AHFS Class:

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

Generic Name(s):

• Ubrogepant

Ubrogepant, a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist (gepant), is an antimigraine agent.1,2,3,4,5,6,7,12

Acute Treatment of Migraine

Ubrogepant is used for the acute treatment of migraine with or without aura in adults.1,2,3,5,6 In clinical studies, treatment with ubrogepant was substantially more effective than placebo in relieving migraine pain and the patient's most bothersome symptoms (e.g., photophobia, phonophobia, nausea) at 2 hours post-dose.1,2,3,4

Ubrogepant is not indicated for the preventive treatment of migraine.1

Efficacy and safety of ubrogepant for the acute treatment of migraine have been established in 2 randomized, double-blind, placebo-controlled, multicenter studies (ACHIEVE I and ACHIEVE II) 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 and who experienced 2-8 migraines with moderate to severe headache pain in each of the 3 months prior to screening.1,2,3,6 Patients with a diagnosis of chronic migraine and/or a history of 15 or more headache days per month on average in the previous 6 months were excluded.2,3 Up to 23% of patients in these studies were taking preventive drugs for migraine at baseline; however, none were receiving drugs that act on the calcitonin gene-related peptide (CGRP) pathway.1

In ACHIEVE I, patients were randomized to receive placebo, ubrogepant 50 mg, or ubrogepant 100 mg; patients in ACHIEVE II were randomized to receive placebo, ubrogepant 25 mg, or ubrogepant 50 mg.1,2,3 Patients in both studies were instructed to treat a migraine of moderate to severe headache pain intensity with a dose of the study medication; a second dose of the study medication (ubrogepant or placebo) or the patient's usual acute migraine treatment was allowed between 2 and 48 hours after the initial treatment for non-responding or recurrent migraine headache.1,2,3 In both studies, the percentages of patients who achieved freedom from headache pain and freedom from the most bothersome symptom (e.g., photophobia, phonophobia, nausea) at 2 hours post-dose, which were the coprimary efficacy end points, were substantially higher in patients receiving ubrogepant 50 or 100 mg compared with those receiving placebo.1,2,3 However, the 25-mg dose of ubrogepant studied in ACHIEVE II was not associated with freedom from the most bothersome symptom compared with placebo.3 In addition, pain relief at 2 hours (a secondary measure of efficacy; defined as a reduction in migraine pain from moderate or severe to mild or none) was achieved in a greater proportion of patients receiving ubrogepant 50 or 100 mg than in those receiving placebo.1,2,3 In ACHIEVE I, 19.2 and 21.2% of patients receiving ubrogepant 50 and 100 mg, respectively, were pain free at 2 hours compared with 11.8% of placebo recipients; freedom from the most bothersome symptom at 2 hours was achieved in 38.6 and 37.7% of patients receiving ubrogepant 50 and 100 mg, respectively, compared with 27.8% of placebo recipients.1,2 In ACHIEVE II, 21.8% of patients receiving ubrogepant 50 mg were pain free at 2 hours compared with 14.3% of placebo recipients, and freedom from the most bothersome symptom was achieved in 38.9% of patients receiving ubrogepant 50 mg compared with 27.4% of placebo recipients.1,3

The beneficial effects of ubrogepant (50- or 100-mg dose with an optional second dose) in the acute treatment of migraine observed in the short-term ACHIEVE trials were maintained during long-term intermittent use in a 1-year, randomized, open-label extension trial.5 Over the 1-year period, pain freedom at 2 hours after the initial ubrogepant dose occurred in 23-25% of ubrogepant-treated migraine attacks and pain relief at 2 hours post-dose occurred in 65-68% of ubrogepant-treated attacks.5 During this 1-year period, 21,454 migraine attacks were treated with 31,968 doses of ubrogepant; an optional second dose of ubrogepant was taken for approximately one-third of the migraine attacks.5 Following short- and long-term intermittent use of ubrogepant in these and other studies, the drug was generally well tolerated with no evidence of hepatic or cardiovascular toxicity.2,3,4,5

Clinical Perspective

The American Headache Society (AHS) guidelines include the oral calcitonin gene-related peptide (CGRP) receptor antagonists (gepants) as one of several drugs with established efficacy in the acute treatment of migraine.12,21 Unlike 5-HT₁ receptor agonists (triptans) and ergot alkaloids, CGRP receptor antagonists do not cause constriction of blood vessels, and therefore may have a role in patients with cardiovascular contraindications to triptans.12,21 Because of the relatively high cost of CGRP receptor antagonists compared with oral triptans in the acute treatment of migraine, AHS recommends that oral CGRP receptor antagonists be considered for use only in patients with migraine who have contraindications to the use of triptans and/or who have an inadequate response or intolerance to at least 2 oral triptans.12,21

Administration

Ubrogepant tablets are administered orally without regard to food.1

Dosage

Acute Treatment of Migraine

For the acute treatment of migraine in adults, the manufacturer recommends an initial single dose of 50 or 100 mg of ubrogepant taken orally.1 If needed, a second dose may be administered at least 2 hours after the first dose.1 In a long-term (1-year) study, approximately one-third of patients required a second dose of ubrogepant to treat their migraine attack.1

The manufacturer states that the maximum dose of ubrogepant in a 24-hour period is 200 mg.1 The manufacturer also states that the safety of treating more than 8 migraines with ubrogepant in a 30-day period has not been established.1

Dosage Modification for Drug Interactions

Dosage adjustments of ubrogepant are recommended in patients concomitantly receiving moderate or weak cytochrome P-450 (CYP) 3A4 inhibitors or inducers as well as in patients receiving breast cancer resistance protein (BCRP) and/or P-glycoprotein (P-gp) only inhibitors.1

Concomitant use of potent CYP3A4 inhibitors or potent CYP3A4 inducers should be avoided during ubrogepant therapy.1

Special Populations

Hepatic Impairment

Dosage adjustment is not necessary in patients with mild (Child-Pugh class A) or moderate hepatic impairment (Child-Pugh class B).1 In patients with severe hepatic impairment (Child-Pugh class C), the manufacturer recommends an initial single dose of 50 mg, which can be followed by a second 50-mg dose after at least 2 hours, if needed, for the acute treatment of migraine.1

Renal Impairment

Dosage adjustment is not necessary in patients with mild or moderate renal impairment (creatinine clearance of 30-89 mL/minute).1 In patients with severe renal impairment (creatinine clearance of 15-29 mL/minute), the manufacturer recommends an initial single dose of 50 mg, which can be followed by a second 50-mg dose after at least 2 hours, if needed, for the acute treatment of migraine.1 Ubrogepant should be avoided in patients with end-stage renal disease (creatinine clearance less than 15 mL/minute).1

Geriatric Patients

Although routine dosage adjustment does not appear to be necessary in geriatric patients, the manufacturer states that dosage selection should generally be cautious, usually starting at the lower end of the dosage range.1

Contraindications

• Concomitant use of potent cytochrome P-450 (CYP) 3A4 inhibitors.1
• History of serious hypersensitivity to ubrogepant or any of its components.1

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions have been reported with ubrogepant administration.1 These reactions include anaphylaxis, dyspnea, facial or throat edema, rash, urticaria, and pruritus and may occur minutes, hours, or days after administration.1 The majority of hypersensitivity reactions were not serious and occurred within hours after ubrogepant administration; however, some reactions led to treatment discontinuation.1 If a serious hypersensitivity reaction occurs, discontinue ubrogepant and initiate appropriate therapy.1

Specific Populations

Pregnancy

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

The 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.1 Clinicians should be aware that published data suggest that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy.1

A registry that monitors outcomes in pregnant women exposed to ubrogepant is available.1 Patients may enroll in the registry by calling 833-277-0206 or visiting [Web].1

Lactation

It is not known whether ubrogepant is distributed into human milk; the drug is distributed into milk in rats in concentrations comparable to peak plasma concentrations.1 The effects of ubrogepant on the breast-fed infant and on milk production also are unknown.1

The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for ubrogepant 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 ubrogepant have not been established in pediatric patients.1

Geriatric Use

Clinical studies of ubrogepant did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently than younger adults.1 In pharmacokinetic studies, no clinically important differences in the pharmacokinetics of ubrogepant were observed between geriatric individuals and younger adults.1,8 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

Ubrogepant exposure is increased by 7, 50, and 115% 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 In patients with severe hepatic impairment, the manufacturer recommends an initial dose of 50 mg followed by a second 50-mg dose after at least 2 hours, if needed.1

Renal Impairment

The pharmacokinetics of ubrogepant 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 less than 15 mL/minute).1

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

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, the manufacturer recommends an initial single dose of 50 mg followed by a second 50-mg dose after at least 2 hours, if needed, in patients with severe renal impairment.1

Ubrogepant should be avoided in patients with end-stage renal disease.1

Common Adverse Effects

Adverse reactions reported in 2% or more of patients receiving ubrogepant for acute treatment of migraine in controlled clinical studies and more frequently than with placebo include nausea, somnolence (including sedation and fatigue), and dry mouth.1

Ubrogepant is metabolized principally by cytochrome P-450 (CYP) 3A4.1 In vitro, the drug is a weak inhibitor of CYP isoenzymes 2C8, 2C9, 2D6, and 2C19; monoamine oxidase-A (MAO-A); and UDP-glucuronosyltransferase (UGT) 1A1.1 This inhibition potential is not expected to be clinically important.1 Ubrogepant does not inhibit CYP isoenzymes 1A2, 2B6, or 3A4.1 The drug also does not induce CYP isoenzymes 1A2, 2B6, or 3A4 at clinically relevant concentrations.1

In vitro studies indicate that ubrogepant is a substrate of breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp).1 The drug is a weak substrate of organic anion transporting polypeptide (OATP) 1B1 and 1B3 and organic anion transporter (OAT) 1, but not a substrate of OAT3.1 Ubrogepant is a weak inhibitor of OATP1B1, OATP1B3, and organic cation transporter (OCT) 2, but does not inhibit P-gp, BCRP, bile salt export pump (BSEP), multidrug resistance-associated protein (MRP) 3 or MRP4, OAT1, OAT3, or sodium taurocholate cotransporting polypeptide (NTCP).1

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 Inhibitors

Concomitant use of ubrogepant and CYP3A4 inhibitors may result in increased systemic exposure to ubrogepant.1 When the potent CYP3A4 inhibitor ketoconazole (multiple doses of 400 mg once daily) was administered concomitantly with ubrogepant (single 20-mg dose), peak plasma concentrations and exposure of ubrogepant were increased 5.3- and 9.7-fold, respectively.1,8 When the moderate CYP3A4 and P-gp inhibitor verapamil (multiple doses of 240 mg once daily) was administered concomitantly with ubrogepant (single 20-mg dose), peak plasma concentrations and exposure of ubrogepant were increased 2.8- and 3.5-fold, respectively.1,8 No dedicated drug interaction study has been conducted with concomitant use of ubrogepant and weak CYP3A4 inhibitors.1,8

The manufacturer states that concomitant use of ubrogepant and potent CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, ketoconazole) should be avoided.1

In patients concurrently receiving a moderate CYP3A4 inhibitor (e.g., ciprofloxacin, cyclosporine, fluconazole, fluvoxamine, grapefruit juice, verapamil), the manufacturer recommends an initial 50-mg dose of ubrogepant; administration of a second dose should be avoided within 24 hours of the initial dose.1

In patients concurrently receiving a weak CYP3A4 inhibitor, the manufacturer recommends an initial 50-mg dose of ubrogepant; a second 50-mg dose, if needed, may be taken at least 2 hours after the initial dose.1

CYP3A4 Inducers

Concomitant use of ubrogepant and potent CYP3A4 inducers may result in decreased systemic exposure to ubrogepant and possible loss of efficacy of the drug.1 When the potent CYP3A4 and P-gp inducer rifampin (600 mg once daily) was administered concomitantly with ubrogepant (single 100-mg dose), peak plasma concentrations and exposure of ubrogepant were decreased by approximately 70 and 80%, respectively.1,8 Concurrent administration of ubrogepant and moderate or weak CYP3A4 inducers has not been evaluated to date in a clinical study.1,8

The manufacturer states that concomitant use of ubrogepant and potent CYP3A4 inducers (e.g., barbiturates, phenytoin, rifampin, St. John's wort [ Hypericum perforatum ]) should be avoided.1

Because of the potential for decreased ubrogepant exposure in patients concurrently receiving a weak or moderate CYP3A4 inducer, the recommended initial dose of ubrogepant in such patients is 100 mg followed by a second 100-mg dose, if needed, after at least 2 hours.1

Drugs Affecting Transport Systems

Drug interaction studies with inhibitors of BCRP and P-gp efflux transporters have not been conducted to date.1 However, based on clinical interaction studies with drugs that are dual inhibitors of CYP3A4 and P-gp and the pharmacokinetic profile of ubrogepant, concomitant use of ubrogepant and BCRP or P-gp only inhibitors may result in increased systemic exposure to ubrogepant.1 The highest predicted potential increase in ubrogepant exposure in such cases is not expected to be more than twofold.1

In patients concurrently receiving BCRP and/or P-gp only inhibitors (e.g., carvedilol, curcumin, eltrombopag, quinidine), the recommended initial dose of ubrogepant is 50 mg followed by a second 50-mg dose, if needed, after at least 2 hours.1 Clinically important drug interactions are not expected with concurrent use of ubrogepant and other transporters.1

Acetaminophen

No clinically important pharmacokinetic interactions for either drug were observed with concomitant administration of ubrogepant and acetaminophen.1

Atogepant

No clinically important pharmacokinetic interactions for either drug were observed with concomitant administration of ubrogepant and atogepant.1

Erenumab

No clinically important pharmacokinetic interactions for either drug were observed with concomitant administration of ubrogepant and erenumab.1

Esomeprazole

No clinically important pharmacokinetic interactions for either drug were observed with concomitant administration of ubrogepant and esomeprazole.1

Galcanezumab

No clinically important pharmacokinetic interactions for either drug were observed with concomitant administration of ubrogepant and galcanezumab.1

Naproxen

No clinically important pharmacokinetic interactions for either drug were observed with concomitant administration of ubrogepant and naproxen.1

Oral Contraceptives

No clinically important pharmacokinetic interactions for either drug were observed with concomitant administration of ubrogepant and an oral contraceptive containing norgestimate and ethinyl estradiol.1

Sumatriptan

In a phase 1 study conducted in healthy individuals, slight alterations in ubrogepant and sumatriptan pharmacokinetics were observed during concurrent administration of these drugs (both given as single, oral 100-mg doses); however, these changes are considered unlikely to be clinically important.1,22 In addition, concurrent administration of ubrogepant and sumatriptan was well tolerated in this study and concurrent use of ubrogepant and 5-HT₁ receptor agonists (triptans) was well tolerated in patients with migraine in the ACHIEVE clinical trials.22

Description

Ubrogepant is a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist (sometimes referred to as gepants).1,2,3,4,5,6,7,12 CGRP is a potent vasodilator and pain-signaling neuropeptide that has been associated with migraine pathophysiology.6,7,9,10,18 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.7,9,10,18 Serum CGRP concentrations are increased during acute migraine attacks and return to normal after resolution of the migraine.6 Furthermore, IV infusion of CGRP has been shown to induce migraines in patients with a history of migraines.6,9,10,18

Ubrogepant 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.6,7 Unlike 5-HT₁ receptor agonists (triptans) and ergot alkaloids that are also used in the treatment of migraine, ubrogepant does not appear to cause vasoconstriction.6,12 Ubrogepant also does not appear to prolong the QT interval in dosages up to twice the maximum recommended daily dosage.1

Ubrogepant exhibits dose-proportional pharmacokinetics within the recommended dosage range.1 Following oral administration, ubrogepant is rapidly absorbed; peak plasma concentrations occur in approximately 1.5 hours.1,22 Administration with a 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.1 The drug is 87% bound to plasma proteins in vitro.1 Ubrogepant is mainly eliminated through metabolism, primarily by cytochrome P-450 (CYP) 3A4.1 The parent compound and 2 glucuronide conjugate metabolites are the most prevalent circulating components in human plasma; the glucuronide metabolites are not expected to contribute to the pharmacologic activity of ubrogepant since they are reportedly about 6000-fold less potent in the CGRP receptor binding assay.1 Ubrogepant is excreted mostly by the biliary/fecal route (about 83%); the renal route is a minor route of elimination (about 9.5%).1,8 Following oral administration of a single, radiolabeled dose of ubrogepant, 42 and 6% of the dose was recovered as unchanged ubrogepant in feces and urine, respectively.1 The elimination half-life of the drug is approximately 5-7 hours.1 Population pharmacokinetic analysis indicates that the pharmacokinetics of ubrogepant are not substantially affected by age, gender, race, or body weight.1,8

Advice to Patients

• Advise patients to read the manufacturer's patient information.1
• Inform patients about the signs and symptoms of hypersensitivity reactions.1 Advise patients to discontinue ubrogepant and seek immediate medical attention if a hypersensitivity reaction occurs.1
• Inform patients that ubrogepant may interact with certain other drugs.1 Therefore, patients should be advised to inform their clinician about the 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).1 Advise patients to inform their clinician of grapefruit or grapefruit juice consumption because dosage adjustment of ubrogepant is recommended during concurrent use.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. Ubrelvy^® (ubrogepant) tablets prescribing information. North Chicago, IL; 2023 Jun.

2. Dodick DW, Lipton RB, Ailani J et al. Ubrogepant for the Treatment of Migraine. N Engl J Med . 2019; 381:2230-2241. [PubMed 31800988]

3. Lipton RB, Dodick DW, Ailani J et al. Effect of Ubrogepant vs Placebo on Pain and the Most Bothersome Associated Symptom in the Acute Treatment of Migraine: The ACHIEVE II Randomized Clinical Trial. JAMA . 2019; 322:1887-1898. [PubMed 31742631]

4. Goadsby PJ, Tepper SJ, Watkins PB et al. Safety and tolerability of ubrogepant following intermittent, high-frequency dosing: Randomized, placebo-controlled trial in healthy adults. Cephalalgia . 2019; 39:1753-1761. [PubMed 31537107]

5. Ailani J, Lipton RB, Hutchinson S et al. Long-Term Safety Evaluation of Ubrogepant for the Acute Treatment of Migraine: Phase 3, Randomized, 52-Week Extension Trial. Headache . 2020; 60:141-152. [PubMed 31913519]

6. Negro A, Martelletti P. Gepants for the treatment of migraine. Expert Opin Investig Drugs . 2019; 28:555-567. [PubMed 31081399]

7. Hargreaves R, Olesen J. Calcitonin Gene-Related Peptide Modulators - The History and Renaissance of a New Migraine Drug Class. Headache . 2019; 59:951-970. [PubMed 31020659]

8. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 211765Orig1s000: Clinical pharmacology review(s). From FDA website. [Web]

9. Edvinsson L, Haanes KA, Warfvinge K et al. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol . 2018; 14:338-350. [PubMed 29691490]

10. Schuster NM, Rapoport AM. Calcitonin Gene-Related Peptide-Targeted Therapies for Migraine and Cluster Headache: A Review. Clin Neuropharmacol . 2017 Jul/Aug; 40:169-174. [PubMed 28644160]

12. American Headache Society. The American Headache Society position statement on integrating new migraine treatments into clinical practice. Headache . 2019; 59:1-18. [PubMed 30536394]

13. Raffaelli B, Reuter U. The biology of monoclonal antibodies: focus on calcitonin gene-related peptide for prophylactic migraine therapy. Neurotherapeutics . 2018; 15:324-35. [PubMed 29616494]

18. Edvinsson L. The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine. Headache . 2017; 57:47-55. [PubMed 28485848]

21. Ailani J, Burch RC, Robbins MS et al. The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache . 2021; 61:1021-1039. [PubMed 34160823]

22. Jakate A, Boinpally R, Butler M et al. Evaluation of the Pharmacokinetic Interaction of Ubrogepant Coadministered With Sumatriptan and of the Safety of Ubrogepant With Triptans. Headache . 2020 Jun 23; [online ahead of print]. [PubMed 32573795]