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
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 (Clcr 30–89 mL/minute): No dosage adjustment necessary.
Severe renal impairment (Clcr 15–29 mL/minute) or end-stage renal disease (Clcr <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 (Clcr 30–89 mL/minute); dosage adjustment not necessary.
Not studied in patients with severe renal impairment (Clcr 15–29 mL/minute) or end-stage renal disease (Clcr <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 (Clcr 30–89 mL/minute): Pharmacokinetics not substantially affected.
Severe renal impairment (Clcr 15–29 mL/minute) or end-stage renal disease (Clcr <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.
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Tablets |
10 mg |
Qulipta |
AbbVie |
30 mg |
Qulipta |
AbbVie |
||
60 mg |
Qulipta |
AbbVie |
AHFS DI Essentials™. © Copyright 2023, Selected Revisions May 23, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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