`≥ 50% MMD responders
`
`
`% Responders
`Difference from placebo
`Odds ratio relative to placebo
`p-value
`Monthly acute migraine-specific medication days
`
`
`Change from baseline
`Difference from placebo
`p-value
`
`
`-2.9
`
`-1.0
`
`< 0.001
`
`
`39.7%
`
`10.2%
`1.6
`
`0.010
`
`
`-1.2
`
`-0.6
`
`0.002
`
`Placebo
`
`N = 288
`
`
`-1.8
`
`
`
`
`29.5%
`
`
`
`
`
`-0.6
`
`
`
`
`
`
`
`
`
` Figure 3: Change from Baseline in Monthly Migraine Days in Study 2a
`
`
`
`
`
` a Least-square means and 95% confidence intervals are presented.
`
`Figure 4 shows the distribution of change from baseline in monthly migraine days at month 3 in bins of 2 days
`
`by treatment group. A treatment benefit over placebo for AIMOVIG is seen across a range of changes from
`baseline in monthly migraine days.
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`
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`Reference ID: 4264882
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`Page 10 of 14
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`Figure 4: Distribution of Change from Baseline in Monthly Migraine Days at Month 3 by Treatment
`
`Group in Study 2
`
`
`
`
`Figure excludes patients with missing data.
`
`The pre-specified analysis for the MPFID was based on at least a 5-point reduction within-patient responder
`definition. AIMOVIG 70 mg once monthly was not significantly better than placebo for the proportion of
`responders for everyday activity [difference from placebo: 4.7%; odds ratio = 1.2; p-value = 0.26] and physical
`impairment [difference from placebo: 5.9%; odds ratio = 1.3; p-value = 0.13]. In an exploratory analysis of the
`change from baseline in the mean MPFID scores at month 3, patients treated with AIMOVIG 70 mg, as
`
`compared to placebo, showed nominally greater reductions of physical impairment scores [difference from
`placebo: -1.3; p-value = 0.021], but not of everyday activities scores [difference from placebo: -1.1; p-value =
`0.061].
`
`Chronic Migraine
`Study 3 (NCT 02066415) was a randomized, multi-center, 3-month, placebo-controlled, double-blind study
`evaluating AIMOVIG as a preventive treatment of chronic migraine. A total of 667 patients with a history of
`chronic migraine with or without aura were randomized to receive AIMOVIG 70 mg (N = 191), AIMOVIG
`140 mg (N = 190), or placebo (N = 286) by subcutaneous injections once monthly for 3 months. Patients were
`allowed to use acute headache treatments including migraine-specific medications (i.e., triptans, ergotamine
`derivatives) and NSAIDs during the study.
`The study excluded patients with medication overuse headache caused by opiate overuse and patients with
`concurrent use of migraine preventive treatments. Patients with myocardial infarction, stroke, transient ischemic
`attacks, unstable angina, coronary artery bypass surgery, or other revascularization procedures within 12 months
`prior to screening were also excluded.
`
`The primary efficacy endpoint was the change from baseline in monthly migraine days at month 3. Secondary
`endpoints included the achievement of a ≥ 50% reduction from baseline in monthly migraine days (“≥ 50%
`MMD responders”) and change from baseline in monthly acute migraine-specific medication days at month 3.
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`
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`Reference ID: 4264882
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`Page 11 of 14
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`A total of 631 (95%) patients completed the 3-month double-blind study. Patients had a median age of 43 years
`(range: 18 to 66 years), 83% were female, and 94% were white. The mean migraine frequency at baseline was
`approximately 18 migraine days per month and was similar across treatment groups.
`
`AIMOVIG treatment demonstrated statistically significant improvements for key efficacy outcomes compared
`to placebo, as summarized in Table 5.
`Table 5: Efficacy Endpoints at Month 3 in Study 3
`
`
` AIMOVIG
`AIMOVIG
`
`70 mg Once Monthly
`
`140 mg Once Monthly
`N = 188
`N = 187
`
`Placebo
`
`N = 281
`
`
`-6.6
`
`-2.5
`< 0.001
`
`
`41.2%
`
`17.7%
`2.3
`< 0.001
`
`
`-4.1
`
`-2.6
`< 0.001
`
`
`-4.2
`
`
`
`
`23.5%
`
`
`
`
`
`-1.6
`
`
`
`
`
`
`-6.6
`
`-2.5
`< 0.001
`
`
`Monthly Migraine Days (MMD)
`
`
`Change from baseline
`Difference from placebo
`p-value
`
`≥ 50% MMD responders
`
`
`
`% Responders
`39.9%
`
`Difference from placebo
`16.4%
`Odds ratio relative to placebo
`2.2
`p-value
`< 0.001
`Monthly acute migraine-specific medication days
`
`
`
`-3.5
`Change from baseline
`
`Difference from placebo
`-1.9
`p-value
`< 0.001
`
`
`
`
`
` Figure 5: Change from Baseline in Monthly Migraine Days in Study 3a
`
`
` a Least-square means and 95% confidence intervals are presented.
`
`
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`Page 12 of 14
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`Reference ID: 4264882
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`Figure 6 shows the distribution of change from baseline in monthly migraine days at month 3 in bins of 3 days
`by treatment group. A treatment benefit over placebo for both doses of AIMOVIG is seen across a range of
`changes from baseline in migraine days.
`
`
`Figure 6: Distribution of Change from Baseline in Monthly Migraine Days at Month 3 by Treatment
`Group in Study 3
`
`
`
`Figure excludes patients with missing data.
`
`
`16
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`
`16.1 How Supplied
`AIMOVIG (erenumab-aooe) injection is a sterile, clear to opalescent, colorless to light yellow solution for
`subcutaneous administration.
`
`The needle shield within the white cap of the AIMOVIG prefilled autoinjector and gray needle cap of the
`
`
`AIMOVIG prefilled syringe contain dry natural rubber (a derivative of latex). Each single-dose prefilled
`SureClick® autoinjector or single-dose prefilled syringe of AIMOVIG contains a Type 1 glass syringe and
`stainless steel needle and delivers 1 mL of 70 mg/mL solution.
`
`AIMOVIG is supplied as follows:
`
`SureClick® Autoinjector
`
`
` Pack of 1 autoinjector: 70 mg/mL single-dose prefilled autoinjector
`
`
`NDC 55513-841-01
` Pack of 2 autoinjectors: 140 mg/2 mL (2 x 70 mg/mL single-dose prefilled autoinjectors)
`
`
`NDC 55513-841-02
`Syringe
` Pack of 1 syringe: 70 mg/mL single-dose prefilled syringe
`
`
`NDC 55513-840-01
` Pack of 2 syringes: 140 mg/2 mL (2 x 70 mg/mL single-dose prefilled syringes)
`
`
`NDC 55513-840-02
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`
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`Reference ID: 4264882
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`16.2 Storage and Handling
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` 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.
`
`
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`17
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`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.
`
`Instruct patients prescribed 140 mg to administer the once monthly dosage as two separate subcutaneous
`injections of 70 mg each.
`
`Advise latex-sensitive patients that the needle shield within the white cap of the AIMOVIG prefilled
`
`autoinjector and gray needle cap of the AIMOVIG prefilled syringe contain dry natural rubber (a derivative of
`latex) that may cause allergic reactions in individuals sensitive to latex [see Dosage and Administration (2.2)].
`
`For more information, go to www.aimovig.com or call 1-800-77-AMGEN (1-800-772-6436).
`
`
`
`
`
`AIMOVIG™ (erenumab-aooe)
`
`Manufactured by:
`
`Amgen Inc.
`
`One Amgen Center Drive
`
`Thousand Oaks, CA 91320-1799 USA
`
`U.S. License No. 1080
`
`Marketed by:
`
`Amgen Inc. (Thousand Oaks, CA 91320), and
`
`Novartis Pharmaceuticals Corporation (East Hanover, NJ 07936)
`
`
`Patent: http://pat.amgen.com/aimovig/
`
`
`© 2018 Amgen Inc. All rights reserved.
`
`v1
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`Reference ID: 4264882
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`Page 14 of 14
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` Patient Information
` AIMOVIGTM (AIM-oh-vig) (erenumab-aooe)
`
`
` injection, for subcutaneous use
`
`
`
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` What is AIMOVIG?
`
`
`
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`
`
` AIMOVIG is a prescription medicine used for the preventive treatment of migraine in adults.
`
`
`
`
` It is not known if AIMOVIG is safe and effective in children under 18 years of age