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Ubrogepant

Class: Calcitonin Gene-related Peptide (CGRP) Antagonists
- CGRP Receptor Antagonists
- Gepants
- Small-molecule Calcitonin Gene-related Peptide Receptor Antagonists
Chemical Name: (3′S)-N-[(3S,5S,6R)-6-Methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl]-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine-3-carboxamide
Molecular Formula: C29H26F3N5O3
CAS Number: 1374248-77-7
Brands: Ubrelvy

Medically reviewed by Drugs.com on May 10, 2021. Written by ASHP.

Introduction

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

Uses for Ubrogepant

Acute Treatment of Migraine

Acute treatment of migraine with or without aura.

In the short-term ACHIEVE clinical studies, ubrogepant was substantially more effective than placebo in relieving migraine pain and the patient's self-identified most bothersome symptom (e.g., photophobia, phonophobia, nausea) at 2 hours post-dose. Efficacy was maintained during long-term intermittent use in a 1-year, randomized, open-label extension trial.

The American Headache Society (AHS) states that the small molecule CGRP receptor antagonists (gepants) ubrogepant and rimegepant have demonstrated efficacy in acute treatment of migraine. Unlike serotonin type 1 (5-hydroxytryptamine type 1; 5-HT1) receptor agonists (triptans) and ergot alkaloids, small molecule CGRP receptor antagonists do not cause constriction of blood vessels; therefore, such drugs may be particularly helpful in patients with cardiovascular contraindications to triptans. However, because of the relatively high cost of small molecule CGRP receptor antagonists compared with oral triptans, the AHS recommends that they be considered for use in patients who have contraindications to use of triptans or who have had an inadequate response to or have been unable to tolerate at least 2 oral triptans. When ubrogepant is used, the AHS recommends treatment for at least 2 migraine attacks to determine clinical efficacy and tolerability.

Not indicated for the preventive treatment of migraine.

Ubrogepant Dosage and Administration

Administration

Oral Administration

Administer tablets orally without regard to food.

Dosage

Adults

Acute Treatment of Migraine
Oral

Initially, 50 or 100 mg orally as a single dose. If needed, may administer a second dose at least 2 hours after the first dose. In a long-term (1-year) study, approximately one-third of patients required a second dose.

Dosage adjustments recommended with concomitant use of moderate or weak CYP3A4 inhibitors or inducers, breast cancer resistance protein (BCRP) inhibitors, and/or P-glycoprotein (P-gp) only inhibitors. Avoid concomitant use of potent CYP3A4 inhibitors or potent CYP3A4 inducers. (See Contraindications under Cautions and see also Interactions.)

Prescribing Limits

Adults

Acute Treatment of Migraine
Oral

Maximum 200 mg in a 24-hour period.

Safety of treating >8 migraines in a 30-day period not established.

Special Populations

Hepatic Impairment

Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment: Dosage adjustment not necessary.

Severe hepatic impairment (Child-Pugh class C): Manufacturer recommends initial single dose of 50 mg; if needed, may administer second 50-mg dose after at least 2 hours. (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild or moderate renal impairment (Clcr 30–89 mL/minute): Dosage adjustment not necessary.

Severe renal impairment (Clcr 15–29 mL/minute): Manufacturer recommends initial single dose of 50 mg; if needed, may administer a second 50-mg dose after at least 2 hours.

End-stage renal disease (Clcr <15 mL/minute): Avoid use. (See Renal Impairment under Cautions.)

Geriatric Patients

Select dosage carefully, usually starting at the low end of the dosage range. (See Geriatric Use under Cautions.)

Cautions for Ubrogepant

Contraindications

  • Concomitant use of potent CYP3A4 inhibitors. (See Interactions.)

Warnings/Precautions

Specific Populations

Pregnancy

No adequate data to date on the developmental risk associated with use of ubrogepant in pregnant women. Based on animal studies, may cause fetal harm. In animal studies, adverse effects on embryofetal development (increased embryofetal mortality, decreased body weight of offspring) observed at dosages higher than those used clinically and that were associated with maternal toxicity.

Estimated rates of major birth defects and miscarriage among deliveries to women with migraine (2.2–2.9 and 17%, respectively) are similar to rates reported in women without migraine. 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 in concentrations comparable to peak plasma concentrations. Effects on the breast-fed infant and on milk production also unknown. Consider developmental and health benefits of breast-feeding, mother's clinical need for ubrogepant, and potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established in pediatric patients.

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. (See Special Populations under Pharmacokinetics.)

Dosage adjustment not necessary in patients with mild (Child-Pugh class A) or moderate hepatic impairment (Child-Pugh class B). In patients with severe (Child-Pugh class C) hepatic impairment, manufacturer recommends an initial dose of 50 mg followed by a second 50-mg dose after at least 2 hours, if needed.

Renal Impairment

Pharmacokinetics not substantially affected 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). Based on its pharmacokinetic profile and a conservative estimate that severe renal impairment is unlikely to cause more than a twofold increase in exposure to ubrogepant, manufacturer recommends an initial dose of 50 mg followed by a second 50-mg dose after at least 2 hours, if needed, in patients with severe renal impairment.

Avoid use in patients with end-stage renal disease (Clcr <15 mL/minute).

Common Adverse Effects

Nausea, somnolence (including sedation and fatigue), dry mouth.

Interactions for Ubrogepant

Metabolized principally by CYP3A4. Substrate of BCRP and P-gp and a weak substrate of organic anion transporting polypeptide (OATP) 1B1 and 1B3 and organic anion transporter (OAT) 1, but not a substrate of OAT3.

Weak inhibitor of CYP isoenzymes 2C8, 2C9, 2D6, and 2C19; monoamine oxidase-A (MAO-A); and UGT1A1 in vitro; not expected to be clinically important. Weak inhibitor of OATP1B1, OATP1B3, and organic cation transporter (OCT) 2.

Does not inhibit CYP isoenzymes 1A2, 2B6, or 3A4; does not induce CYP isoenzymes 1A2, 2B6, or 3A4 at clinically relevant concentrations. Does not inhibit P-gp, BCRP, bile salt export pump (BSEP), multidrug resistance-associated protein (MRP) 3 or 4, OAT1, OAT3, or sodium taurocholate cotransporting polypeptide (NTCP).

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Concomitant use of ubrogepant and CYP3A4 inhibitors may result in increased systemic exposure to ubrogepant. Specific studies with known moderate or potent inhibitors of CYP3A4 indicate magnitude of increase may be substantial with concurrent use of these drugs. (See Specific Drugs and Food under Interactions.)

Weak CYP3A4 inhibitors: No dedicated drug interaction study has been conducted with concomitant use of ubrogepant and weak CYP3A4 inhibitors. If used concomitantly with a weak CYP3A4 inhibitor, recommended dosage is a single 50-mg dose initially followed by a second 50-mg dose, if needed, after at least 2 hours.

Moderate CYP3A4 inhibitors: If used concomitantly with a moderate CYP3A4 inhibitor, recommended dosage is a 50-mg dose initially; avoid taking a second dose within 24 hours of initial dose.

Potent CYP3A4 inhibitors: Avoid concomitant use of potent CYP3A4 inhibitors.

Potent CYP3A4 inducers: Concomitant use of ubrogepant and potent CYP3A4 inducers may result in decreased systemic exposure and efficacy of ubrogepant. Avoid concomitant use with potent CYP3A4 inducers.

Weak or moderate CYP3A4 inducers: Because of potential for decreased ubrogepant exposure in patients receiving a weak or moderate CYP3A4 inducer, recommended dosage is a single 100-mg dose initially followed by a second 100-mg dose after at least 2 hours, if needed.

BCRP and/or P-gp Only Inhibitors

Based on clinical interaction studies with drugs that are dual inhibitors of CYP3A4 and P-gp, concomitant use of ubrogepant and BCRP or P-gp only inhibitors may result in increased systemic exposure of ubrogepant. Highest predicted potential increase in ubrogepant exposure not expected to be more than twofold.

In patients receiving P-gp only inhibitors and/or BCRP inhibitors, recommended dosage is an initial single 50-mg dose followed by a second 50-mg dose after at least 2 hours, if needed.

Specific Drugs and Food

Drug or Food

Interaction

Comments

Acetaminophen

No clinically important pharmacokinetic interactions observed

Antifungals, azole (fluconazole, itraconazole, ketoconazole)

Possible increased systemic exposure to ubrogepant

Fluconazole (moderate CYP3A4 inhibitor): Possible increased systemic exposure to ubrogepant

Ketoconazole (potent CYP3A4 inhibitor): Increased peak plasma concentration and exposure to ubrogepant 5.3- and 9.7-fold, respectively

Fluconazole: Administer initial single 50-mg dose of ubrogepant; avoid taking a second dose within 24 hours of initial dose

Itraconazole, ketoconazole: Avoid concomitant use

Barbiturates (e.g., phenobarbital)

Barbiturates (potent CYP3A4 inducers): Possible decreased exposure and loss of efficacy of ubrogepant

Avoid concomitant use

Carvedilol

Possible increased systemic exposure to ubrogepant (not expected to exceed twofold)

Administer initial single 50-mg dose of ubrogepant followed by a second 50-mg dose after 2 hours, if needed

Ciprofloxacin

Possible increased systemic exposure to ubrogepant

Administer initial single 50-mg dose of ubrogepant; avoid taking a second dose within 24 hours of initial dose

Clarithromycin

Possible increased systemic exposure to ubrogepant

Avoid concomitant use

Curcumin

Possible increased systemic exposure to ubrogepant (not expected to exceed twofold)

Administer initial single 50-mg dose of ubrogepant followed by a second 50-mg dose after 2 hours, if needed

Cyclosporine

Possible increased systemic exposure to ubrogepant

Administer initial single 50-mg dose of ubrogepant; avoid taking a second dose within 24 hours of initial dose

Eltrombopag

Possible increased systemic exposure to ubrogepant (not expected to exceed twofold)

Administer initial single 50-mg dose of ubrogepant followed by a second 50-mg dose after 2 hours, if needed

Esomeprazole

No clinically important pharmacokinetic interactions observed

Fluvoxamine

Possible increased systemic exposure to ubrogepant

Administer initial single 50-mg dose of ubrogepant; avoid taking a second dose within 24 hours of initial dose

Grapefruit or grapefruit juice

Possible increased systemic exposure to ubrogepant with consumption of grapefruit (moderate CYP3A4 inhibitor)

Administer initial single 50-mg dose of ubrogepant; avoid taking a second dose within 24 hours of initial dose if grapefruit or grapefruit juice is consumed

Naproxen

No clinically important pharmacokinetic interactions observed

Oral contraceptives

No clinically important pharmacokinetic interactions observed with oral contraceptive containing norgestimate and ethinyl estradiol

Phenytoin

Phenytoin (potent CYP3A4 inducer): Possible decreased exposure and loss of efficacy of ubrogepant

Avoid concomitant use

Quinidine

Possible increased systemic exposure to ubrogepant (not expected to exceed twofold)

Administer initial single 50-mg dose of ubrogepant followed by a second 50-mg dose after 2 hours, if needed

Rifampin

Rifampin (potent CYP3A4 and P-gp inducer): Substantially decreased peak plasma concentration and exposure to ubrogepant (by approximately 70 and 80%, respectively); potential for loss of efficacy of ubrogepant

Avoid concomitant use

St. John's wort (Hypericum perforatum)

St. John's wort (potent CYP3A4 inducer): Possible decreased exposure and loss of efficacy of ubrogepant

Avoid concomitant use

Sumatriptan

Slight alterations in ubrogepant and sumatriptan pharmacokinetics observed in a phase 1 study; unlikely to be clinically important

Concurrent administration well tolerated in healthy individuals in a phase 1 study; combined use of ubrogepant and 5-HT1 receptor agonists (triptans) well tolerated in patients with migraine in the ACHIEVE clinical trials

Verapamil

Verapamil (moderate CYP3A4 inhibitor) increased peak plasma concentrations and exposure of ubrogepant 2.8- and 3.5-fold, respectively

Administer initial single 50-mg dose of ubrogepant; avoid taking a second dose within 24 hours of initial dose

Ubrogepant Pharmacokinetics

Absorption

Bioavailability

Exhibits dose-proportional pharmacokinetics within the recommended dosage range.

Rapidly absorbed; peak plasma concentrations occur approximately 1.5 hours following oral administration.

Food

High-fat meal delays time to peak plasma concentration by 2 hours and decreases peak concentration by 22%, but does not affect systemic exposure to the drug.

Special Populations

Mild hepatic impairment (Child-Pugh class A): Exposure increased by 7%.

Moderate hepatic impairment (Child-Pugh class B): Exposure increased by 50%.

Severe hepatic impairment (Child-Pugh class C): Exposure increased by 115%.

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

Severe renal impairment (Clcr 15–29 mL/minute): Not studied; unlikely to cause more than a twofold increase in exposure to ubrogepant.

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; distributed into milk in rats at concentrations comparable to peak plasma concentrations.

Plasma Protein Binding

87%.

Elimination

Metabolism

Eliminated mainly through metabolism, primarily by CYP3A4. Parent compound (ubrogepant) and 2 glucuronide conjugate metabolites are most prevalent circulating components in human plasma; the glucuronide metabolites are not expected to contribute to pharmacologic activity.

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 (6%) as unchanged drug.

Half-life

Approximately 5–7 hours.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 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; these 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) and ergot alkaloids, ubrogepant does not appear to cause vasoconstriction. Also does not appear to prolong the QT interval in dosages up to twice the maximum recommended daily dosage.

Advice to Patients

  • Advise patients to read the manufacturer's patient information.

  • Inform patients that ubrogepant 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., curcumin, St. John's wort) as well as any concomitant illnesses (e.g., hepatic or renal disease). Importance of advising patients to inform their clinician of grapefruit or grapefruit juice consumption because dosage adjustment is recommended during concurrent use. (See Interactions.)

  • Importance of women informing clinicians if they are or plan to become pregnant or are breast-feeding or plan to breast-feed. (See Pregnancy under Cautions.)

  • 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.

Ubrogepant

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

50 mg

Ubrelvy

Allergan

100 mg

Ubrelvy

Allergan

AHFS DI Essentials™. © Copyright 2022, Selected Revisions May 10, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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