What are the recommended adult dosing, contraindications, precautions (including hepatic impairment, pregnancy, lactation, pediatric use, and cardiovascular disease) and drug interactions for ubrogepant in the acute treatment of migraine?

Ubrogepant for Acute Migraine Treatment

Ubrogepant is recommended as a third-line option for moderate to severe acute episodic migraine in nonpregnant adults who have failed or cannot tolerate combination therapy with a triptan plus an NSAID or acetaminophen. 1

Position in Treatment Algorithm

• First-line therapy should be an NSAID (ibuprofen 400-800 mg, naproxen 500-825 mg, or aspirin 1000 mg) or acetaminophen 1000 mg for mild to moderate migraine. 1
• Second-line therapy requires adding a triptan to the NSAID (or to acetaminophen when NSAIDs are contraindicated). 1
• Only after documented failure of triptan-NSAID combinations should CGRP antagonists like ubrogepant be considered. 1, 2
• Ubrogepant is positioned alongside other gepants (rimegepant, zavegepant) and ahead of lasmiditan (ditan), which is reserved for patients who fail all other treatments. 1

Adult Dosing

• 50 mg or 100 mg orally at the onset of migraine attack. 3, 4
• A second dose may be taken if needed, with a maximum of 200 mg within any 48-hour period. 5
• Limit use to no more than 8 migraine attacks per 30-day period to prevent medication-overuse headache. 6
• The 50-mg dose achieved pain freedom in 21.8% of patients at 2 hours (vs. 14.3% placebo; absolute difference 7.5%, P=0.01), while the 100-mg dose achieved 21.2% pain freedom (vs. 14.3% placebo, P<0.001). 3, 4
• The 50-mg dose was more effective than the 100-mg dose for eliminating the most bothersome symptom at 2 hours (38.9% vs. 34.1% vs. 27.4% placebo). 3

Contraindications

• End-stage renal disease (creatinine clearance <15 mL/min or requiring dialysis). 7
• Pregnancy: Ubrogepant should be avoided in pregnant patients; acetaminophen 1000 mg is the recommended first-line treatment during pregnancy. 2, 7
• Concurrent use with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, itraconazole) is contraindicated due to significantly increased ubrogepant exposure. 5

Precautions

Hepatic Impairment

• Mild to moderate hepatic impairment: No dose adjustment required. 5
• Severe hepatic impairment (Child-Pugh C): Avoid use due to lack of safety data. 5
• Unlike earlier gepants, ubrogepant is free from hepatotoxicity at therapeutic doses; no cases of Hy's Law were observed in the 52-week safety trial. 8
• Twenty cases of ALT/AST elevations ≥3 times the upper limit of normal were reviewed by an independent adjudication committee, with no clinically significant hepatotoxicity identified. 8

Pregnancy and Lactation

• Pregnancy Category: Not formally assigned; animal studies showed no teratogenicity, but human data are lacking. 7
• Lactation: Unknown whether ubrogepant is excreted in breast milk; use caution and consider risk-benefit. 7
• Women of childbearing potential should discuss adverse effects of pharmacologic treatments during pregnancy before initiating therapy. 1

Pediatric Use

• Not approved for use in patients under 18 years of age; safety and efficacy have not been established in pediatric populations. 5

Cardiovascular Disease

• No vasoconstriction: Unlike triptans, ubrogepant does not cause vasoconstriction and is safe for patients with cardiovascular disease, uncontrolled hypertension, or cerebrovascular disease—conditions that contraindicate triptan use. 6, 5
• This makes ubrogepant a preferred alternative when triptans are contraindicated due to ischemic heart disease, previous myocardial infarction, coronary artery vasospasm, uncontrolled hypertension, history of stroke or TIA, or basilar/hemiplegic migraine. 6

Drug Interactions

• Strong CYP3A4 inhibitors (ketoconazole, clarithromycin, itraconazole): Contraindicated; significantly increase ubrogepant plasma concentrations. 5
• Moderate CYP3A4 inhibitors (e.g., verapamil, cyclosporine, ciprofloxacin): Reduce ubrogepant dose to 50 mg; avoid a second dose within 24 hours. 5
• Strong CYP3A4 inducers (rifampin, phenytoin, carbamazepine): May reduce ubrogepant efficacy; avoid concomitant use. 5
• Weak or moderate CYP3A4 inducers: No dose adjustment required, but monitor for reduced efficacy. 5
• BCRP inhibitors (e.g., cyclosporine): May increase ubrogepant exposure; use with caution. 5

Safety Profile

• Most common adverse events (within 48 hours): nausea (2.0-2.5%), dizziness (1.4-2.1%), somnolence (0.4-4.1%), dry mouth (0.4-4.1%), and oropharyngeal pain. 3, 4, 7
• Adverse events were more frequent with the 100-mg dose (16.3%) compared to 50 mg (9.4%) or placebo (12.8%). 4
• In the 52-week safety trial, treatment-emergent adverse events were reported in 66% (50 mg) and 73% (100 mg) of participants, with upper respiratory tract infection being the most common (<12%). 8
• Treatment-related adverse events occurred in only 10-11% of participants across both doses. 8
• Serious adverse events were rare (2-3%) and included appendicitis, spontaneous abortion, pericardial effusion, and seizure; none occurred within 48 hours of dosing. 8, 4
• No hepatotoxicity was observed at therapeutic doses, distinguishing ubrogepant from earlier gepants. 5, 8

Critical Medication-Overuse Prevention

• Limit ubrogepant to ≤2 days per week (≤10 days per month) to prevent medication-overuse headache, which can paradoxically increase headache frequency and lead to daily headaches. 1, 6, 2
• If acute treatment is needed more than twice weekly, initiate preventive migraine therapy immediately rather than increasing ubrogepant frequency. 1, 6
• The 2-days-per-week limit is non-negotiable and applies to all acute migraine medications, including triptans, NSAIDs, and gepants. 1, 6

Clinical Pearls

• Counsel patients to take ubrogepant as early as possible after migraine onset to maximize efficacy; early treatment when pain is still mild yields better outcomes. 1, 2
• One in five patients (approximately 20%) achieved complete pain freedom with a single dose of ubrogepant. 5
• Ubrogepant is equally effective in alleviating migraine-associated symptoms such as nausea, photophobia, and phonophobia. 5
• Ubrogepant is not effective as preventive therapy; it is indicated only for acute treatment of individual migraine attacks. 5
• Over 21,454 migraine attacks were treated with 31,968 doses of ubrogepant in the long-term safety trial, demonstrating consistent tolerability with intermittent use. 8

Common Pitfalls to Avoid

• Do not prescribe ubrogepant as first-line therapy; patients must first fail or be unable to tolerate triptan-NSAID combination therapy. 1
• Do not exceed 200 mg in 48 hours or treat more than 8 attacks per month to avoid medication-overuse headache. 6, 5
• Do not use ubrogepant in patients taking strong CYP3A4 inhibitors due to contraindication. 5
• Do not substitute ubrogepant for preventive therapy; if patients require acute treatment more than twice weekly, initiate preventive medications (beta-blockers, topiramate, CGRP monoclonal antibodies, or onabotulinumtoxinA). 1, 6