Highlights

Indications and usage

Atogepant is a calcitonin gene-related peptide receptor antagonist indicated for the preventive treatment of migraine in adults.

Dosage and administration

Recommended dosage

Atogepant is taken orally with or without food.

Episodic migraine. The recommended dosage of atogepant for episodic migraine is 10 mg, 30 mg, or 60 mg taken once daily.

Chronic migraine. The recommended dosage of atogepant for chronic migraine is 60 mg taken once daily.

Dosage modifications

Dosing modifications for concomitant use of specific drugs and for patients with renal impairment are provided in Table 1.

Table 1. Dosage Modifications for Drug Interactions and for Specific Populations

Contraindications

Atogepant is contraindicated in patients with a history of hypersensitivity to atogepant or any of the components of atogepant. Reactions have included anaphylaxis and dyspnea.

Warnings and precautions

Adverse reactions

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 practice.

The safety of atogepant was evaluated in 2657 patients with migraine who received at least one dose of atogepant. Of these, 1225 patients were exposed to atogepant for at least 6 months, and 826 patients were exposed for 12 months.

In the 12-week, placebo-controlled clinical studies (Studies 1, 2, and 3), 314 patients received at least one dose of atogepant 10 mg once daily, 411 patients received at least one dose of atogepant 30 mg once daily, 678 patients received at least one dose of atogepant 60 mg once daily, and 663 patients received placebo. Approximately 88% were female, 75% were White, 13% were Black, 10% were Asian, and 10% were of Hispanic or Latino ethnicity. The mean age at study entry was 41 years (range 18 to 74 years).

The most common adverse reactions (incidence at least 4% and greater than placebo) are nausea, constipation, and fatigue/somnolence.

Table 2 summarizes the adverse reactions that occurred during Studies 1, 2, and 3.

Table 2. Adverse Reactions Occurring with an Incidence of At Least 2% for Atogepant and Greater than Placebo in Studies 1, 2, and 3*

The adverse reactions that most commonly led to the discontinuation of atogepant in these studies were nausea (0.6%), constipation (0.5%), and fatigue/somnolence (0.2%).

Liver enzyme elevations. In Study 1, Study 2, and Study 3, the rate of transaminase elevations over three times the upper limit of normal was similar between patients treated with atogepant (0.9%) and those treated with placebo (1.2%). However, there were cases with transaminase elevations over three times the upper limit of normal that were temporally associated with atogepant treatment; these were asymptomatic and resolved within 8 weeks of discontinuation. There were no cases of severe liver injury or jaundice.

Decreases in body weight. In Study 1, Study 2, and Study 3, the proportion of patients with a weight decrease of at least 7% at any point was 2.5% for placebo, 3.8% for atogepant 10 mg, 3.2% for atogepant 30 mg, and 5.3% for atogepant 60 mg.

Postmarketing experience

The following adverse reactions have been identified during post-approval use of atogepant. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders. Hypersensitivity (eg, anaphylaxis, dyspnea, rash, pruritus, urticaria, facial edema).

Drug interactions

CYP3A4 inhibitors. Co-administration of atogepant with itraconazole, a strong CYP3A4 inhibitor, resulted in a significant increase in exposure of atogepant in healthy subjects. For episodic migraine, the recommended dosage of atogepant with concomitant use of strong CYP3A4 inhibitors is 10 mg once daily. For chronic migraine, avoid concomitant use of strong CYP3A4 inhibitors with atogepant. No dosage adjustment of atogepant is needed with concomitant use of moderate or weak CYP3A4 inhibitors.

CYP3A4 inducers. Co-administration of atogepant with steady state rifampin, a strong CYP3A4 inducer, resulted in a significant decrease in exposure of atogepant in healthy subjects. Concomitant administration of atogepant with moderate inducers of CYP3A4 can also result in decreased exposure of atogepant. Co-administration of atogepant with steady-state topiramate, a weak CYP3A4 inducer, resulted in decreased exposure of atogepant in healthy subjects. For episodic migraine, the recommended dosage of atogepant with concomitant use of strong, moderate, or weak CYP3A4 inducers is 30 mg or 60 mg once daily. For chronic migraine, avoid concomitant use of strong, moderate, or weak CYP3A4 inducers with atogepant.

OATP inhibitors. Co-administration of atogepant with single-dose rifampin, an OATP inhibitor, resulted in a significant increase in exposure of atogepant in healthy subjects. For episodic migraine, the recommended dosage of atogepant with concomitant use of OATP inhibitors is 10 mg or 30 mg once daily. For chronic migraine, the recommended dosage of atogepant with concomitant use of OATP inhibitors is 30 mg once daily.

Other drug interaction evaluations. Co-administration of atogepant with oral contraceptive components ethinyl estradiol and levonorgestrel, famotidine, esomeprazole, acetaminophen, naproxen, sumatriptan, or ubrogepant did not result in significant pharmacokinetic interactions for either atogepant or co-administered drugs. Co-administration of atogepant with topiramate did not result in clinically significant changes in the pharmacokinetics of topiramate.

Use in specific populations

Pregnancy

Risk summary. There are no adequate data on the developmental risk associated with the use of atogepant in pregnant women. In animal studies, oral administration of atogepant during the period of organogenesis (rats and rabbits) or throughout pregnancy and lactation (rats) resulted in adverse developmental effects (decreased fetal and offspring body weight in rats; increased incidence of fetal structural variations in rabbits) at exposures greater than those used clinically.

In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The estimated rate of major birth defects (2.2% to 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. Oral administration of atogepant (0, 5, 15, 125, or 750 mg/kg/day) to pregnant rats during the period of organogenesis resulted in decreases in fetal body weight and in skeletal ossification at the two highest doses tested (125 and 750 mg/kg), which were not associated with maternal toxicity. At the no-effect dose (15 mg/kg/day) for adverse effects on embryofetal development, plasma exposure (AUC) was approximately four times that in humans at the maximum recommended human dose of 60 mg/day.

Oral administration of atogepant (0, 30, 90, or 130 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in an increase in fetal visceral and skeletal variations at the highest dose tested (130 mg/kg/day), which was associated with minimal maternal toxicity. At the no-effect dose (90 mg/kg/day) for adverse effects on embryofetal development, plasma exposure (AUC) was approximately three times that in humans at the maximum recommended human dose.

Oral administration of atogepant (0, 15, 45, or 125 mg/kg/day) to rats throughout gestation and lactation resulted in decreased pup body weight at the highest dose tested (125 mg/kg/day), which persisted into adulthood. At the no-effect dose (45 mg/kg/day) for adverse effects on pre- and postnatal development, plasma exposure (AUC) was approximately five times that in humans at the maximum recommended human dose.

Lactation

There are no data on the presence of atogepant in human milk, the effects of atogepant on the breastfed infant, or the effects of atogepant on milk production. In lactating rats, oral dosing with atogepant resulted in levels of atogepant in milk approximately 2-fold higher than that in maternal plasma. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for atogepant and any potential adverse effects on the breastfed infant from atogepant or from the underlying maternal condition.

Pediatric use

Safety and effectiveness in pediatric patients have not been established.

Geriatric use

Population pharmacokinetic modeling suggests no clinically significant pharmacokinetic differences between elderly and younger subjects. Clinical studies of atogepant did not include sufficient numbers of patients aged 65 years 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.

Renal impairment

The renal route of elimination plays a minor role in the clearance of atogepant. For episodic migraine, in patients with severe renal impairment (CLcr 15-29 mL/min) and in patients with end-stage renal disease (CLcr <15 mL/min), the recommended dosage of atogepant is 10 mg once daily; in patients with end-stage renal disease undergoing intermittent dialysis, atogepant should preferably be taken after dialysis. For chronic migraine, avoid atogepant use in patients with severe renal impairment and in patients with end-stage renal disease. No dose adjustment is recommended for patients with mild or moderate renal impairment.

Hepatic impairment

No dose adjustment of atogepant is recommended for patients with mild or moderate hepatic impairment. Avoid use of atogepant in patients with severe hepatic impairment.

Clinical pharmacology

Mechanism of action

Atogepant is a calcitonin gene-related peptide receptor antagonist.

Pharmacodynamics

Cardiac electrophysiology. At a dose five times the maximum recommended daily dose, atogepant does not prolong the QT interval to any clinically relevant extent.

Pharmacokinetics

Absorption. Following oral administration of atogepant, atogepant is absorbed with peak plasma concentrations at approximately 1 to 2 hours. Atogepant displays dose-proportional pharmacokinetics up to 170 mg per day (approximately three times the highest recommended dosage), with no accumulation.

Effect of food. When atogepant was administered with a high-fat meal, the food effect was not significant (AUC and C_MAX were reduced by approximately 18% and 22%, respectively, with no effect on median time to maximum atogepant plasma concentration). Atogepant was administered without regard to food in clinical efficacy studies.

Distribution. Plasma protein binding of atogepant was not concentration-dependent in the range of 0.1 to 10 μM; the unbound fraction of atogepant was approximately 4.7% in human plasma. The mean apparent volume of distribution of atogepant (Vz/F) after oral administration is approximately 292 L.

Elimination.

Metabolism. Atogepant is eliminated mainly through metabolism, primarily by CYP3A4. The parent compound (atogepant), and a glucuronide conjugate metabolite (M23) were the most prevalent circulating components in human plasma.

Excretion. The elimination half-life of atogepant is approximately 11 hours. The mean apparent oral clearance (CL/F) of atogepant is approximately 19 L/hr. Following single oral dose of 50 mg C-atogepant to healthy male subjects, 42% and 5% of the dose was recovered as unchanged atogepant in feces and urine, respectively.

Specific populations.

Patients with renal impairment. The renal route of elimination plays a minor role in the clearance of atogepant. Based on a population pharmacokinetic analysis, there is no significant difference in the pharmacokinetics of atogepant in patients with mild or moderate renal impairment (CLcr 30 to 89 mL/min) relative to those with normal renal function (CLcr >90 mL/min). Patients with severe renal impairment or end-stage renal disease (CLcr <30 mL/min) have not been studied.

Patients with hepatic impairment. In patients with pre-existing mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C) hepatic impairment, the total atogepant exposure was increased by 24%, 15%, and 38%, respectively. Due to a potential for liver injury in patients with severe hepatic impairment, avoid use of atogepant in patients with severe hepatic impairment.

Other specific populations. Based on a population pharmacokinetic analysis, age, sex, race, and body weight did not have a significant effect on the pharmacokinetics (C_max and AUC) of atogepant. Therefore, no dose adjustments are warranted based on these factors.

Nonclinical toxicology

Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenicity. Atogepant was administered orally to mice (0, 5, 20, or 75 mg/kg/day in males; 0, 5, 30, 160 mg/kg/day in females) and rats (0, 10, 20, or 100 mg/kg in males; 0, 25, 65, or 200 mg/kg in females) for up to 2 years. There was no evidence of drug-related tumors in either species. Plasma exposures at the highest doses tested in mice and rats were approximately 8 and 20 to 35 times, respectively, that in humans at the maximum recommended human dose of 60 mg/day.

Mutagenicity. Atogepant was negative in in vitro (Ames, chromosomal aberration test in Chinese Hamster Ovary cells) and in vivo (rat bone marrow micronucleus) assays.

Impairment of fertility. Oral administration of atogepant (0, 5, 20, or 125 mg/kg/day) to male and female rats prior to and during mating and continuing in females to Gestation Day 7 resulted in no adverse effects on fertility or reproductive performance. Plasma exposures (AUC) at the highest dose tested are approximately 15 times that in humans at the maximum recommended human dose.

Clinical studies

Episodic migraine

The efficacy of atogepant for the preventive treatment of episodic migraine in adults was demonstrated in two randomized, multicenter, double-blind, placebo-controlled studies (Study 1 and Study 2). The studies enrolled patients with at least a 1-year history of migraine with or without aura, according to the International Classification of Headache Disorders (ICHD-3) diagnostic criteria.

In Study 1 (NCT03777059), 910 patients were randomized 1:1:1:1 to receive atogepant 10 mg (N = 222), atogepant 30 mg (N = 230), atogepant 60 mg (N = 235), or placebo (N = 223), once daily for 12 weeks. In Study 2 (NCT02848326), 652 patients were randomized 1:2:2:2 to receive atogepant 10 mg (N = 94), atogepant 30 mg (N = 185), atogepant 60 mg (N = 187), or placebo (N = 186), once daily for 12 weeks. In both studies, patients were allowed to use acute headache treatments (ie, triptans, ergotamine derivatives, NSAIDs, acetaminophen, and opioids) as needed. The use of a concomitant medication that acts on the CGRP pathway was not permitted for either acute or preventive treatment of migraine. The studies excluded patients with myocardial infarction, stroke, or transient ischemic attacks within 6 months prior to screening.

Study 1. The primary efficacy endpoint was the change from baseline in mean monthly migraine days (MMD) across the 12-week treatment period. Secondary endpoints included the change from baseline in mean monthly headache days, the change from baseline in mean monthly acute medication use days, the proportion of patients achieving at least a 50% reduction from baseline in mean MMD (3-month average), the change from baseline in mean monthly Activity Impairment in Migraine-Diary (AIM-D) Performance of Daily Activities (PDA) domain scores, the change from baseline in mean monthly AIM-D Physical Impairment (PI) domain scores, across the 12-week treatment period, and the change from baseline at Week 12 for Migraine Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) Role Function-Restrictive (RFR) domain scores.

The AIM-D evaluates difficulty with performance of daily activities (PDA domain) and physical impairment (PI domain) due to migraine, with scores ranging from 0 to 100. Higher scores indicate greater impact of migraine, and reductions from baseline indicate improvement. The MSQ v2.1 Role Function-Restrictive (RFR) domain score assesses how often migraine impacts function related to daily social and work-related activities over the past 4 weeks, with scores ranging from 0 to 100. Higher scores indicate lesser impact of migraine on daily activities, and increases from baseline indicate improvement.

Patients had a mean age of 42 years (range 18 to 73 years), 89% were female, 83% were White, 14% were Black, and 9% were of Hispanic or Latino ethnicity. The mean migraine frequency at baseline was approximately 8 migraine days per month and was similar across treatment groups. A total of 805 (88%) patients completed the 12-week double-blind study period.

For a summary of key efficacy results from this study, see patient label information on the DAILYMED website.

Study 2. The primary efficacy endpoint was the change from baseline in mean monthly migraine days across the 12-week treatment period.

Patients had a mean age of 40 years (range: 18 to 74 years); 87% were female, 76% were White, 20% were Black, and 15% were of Hispanic or Latino ethnicity. The mean migraine frequency at baseline was approximately 8 migraine days per month. A total of 541 (83%) patients completed the 12-week double-blind study period.

In Study 2, there was a significantly greater reduction in mean monthly migraine days across the 12-week treatment period in all three atogepant treatment groups, compared with placebo.

For a summary of key efficacy results from this study, see patient label information on the DAILYMED website.

Chronic migraine

Study 3. The efficacy of atogepant for the preventive treatment of chronic migraine in adults was demonstrated in a randomized, multicenter, double-blind, placebo-controlled study (Study 3). The study enrolled patients with at least a 1-year history of chronic migraine, according to the ICHD-3 diagnostic criteria.

Study 3 (NCT03855137) included randomization of patients to atogepant 60 mg once daily (N = 262) or placebo (N = 259) for 12 weeks. A subset of patients (11%) was allowed to use one concomitant migraine preventive medication. Patients were allowed to use acute headache treatments (ie, triptans, ergotamine derivatives, NSAIDs, acetaminophen, and opioids) as needed. Patients with medication overuse headache also were enrolled. The use of a concomitant medication that acts on the CGRP pathway was not permitted for either acute or preventive treatment of migraine. The study excluded patients with myocardial infarction, stroke, or transient ischemic attacks within 6 months prior to screening.

The primary efficacy endpoint was the change from baseline in mean MMD across the 12-week treatment period. Secondary endpoints included the change from baseline in mean monthly headache days, the change from baseline in mean monthly acute medication use days, the proportion of patients achieving at least a 50% reduction from baseline in mean MMD (3-month average), the change from baseline in mean monthly AIM-D PDA domain scores, the change from baseline in mean monthly AIM-D PI domain scores, across the 12-week treatment period, and the change from baseline at Week 12 for MSQ v2.1 RFR domain scores.

Patients had a mean age of 42 years (range 18 to 74 years), 87% were female, 60% were White, 3% were Black, 36% were Asian, and 4% were of Hispanic or Latino ethnicity. The mean migraine frequency at baseline was approximately 19 migraine days per month and was similar across treatment groups. A total of 463 (89%) of these patients completed the 12-week double-blind study period.

For a summary of key efficacy results from this study, see patient label information on the DAILYMED website.

Patient counseling information

Advise the patient to read the FDA-approved patient labeling.

Hypersensitivity reactions. Inform patients about the signs and symptoms of hypersensitivity reactions and that these reactions can occur with atogepant. Advise patients to discontinue atogepant and seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction.

Drug interactions. Inform patients that atogepant may interact with certain other drugs, and that dosage modifications of atogepant may be recommended when used with some other drugs. Advise patients to report to their healthcare provider the use of any other prescription medications, over-the-counter medications, herbal products, or grapefruit juice.