AJOVY (Page 2 of 6)

8 USE IN SPECIFIC POPULATIONS

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

Safety and effectiveness in pediatric patients have not been established.

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.

11 DESCRIPTION

Fremanezumab-vfrm is a fully humanized IgG2Δa/kappa monoclonal antibody specific for calcitonin gene-related peptide (CGRP) ligand. Fremanezumab-vfrm is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cells. The antibody consists of 1324 amino acids and has a molecular weight of approximately 148 kDa.

AJOVY (fremanezumab-vfrm) injection is a sterile, preservative-free, clear to opalescent, colorless to slightly yellow solution for subcutaneous injection, supplied in a single-dose 225 mg/1.5 mL prefilled autoinjector and a single-dose 225 mg/1.5 mL prefilled syringe.

Each prefilled autoinjector or prefilled syringe delivers 1.5 mL of solution containing 225 mg fremanezumab-vfrm, disodium ethylenediaminetetraacetic acid dihydrate (EDTA) (0.204 mg), L-histidine (0.815 mg), L-histidine hydrochloride monohydrate (3.93 mg), polysorbate-80 (0.3 mg), sucrose (99 mg), and Water for Injection, and has a pH of 5.5.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

The relationship between the pharmacodynamic activity and the mechanism(s) by which fremanezumab-vfrm exerts its clinical effects is unknown.

12.3 Pharmacokinetics

Absorption

After single subcutaneous (SC) administrations of 225 mg, 675 mg, and 900 mg fremanezumab-vfrm, median time to maximum concentrations (tmax) was 5 to 7 days. Dose-proportionality, based on population PK, was observed between 225 mg to 900 mg. Steady state was achieved by approximately 168 days (about 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

A population PK analysis assessing effects of age, race, sex, and weight was conducted on data from 2287 subjects. No dose adjustments are recommended for AJOVY.

Patients with Hepatic or Renal Impairment

Hepatic/renal impairment is not expected to affect the pharmacokinetics of fremanezumab. A population PK analysis of integrated data from the AJOVY clinical studies did not reveal a difference in the pharmacokinetics of fremanezumab in patients with mild hepatic impairment, relative to those with normal hepatic function. There were only 4 patients with moderate hepatic impairment, and no patient with severe hepatic impairment in fremanezumab clinical studies. No dedicated hepatic/renal impairment studies were conducted to assess the effect of hepatic or renal impairment on the pharmacokinetics of fremanezumab.

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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies of fremanezumab-vfrm were not conducted.

Mutagenesis

Genetic toxicology studies of fremanezumab-vfrm were not conducted.

Impairment of Fertility

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 effects on male or female fertility were observed. The highest dose tested was associated with plasma exposures (AUC) approximately 2 times that in humans at a dose of 675 mg.

14 CLINICAL STUDIES

The efficacy of AJOVY was evaluated as a preventive treatment of episodic or chronic migraine in two multicenter, randomized, 3-month, double-blind, placebo-controlled studies (Study 1 and Study 2, respectively).

Episodic Migraine

Study 1 (NCT 02629861) included adults with a history of episodic migraine (patients with <15 headache days per month). All patients were randomized (1:1:1) to receive subcutaneous injections of either AJOVY 675 mg every three months (quarterly), AJOVY 225 mg monthly, or placebo monthly, over a 3-month treatment period. Patients were allowed to use acute headache treatments during the study. A subset of patients (21%) was allowed to use one additional concomitant preventive medication.

The study excluded patients with a history of significant cardiovascular disease, vascular ischemia, or thrombotic events, such as cerebrovascular accident, transient ischemic attacks, deep vein thrombosis, or pulmonary embolism.

The primary efficacy endpoint was the mean change from baseline in the monthly average number of migraine days during the 3-month treatment period. Secondary endpoints included the proportion of patients reaching at least a 50% reduction in monthly average number of migraine days during the 3-month treatment period, the mean change from baseline in the monthly average number of days of use of any acute headache medication during the 3-month treatment period, and the mean change from baseline in the number of migraine days during the first month of the treatment period.

In Study 1, a total of 875 patients (742 females, 133 males), ranging in age from 18 to 70 years, were randomized. A total of 791 patients completed the 3-month double-blind phase. The mean migraine frequency at baseline was approximately 9 migraine days per month, and was similar across treatment groups.

Both monthly and quarterly dosing regimens of AJOVY demonstrated statistically significant improvements for efficacy endpoints compared to placebo over the 3-month period, as summarized in Table 2.

Table 2: Efficacy Endpoints in Study 1
Study 1Efficacy Endpoint AJOVY 225 mgMonthly(N=287) AJOVY 675 mgQuarterly(N=288) Placebo(N=290)
Monthly migraine days (MMD)
Baseline migraine days8.99.29.1

Change from baseline

-3.7

-3.4

-2.2

Difference from placebo-1.5-1.2
p-value<0.001<0.001
≥50% MMD responders

% responders

47.7%

44.4%

27.9%

Difference from placebo19.8%16.5%
p-value <0.001<0.001
Monthly acute headache medication days

Change from baseline

-3.0

-2.9

-1.6

Difference from placebo-1.4-1.3
p-value<0.001<0.001

Figure 1 displays the mean change from baseline in the average monthly number of migraine days in Study 1.

Figure 1: Change from Baseline in Monthly Migraine Days in Study 1a

Figure 1
(click image for full-size original)

Figure 2 shows the distribution of change from baseline in mean monthly migraine days in bins of 2 days by treatment group in Study 1. A treatment benefit over placebo for both doses of AJOVY is seen across a range of changes from baseline in monthly migraine days.

Figure 2: Distribution of Change from Baseline in Mean Monthly Migraine Days by Treatment Group in Study 1

Figure 2
(click image for full-size original)

Chronic Migraine

Study 2 (NCT 02621931) included adults with a history of chronic migraine (patients with ≥15 headache days per month). All patients were randomized (1:1:1) to receive subcutaneous injections of either AJOVY 675 mg starting dose followed by 225 mg monthly, 675 mg every 3 months (quarterly), or placebo monthly, over a 3-month treatment period. Patients were allowed to use acute headache treatments during the study. A subset of patients (21%) was allowed to use one additional concomitant, preventive medication.

The study excluded patients with a history of significant cardiovascular disease, vascular ischemia, or thrombotic events, such as cerebrovascular accident, transient ischemic attacks, deep vein thrombosis, or pulmonary embolism.

The primary efficacy endpoint was the mean change from baseline in the monthly average number of headache days of at least moderate severity during the 3-month treatment period. The secondary endpoints were the mean change from baseline in the monthly average number of migraine days during the 3-month treatment period, the proportion of patients reaching at least 50% reduction in the monthly average number of headache days of at least moderate severity during the 3-month treatment period, the mean change from baseline in the monthly average number of days of use of any acute headache medication during the 3-month treatment period, and the mean change from baseline in the number of headache days of at least moderate severity during the first month of treatment.

In Study 2, a total of 1130 patients (991 females, 139 males), ranging in age from 18 to 70 years, were randomized. A total of 1034 patients completed the 3-month double-blind phase.

Both monthly and quarterly dosing regimens of AJOVY treatment demonstrated statistically significant improvement for key efficacy outcomes compared to placebo, as summarized in Table 3.

Table 3: Efficacy Endpoints in Study 2

Study 2Efficacy Endpoint

AJOVY 225 mga Monthly(N=375)

AJOVY 675 mgQuarterly(N=375)

Placebo(N=371)

Baseline headache days of any severityb 20.320.420.3
Baseline headache days of at least moderate severityc 12.813.213.3

Change from baseline in the monthly average number of headache days of at least moderate severity

-4.6

-4.3

-2.5

Difference from placebo-2.1-1.8
p-value<0.001<0.001

Change from baseline in the monthly average number of migraine days in patients

-5.0

-4.9

-3.2

Change from baseline in monthly average number of headache days of at least moderate severity at 4 weeks after 1st dose

-4.6

-4.6

-2.3

Percentage of patients with ≥ 50% reduction in monthly average number of headache days of at least moderate severity

40.8%

37.6%

18.1%

Change from baseline in monthly average number of days of acute headache medication

-4.2

-3.7

-1.9

a In Study 2, patients received a 675 mg starting dose.
b Used for chronic migraine diagnosis. c Used for primary endpoint analysis.

Figure 3 displays the mean change from baseline in the average monthly number of headache days of at least moderate severity in Study 2.

Figure 3: Change from Baseline in Monthly Headache Days of At Least Moderate Severity in Study 2a

Figure 3
(click image for full-size original)

Figure 4 shows the distribution of change from baseline in monthly headache days of at least moderate severity at month 3 in bins of 3 days by treatment group. A treatment benefit over placebo for both dosing regimens of AJOVY is seen across a range of changes from baseline in headache days.

Figure 4: Distribution of Mean Change from Baseline in Monthly Headache Days of At Least Moderate Severity by Treatment Group in Study 2

Figure 4
(click image for full-size original)

*In Study 2, patients received a 675 mg starting dose.

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