Atogepant (Monograph)

Brand name: Qulipta
Drug class: Calcitonin Gene-related Peptide (CGRP) Antagonists
Chemical name: (3'S)-N-[(3S,5S,6R)-6-methyl-2-oxo-1- (2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2'-oxo-1',2',5,7- tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridine]-3-carboxamide
Molecular formula: C29H23F6N5O3
CAS number: 1374248-81-3

Medically reviewed by Drugs.com on May 23, 2022. Written by ASHP.

Introduction

Antimigraine agent; a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist.

Uses for Atogepant

Preventive Treatment of Migraine

Preventive treatment of episodic migraine in adults.

Current consensus statement from the American Headache Society (AHS) discuss the evidence for atogepant in the preventive treatment of migraines. 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. Repeated treatment with these drugs does not appear to be associated with medication overuse headache or liver toxicity.

Atogepant Dosage and Administration

Administration

Oral Administration

Administer orally without regard to food.

Dosage

Adults

Preventive Treatment of Migraine

Oral

10, 30, or 60 mg once daily. Use lowest effective dosage.

Dosage adjustment of atogepant is necessary if the drug is used concomitantly with a strong CYP3A4 inhibitor, a strong or moderate CYP3A4 inducer, or an organic anion transport protein (OATP) inhibitor.

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

If concomitant use with a strong or moderate CYP3A4 inducer (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort, efavirenz, etravirine) is necessary, the manufacturer ecommends a dosage of atogepant 30 or 60 mg once daily.

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

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe hepatic impairment (Child-Pugh class C): Avoid use.

Renal Impairment

Mild or moderate renal impairment (Cl_cr 30–89 mL/minute): No dosage adjustment necessary.

Severe renal impairment (Cl_cr 15–29 mL/minute) or end-stage renal disease (Cl_cr <15 mL/minute): Recommended dosage is 10 mg once daily. For patients with end-stage renal disease undergoing intermittent dialysis, manufacturer states that it is preferable to administer atogepant after dialysis.

Geriatric Patients

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

Cautions for Atogepant

Contraindications

None.

Warnings/Precautions

Specific Populations

Pregnancy

No adequate data on developmental risk associated with use of atogepant in pregnant women. Based on animal studies, may cause fetal harm. Adverse effects on embryofetal development (e.g., decreased fetal and offspring body weight, increased fetal structural variations) observed in animals at dosages higher than those used clinically.

Possible increased risk of preeclampsia and gestational hypertension during pregnancy in women with migraine.

Lactation

Not known whether distributed into human milk; distributed into milk in rats. Effects on the breast-fed infant and on milk production not known. Consider known benefits of breast-feeding along with mother's clinical need for atogepant and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. Clinically important pharmacokinetic differences not observed between geriatric and younger individuals.

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

Hepatic Impairment

Exposure is increased in patients with hepatic impairment.

Dosage adjustment not necessary in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.

Avoid use in patients with severe (Child-Pugh class C) hepatic impairment.

Renal Impairment

Pharmacokinetics not substantially altered in patients with mild or moderate renal impairment (Cl_cr 30–89 mL/minute); dosage adjustment not necessary.

Not studied in patients with severe renal impairment (Cl_cr 15–29 mL/minute) or end-stage renal disease (Cl_cr <15 mL/minute). Recommended dosage is 10 mg once daily in patients with severe renal impairment or end-stage renal disease.

Common Adverse Effects

Common adverse reactions (≥4%) include nausea, constipation, and fatigue.

Interactions for Atogepant

Metabolized principally by CYP3A4.

In vitro, 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. Does not induce CYP1A2, 2B6, or 3A4 at clinically relevant concentrations.

In vitro, 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; not a substrate of OAT3, organic cation transporter (OCT) 2, or multidrug and toxic compound extrusion (MATE) 1. In vitro, weak inhibitor of OATP1B1, OATP1B3, OCT2, and MATE1; not expected to be clinically important. In vitro, 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).

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Strong CYP3A4 inhibitors: Potential increased exposure to atogepant. Recommended atogepant dosage is 10 mg once daily during concomitant use. (See Specific Drugs and Foods under Interactions.)

Moderate CYP3A4 inhibitors or weak CYP3A4 inhibitors : No dosage adjustment is necessary.

Strong or moderate CYP3A4 inducers: Possible decreased exposure to atogepant. Recommended atogepant dosage is 30 or 60 mg once daily during concomitant use. (See Specific Drugs and Foods under Interactions.)

OATP Inhibitors

Potential pharmacokinetic interaction (increased serum atogepant concentrations). Recommended atogepant dosage is 10 or 30 mg once daily during concomitant use.

Specific Drugs and Foods

Drug	Interaction	Comments
Antifungals, azole (fluconazole, itraconazole, ketoconazole)	Possible increased systemic exposure to atogepant Fluconazole (moderate CYP3A4 inhibitor): Possible increased systemic exposure to atopegant Intraconazole (strong CYP3A4 inhibitor): Increased peak plasma concentration and exposure to atopegant by 2.15- and 5.5-fold, respectively	Fluconazole: Interaction not expected to be clinically important; dosage adjustment of atogepant not necessary Itraconazole, ketoconazole: Recommended atogepant dosage is 10 mg once daily
Carbamazepine	Possible decreased systemic exposure to atogepant	Recommended atogepant dosage is 30 or 60 mg once daily
Ciprofloxacin	Possible increased systemic exposure to atogepant	Interaction not expected to be clinically important; dosage adjustment of atogepant not necessary
Cimetidine	Possible increased systemic exposure to atogepant	Interaction not expected to be clinically important; dosage adjustment of atogepant not necessary
Clarithromycin	Possible increased systemic exposure to atogepant	Recommended atogepant dosage is 10 mg once daily
Cyclosporine	Possible increased systemic exposure to atogepant	Interaction not expected to be clinically important; dosage adjustment of atogepant not necessary
Efavirenz	Possible decreased systemic exposure to atogepant	Recommended atogepant dosage is 30 or 60 mg once daily
Esomeprazole	Possible increased systemic exposure to atogepant	Interaction not expected to be clinically important; dosage adjustment of atogepant not necessary
Etravirine	Possible decreased systemic exposure to atogepant	Recommended atogepant dosage is 30 or 60 mg once daily
Fluvoxamine	Possible increased systemic exposure to atogepant	Interaction not expected to be clinically important; dosage adjustment of atogepant not necessary
Grapefruit or grapefruit juice	Possible increased systemic exposure to atopegant with consumption of grapefruit (moderate CYP3A4 inhibitor)	Interaction not expected to be clinically important; dosage adjustment of atogepant not necessary
Phenytoin	Possible decreased systemic exposure to atogepant	Recommended atogepant dosage is 30 or 60 mg once daily
Quinidine	Increased peak plasma concentration and exposure to atogepant by 4 and 26%, respectively, in healthy individuals	Interaction not expected to be clinically important; dosage adjustment of atogepant not necessary
Rifampin	Steady-state rifampin: Decreased peak plasma concentration and exposure to atopegant by approximately 30 and 60%, respectively Single-dose rifampin: Increased peak plasma concentration and exposure to atogepant by 2.23- and 2.85-fold, respectively	Recommended atogepant dosage is 30 or 60 mg once daily
St. John’s wort (Hypericum perforatum)	Possible decreased systemic exposure to atogepant	Recommended atogepant dosage is 30 or 60 mg once daily

Atogepant Pharmacokinetics

Absorption

Bioavailability

Exhibits dose-proportional pharmacokinetics within the recommended dosage range.

Rapidly absorbed; peak plasma concentrations occur approximately 1–2 hours following oral administration.

Food

High-fat meal decreased peak plasma concentration and AUC by 22 and 18%, respectively, but did not affect the median time to peak concentration.

Special Populations

Mild hepatic impairment (Child-Pugh class A): Exposure increased by 24%.

Moderate hepatic impairment (Child-Pugh class B): Exposure increased by 15%.

Severe hepatic impairment (Child-Pugh class C): Exposure increased by 38%.

Mild or moderate renal impairment (Cl_cr 30–89 mL/minute): Pharmacokinetics not substantially affected.

Severe renal impairment (Cl_cr 15–29 mL/minute) or end-stage renal disease (Cl_cr <15 mL/minute): Not studied.

Age, sex, race, and body weight do not substantially affect pharmacokinetics.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

95%.

Elimination

Metabolism

Eliminated mainly through metabolism, primarily by CYP3A4. Parent compound and a glucuronide conjugate metabolite are most prevalent circulating components in human plasma.

Elimination Route

Excreted mainly by the biliary/fecal route; renal route is a minor route of elimination. Following a single oral dose, eliminated in feces (42%) and urine (5%) as unchanged drug.

Half-life

Approximately 11 hours.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted between 15–30°C).

Actions

Small molecule calcitonin gene-related peptide (CGRP) receptor antagonist (sometimes referred to as a gepant); binds to CGRP receptors with high affinity, blocking the binding of CGRP to the receptor and preventing subsequent receptor activation.
CGRP is a potent vasodilator and pain-signaling neuropeptide that has been associated with migraine pathophysiology. 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.
Increased serum CGRP concentrations observed in individuals during acute migraine attacks; serum CGRP concentrations return to normal after resolution of the migraine. IV infusion of CGRP induces migraines in patients with a history of migraines.
Unlike 5-HT₁ receptor agonists (triptans), CGRP receptor antagonists do not appear to cause vasoconstriction. Atogepant does not appear to prolong the QT interval in dosages up to 5 times the maximum recommended daily dosage.

Advice to Patients

Advise patients to read the manufacturer's patient information.
Inform patients that atogepant may interact with certain other drugs. 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).
Importance of women informing clinicians if they are or plan to become pregnant or are breast-feeding or plan to breast-feed.
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.