AHFS Class:

• Calcitonin Gene-related Peptide (CGRP) Antagonists 28:32.12

Generic Name(s):

• Atogepant

Atogepant, a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, is an antimigraine agent.1,2,3,4,7

Preventive Treatment of Episodic Migraine

Atogepant is used for the preventive treatment of episodic migraine in adults.1 In clinical studies, atogepant was more effective than placebo in reducing monthly migraine days in patients with episodic migraine.1,2,3,4

Clinical Experience

Efficacy of atogepant for the preventive treatment of episodic migraine has been established in 2 randomized, double-blind, placebo-controlled, multicenter studies (Study 1 and Study 2) in adults with at least a 1-year history of migraine, with or without aura, according to the International Classification of Headache Disorders, third edition, beta version (ICHD-3 beta) diagnostic criteria.1,2,3,4 Both studies included patients with episodic migraine (i.e., experiencing at least 4 migraine days but no more than 14 headache days per month). 1,2,3,4 Both studies evaluated atogepant dosages of 10 mg, 30 mg, and 60 mg administered orally once daily for 12 weeks.1,2,3 Patients were permitted to use acute headache treatments, including antimigraine agents (e.g., selective serotonin type 1 [5-hydroxytryptamine type 1; 5-HT₁] receptor agonists [triptans], ergot alkaloids), nonsteroidal anti-inflammatory agents (NSAIAs), acetaminophen, and opiates as needed during both studies.1,2,3,4 Use of other drugs that act on the calcitonin gene-related peptide (CGRP) pathway for acute or preventive headache treatment was not permitted.1 Both studies excluded patients with a history of myocardial infarction (MI), stroke, or transient ischemic attack (TIA) within 6 months prior to screening.1 The primary efficacy endpoint in both studies was the change from baseline in mean monthly migraine days over the first 12 weeks of treatment.1,2,3 In Study 1, additional endpoints included the change from baseline in mean monthly headache days, the change from baseline in mean monthly acute medication use days, and the percentages of patients with 50% or greater reductions from baseline in monthly migraine days over the first 12 weeks of treatment.1,2 In Study 2, additional endpoints included the change from baseline in mean monthly headache days over the first 12 weeks of treatment.1

In Study 1, 805 patients completed the 12-week, double-blind, treatment phase and 873 patients were included in the intent-to-treat analysis.1,2,4 From a mean baseline of 7.5 to 7.9 migraine days per month, monthly migraine days were reduced by 3.7, 3.9, or 4.2 days in patients who received atogepant 10, 30, or 60 mg, respectively, compared with a reduction of 2.5 days in patients who received placebo.1,2 From a mean baseline of 8.4 to 9 headache days per month, monthly headache days were reduced by 3.9, 4.0, or 4.2 days in patients who received atogepant 10, 30, or 60 mg, respectively, compared with a reduction of 2.5 days in patients receiving placebo.1,2 In addition, a ≥50% reduction in mean migraine days per month was achieved by 56, 59, and 61% of patients receiving the 10-, 30-, and 60-mg daily dosage of atogepant compared with 29% of those receiving placebo.1,2

In Study 2, 541 patients completed the 12-week, double-blind, treatment phase and 629 were included in the intent-to-treat analysis.1 From a mean baseline of approximately 7.6 to 7.8 migraine days per month, monthly migraine days were reduced by 4.0, 3.8, or 3.6 days in patients who received atogepant 10, 30, or 60 mg, respectively, compared with a reduction of 2.8 days in patients who received placebo.1,3 From a mean baseline of 8.9 to 9.1 headache days per month, monthly headache days were reduced by 4.3, 4.2, or 3.9 days in patients who received atogepant 10, 30, or 60 mg, respectively, compared with a reduction of 2.9 days in patients receiving placebo.1

Clinical Perspective

The current consensus statement from the American Headache Society (AHS) discusses the evidence for atogepant in the preventive treatment of episodic migraine.8 The AHS states that treatment plans involving the preventive use of "gepants" should be based on regimens used in clinical trials and individualized according to the needs of each patient.8 Repeated treatment with these drugs does not appear to be associated with medication overuse headache or liver toxicity.8

Preventative Treatment of Chronic Migraine

Atogepant is used for the preventive treatment of chronic migraine in adults.1 In a clinical study, atogepant was more effective than placebo in reducing monthly migraine days in patients with chronic migraine.1

Clinical Experience

The efficacy of atogepant for the preventive treatment of chronic migraine in adults with at least a 1-year history of chronic migraine (according to ICHD-3 diagnostic criteria) was evaluated in a randomized, multicenter, double-blind, placebo-controlled study.1 The study included patients with medication overuse headache.1 A subset of patients (11%) was allowed to use one concomitant migraine preventive medication.1 Patients in this study were allowed to use acute headache treatments (i.e., triptans, ergotamine derivatives, NSAIAs, acetaminophen, and opioids) as needed.1 Use of concomitant medications that act on the CGRP pathway was not permitted for either acute or preventive treatment of migraine.1 The study excluded patients with myocardial infarction, stroke, or transient ischemic attacks within 6 months prior to screening.1 The primary efficacy endpoint in the study was the change from baseline in mean monthly migraine days over the first 12 weeks of treatment.1 Additional endpoints included the change from baseline in mean monthly headache days, the change from baseline in mean monthly acute medication use days and the proportion of patients achieving at least a 50% reduction from baseline in mean monthly migraine days (3-month average).1

In this study, patients were randomized to atogepant 60 mg once daily or placebo for 12 weeks.1 Monthly migrane days were reduced by a mean of 6.9 (from a baseline of 19.2) in patients who received atogepant and by a mean of 5.1 (from a baseline of 18.9) in patients who received placebo.1 Monthly headache days were reduced by a mean of 7.0 (from a baseline of 21.5) in patients who received atogepant and by a mean of 5.1 (from a baseline of 21.4) in patients who received placebo.1 In addition, a ≥50% reduction in mean migraine days per month was achieved by 41% of patients receiving atogepant compared with 26% of those receiving placebo.1

Clinical Perspective

Although the current consensus statement from the American Headache Society (AHS) does not discuss the specific evidence for use of atogepant in the preventive treatment of chronic migraines, AHS states that treatment plans involving the preventive use of the "gepant" class of medications should be based on regimens used in clinical trials and individualized according to the needs of each patient.8

Administration

Atogepant tablets are administered orally without regard to food.1

Store atogepant tablets at 20-25°C (excursions permitted between 15-30°C).1

Dosage

Adults

Preventive Treatment of Episodic Migraine

For the preventive treatment of episodic migraine, the recommended dosage of atogepant is 10, 30, or 60 mg taken orally once daily.1 Atogepant should be given at the lowest effective dosage.5,8

Dosage Modifications for Concomitant Therapy

Dosage adjustment of atogepant is necessary if the drug is used concomitantly with a strong cytochrome P-450 (CYP) 3A4 inhibitor, a CYP3A4 inducer (strong, moderate, or weak), or an organic anion transport protein (OATP) inhibitor.1

If concomitant use with a strong CYP3A4 inhibitor (e.g., itraconazole) is necessary, the manufacturer recommends an atogepant dosage of 10 mg once daily.1

If concomitant use with a CYP3A4 inducer (e.g., rifampin, ) is necessary, the manufacturer recommends an atogepant dosage of 30 or 60 mg once daily.1

If concomitant use with an OATP inhibitor is necessary, the manufacturer recommends an atogepant dosage of 10 or 30 mg once daily.1

Preventive Treatment of Chronic Migraine

For the preventive treatment of chronic migraine, the recommended dosage of atogepant is 60 mg taken orally once daily.1

Dosage Modifications for Concomitant Therapy

Avoidance of use or dosage modification of atogepant is necessary if the drug is used concomitantly with a strong CYP3A4 inhibitor, a CYP3A4 inducer (strong, moderate, or weak), or an organic anion transport protein (OATP) inhibitor.1

Avoid concomitant use with a strong CYP3A4 inhibitor (e.g., itraconazole).1

Avoid concomitant use with a CYP3A4 inducer (e.g., rifampin).1

If concomitant use with an OATP inhibitor is necessary, the manufacturer recommends an atogepant dosage of 30 mg once daily.1

Special Populations

Hepatic Impairment

Dosage adjustment is not necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1 Avoid use of atogepant in patients with severe hepatic impairment (Child-Pugh class C).1

Renal Impairment

Dosage adjustment is not necessary in patients with mild or moderate renal impairment (creatinine clearance 30-89 mL/minute).1

In patients with severe renal impairment (creatinine clearance 15-29 mL/minute) or end-stage renal disease (creatinine clearance <15 mL/minute), the recommended dosage of atogepant for prevention of episodic migraine is 10 mg once daily.1 In patients with end-stage renal disease undergoing intermittent dialysis, the manufacturer states that it is preferable to administer atogepant after dialysis.1 Use of atogepant for the prevention of chronic migraine should be avoided in patients with severe renal impairment or end-stage renal disease.1

Geriatric Patients

Select dosage with caution, usually starting at the low end of the dosage range.1

Contraindications

• Contraindicated in patients with a history of hypersensitivity to atogepant or any of the inactive ingredients in the formulation.1

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, dyspnea, rash, pruritus, urticaria, and facial edema, have been reported with use of atogepant.1 Hypersensitivity reactions can occur days after administration.1 If a hypersensitivity reaction occurs, discontinue atogepant and institute appropriate therapy1

Specific Populations

Pregnancy

There are no adequate data on the developmental risk associated with the use of atogepant in pregnant women.1 Based on animal studies, the drug may cause fetal harm.1 In animal studies, adverse effects on embryofetal development (e.g., decreased fetal and offspring body weight in rats, increased fetal structural variations in rabbits) were observed following administration of the drug during pregnancy and lactation at dosages higher than those used clinically.1

Published data suggest that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy.1

Lactation

It is not known whether atogepant is distributed into human milk; the drug is distributed into milk in rats.1 The effects of atogepant on the breast-fed infant and on milk production are not known.1

Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for atogepant and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1

Pediatric Use

Safety and efficacy of atogepant have not been established in pediatric patients.1

Geriatric Use

Clinical studies of atogepant did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently than younger adults.1 In pharmacokinetic studies, no clinically important differences in the pharmacokinetics of atogepant were observed between geriatric individuals and younger adults.1 The manufacturer states that, in general, dosage selection for geriatric patients should be cautious and start at the low end of the dosage range.1

Hepatic Impairment

Atogepant exposure is increased by 24, 15, and 38% in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment, respectively.1

Dosage adjustment is not necessary in patients with mild or moderate hepatic impairment.1

Avoid use of atogepant in patients with severe hepatic impairment.1

Renal Impairment

The pharmacokinetics of atogepant are not substantially affected in patients with mild or moderate renal impairment (creatinine clearance of 30-89 mL/minute).1 The drug has not been studied in patients with severe renal impairment (creatinine clearance of 15-29 mL/minute) or end-stage renal disease (creatinine clearance <15 mL/minute).1

Dosage adjustment is not necessary in patients with mild or moderate renal impairment.1 In patients with severe renal impairment or end-stage renal disease, the recommended dosage of atogepant is 10 mg once daily for prevention of episodic migraine.1 Avoid use of atogepant for the prevention of chronic migraine in patients with severe renal impairment or end-stage renal disease.1

Common Adverse Effects

Common adverse reactions reported in ≥4% of patients receiving atogepant in clinical studies include nausea, constipation, and fatigue/somnolence.1

Atogepant is metabolized principally by cytochrome P-450 (CYP) 3A4.1 In vitro, the drug does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4; monoamine oxidase-A (MAO-A); or uridine diphosphate-glucuronosyltransferase (UGT) 1A1 at clinically relevant concentrations.1 The drug also does not induce CYP isoenzymes 1A2, 2B6, or 3A4 at clinically relevant concentrations.1

In vitro studies indicate that atogepant is a substrate of breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), organic anion transporting polypeptide (OATP) 1B1 and 1B3, and organic anion transporter (OAT) 1, but is not a substrate of OAT3, organic cation transporter (OCT) 2, or multidrug and toxic compound extrusion (MATE) 1.1,5 The drug is a weak inhibitor of OATP1B1, OATP1B3, OCT2, and MATE1; however, this inhibition potential is not expected to be clinically important.1 Atogepant does not inhibit P-gp, BCRP, bile salt export pump (BSEP), multidrug resistance protein (MRP) 3, MRP4, OAT1, OAT3, or sodium taurocholate cotransporting polypeptide (NTCP).1

Drugs and Foods Affecting Hepatic Microsomal Enzymes

CYP3A4 Inhibitors

Concomitant use of atogepant and CYP3A4 inhibitors may result in increased systemic exposure to atogepant.1 When the strong CYP3A4 inhibitor itraconazole was administered concomitantly with atogepant, peak plasma concentrations and exposure of atogepant were increased by 2.15- and 5.5-fold, respectively.1 Pharmacokinetic models suggest that moderate or weak inhibitors of CYP3A4 may increase the AUC of atogepant by 1.7- and 1.1-fold, respectively.1

In patients with episodic migraine concurrently receiving a strong CYP3A4 inhibitor (e.g., itraconazole), the manufacturer recommends an atogepant dosage of 10 mg once daily.1 For patients with chronic migraine, avoid use of strong CYP3A4 inhibitors with atogepant.1

Dosage adjustments are not required if atogepant is used concomitantly with a moderate or weak CYP3A4 inhibitor.1

CYP3A4 Inducers

Concomitant use of atogepant and CYP3A4 inducers may result in decreased systemic exposure to atogepant.1 When the strong CYP3A4 inducer rifampin (at steady-state) was administered concomitantly with atogepant, peak plasma concentrations and exposure of atogepant were decreased by 30 and 60%, respectively.1

Concomitant administration of atogepant with moderate inducers of CYP3A4 can also result in decreased exposure of atogepant.1 When atogepant was administered concomitantly with topiramate, a weak CYP3A4 inducer (at steady-state), peak plasma concentrations and exposure of atogepant were decreased by 24 and 25%, respectively; there were no clinically significant changes in the pharmacokinetics of topiramate.1

In patients with episodic migraine concurrently receiving a weak, moderate, or potent CYP3A4 inducer (e.g., rifampin), the manufacturer recommends an atogepant dosage of 30 or 60 mg once daily.1 In patients with chronic migraine, avoid concomitant use of CYP3A4 inducers with atogepant.1

Drugs Affecting Transport Systems

OATP Inhibitors

Concomitant use of atogepant and OATP inhibitors may result in increased systemic exposure to atogepant.1 When the OATP inhibitor rifampin (single-dose) was administered concomitantly with atogepant, peak plasma concentrations and exposure of atogepant were increased by 2.23- and 2.85-fold, respectively.1

In patients with episodic migraine concurrently receiving an OATP inhibitor, the manufacturer recommends an atogepant dosage of 10 or 30 mg once daily.1 In patients with chronic migraine concurrently receiving an OATP inhibitor, the manufacturer recommends an atogepant dosage of 30 mg once daily.1

Other Transporters

Concomitant use of atogepant and BCRP and/or P-gp inhibitors may result in increased systemic exposure to atogepant.1 When the P-gp inhibitor quinidine was administered concomitantly with atogepant, peak plasma concentrations and exposure of atogepant increased by 4 and 26%, respectively, in healthy individuals.1 However, the changes in atogepant exposure following concomitant use with a P-gp inhibitor is not expected to be clinically significant.1

Description

Atogepant is a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist (sometimes referred to as a gepant).1,2,3,4,7 CGRP is a potent vasodilator and pain-signaling neuropeptide that has been associated with migraine pathophysiology.5,6,7 CGRP and its receptors are located at sites that are relevant to migraine development such as the trigeminal neurons and are also widely distributed throughout the central and peripheral nervous systems as well as in nonneuronal tissues throughout the body.5,7 Serum CGRP concentrations are increased during acute migraine attacks and return to normal after resolution of the migraine.2,7 Furthermore, IV infusion of CGRP has been shown to induce migraines in patients with a history of migraine.2,7

Atogepant and other small molecule CGRP receptor antagonists bind to CGRP receptors with high affinity, blocking the binding of CGRP to the receptor and preventing subsequent receptor activation.5,7 Unlike 5-HT₁ receptor agonists (triptans), CGRP receptor antagonists do not appear to cause vasoconstriction.7 Atogepant does not appear to prolong the QT interval in dosages up to 5 times the maximum recommended daily dosage.1

Atogepant exhibits dose-proportional pharmacokinetics within the recommended dosage range.1 Following oral administration, atogepant is rapidly absorbed;5 peak plasma concentrations occur in approximately 1-2 hours.1 Administration with a high-fat meal decreased peak plasma concentrations and AUC of the drug by 22 and 18%, respectively, but did not affect the median time to peak plasma concentration.1 The drug is 95% bound to plasma proteins in vitro.1 Atogepant is mainly eliminated through metabolism, primarily by cytochrome P-450 (CYP) 3A4.1 The parent compound and a glucuronide conjugate metabolite are the most prevalent circulating components in human plasma.1 Atogepant is excreted mostly by the biliary/fecal route (about 81%); the renal route is a minor route of elimination (about 8%).1,5 Following oral administration of a single, radiolabeled dose of atogepant, 42 and 5% of the dose was recovered as unchanged atogepant in feces and urine, respectively.1 The elimination half-life of the drug is approximately 11 hours.1,5 Population pharmacokinetic analysis indicates that the pharmacokinetics of atogepant are not substantially affected by age, sex, race, or body weight.1,5

Advice to Patients

• Inform patients about the risk of hypersensivity reactions and possible signs and symptoms of such reactions.1 Advise patients to discontinue atogepant and seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction.1
• Inform patients that atogepant may interact with certain other drugs.1 Advise patients to inform their clinician about concomitant use of any prescription and OTC drugs and dietary or herbal supplements (e.g., St. John's wort) as well as any concomitant illnesses (e.g., hepatic or renal disease).1
• Importance of women informing clinicians if they are or plan to become pregnant or are breast-feeding or plan to breast-feed.1
• Importance of informing patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Abbvie Inc. Qulipta^® (atogepant) tablets prescribing information. North Chicago, IL; 2023 Jun. [Web]

2. Ailani J, Lipton RB, Goadsby PJ, Ailani J et al. Atogepant for the Preventive Treatment of Migraine. N Engl J Med . 2021; 19:695-706. [PubMed 34407343]

3. Goadsby PJ, Dodick DW, Ailani J et al. Safety, tolerability, and efficacy of orally administered atogepant for the prevention of episodic migraine in adults: a double-blind, randomised phase 2b/3 trial. Lancet Neurol . 2020; 19:727-37. [PubMed 32822633]

4. Schwedt TJ, Lipton RB, Ailani J et al. Time course of efficacy of atogepant for the preventive treatment of migraine: Results from the randomized, double-blind ADVANCE trial. Cephalalgia . 2021 Sep 14; [PubMed 34521260]

5. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 215206Orig1s000: Integrated review(s). From FDA website. [Web]

6. Boinpally R, Abhijeet J, Butler M et al. Single-Dose Pharmacokinetics and Safety of Atogepant in Adults With Hepatic Impairment: Results From an Open-Label, Phase 1 Trial. Clin Pharmacol Drug Dev . 2021; 10:726-33. [PubMed 33501783]

7. Wattiez AS, Sowers LP, Russo AF. Calcitonin gene-related peptide (CGRP): role in migraine pathophysiology and therapeutic targeting. Expert Opin Ther Targets . 2020; 24:91-100. [PubMed 32003253]

8. Ailani J, Burch RC, Robbins MS. The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache . 2021; 61:1021-39<ref-callout href="r3210621">1</ref-callout> . [PubMed 34160823]