By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved the first oral, nonpeptide, small molecule, calcitonin gene-related peptide (CGRP) receptor antagonist (“gepant”) for the treatment of acute migraine. CGRP is believed to play a role in the pathogenesis of migraine. This differs from the monoclonal antibodies against CGRP receptors previously approved for migraine prevention (i.e., galcanezumab, fremanezumab, erenumab). Ubrogepant is distributed as Ubrelvy.
Ubrogepant is indicated for the acute treatment of migraine with or without aura in adults.1
The recommended dose is 50 mg or 100 mg taken orally as needed.1 A second dose, if needed, may be taken at least two hours after the initial dose. A second dose should be avoided within 24 hours with a concomitant dose of a moderate CYP3A4 inhibitor. The maximum dose is 200 mg in a 24-hour period. For severe hepatic or renal impairment, the dose is 50 mg initially and a second dose of 50 mg at least two hours apart. Ubrogepant is available as 50 mg and 100 mg tablets.
Ubrogepant provides a drug with a new mechanism of action for the treatment of acute migraine.
In animal studies with greater doses than those used clinically in humans, fetal harm was observed.1 Ubrogepant should not be taken with a strong CYP3A4 inhibitor (e.g., clarithromycin) or CYP3A4 inducer (e.g., phenytoin, St. John’s wort). There are no head-to-head studies comparing ubrogepant to current acute treatments such as triptans.
The efficacy of ubrogepant was determined in two randomized, double-blind, placebo-controlled studies.1-3 Study participants presented with a history of two to eight migraines per month, with moderate-to-severe headache pain in each of the three months before screening. In study 1, participants were randomized to ubrogepant 50 mg (n = 556), 100 mg (n = 557), or placebo (n = 559). In study 2, participants were randomized to ubrogepant 25 mg (n = 561), 50 mg (n = 562), and placebo (n = 563). In both studies, participants were instructed to treat a migraine with moderate-to-severe headache pain intensity. Coprimary endpoints were percent of subjects achieving freedom from pain and absence of the most bothersome symptom (MBS) associated with migraine at two hours after the initial dose. Freedom from pain was defined as change in severity of pain from moderate or severe to no pain. MBS included photophobia, phonophobia, and nausea. Percent pain-free responses in study 1 were 19.2% for 50 mg, 21.2% for 100 mg, and 11.8% for placebo. In study 2, they were 20.7% for 25 mg, 21.8% for 50 mg, and 14.3% for placebo. Percent MBS responses in study 1 were 38.6% for 50 mg, 37.7% for 100 mg, and 27.8% for placebo. In study 2, percent MBS responses were 34.1% for 50 mg, 38.9% for 100 mg, and 27.4% for placebo. All doses achieved statistical significance vs. placebo for freedom from pain. Only the 50 mg and 100 mg groups achieved statistical significance in terms of MBS response. In a long-term safety assessment (n = 813), with intermittent use 2.5% withdrew due to adverse reactions.1 More frequent adverse reactions were nausea (2-4%) and somnolence (2-3%).
Migraine is a common and disabling neurologic condition, with a one-year prevalence in women of 18% and 6% in men.4 The American Headache Society considers triptans, ergotamine derivatives, and nonsteroidal anti-inflammatory drugs effective acute treatments.4 Triptans are first-line treatment, but they are not suitable for patients with vascular risk factors (e.g., ischemic or vasospastic coronary artery disease). In addition, effectiveness and tolerability vary between agents and patients.5 CGRP is a potent vasodilator and is believed to protect organs from ischemia. In theory, CGRP blockade with drugs such as ubrogepant could produce a negative outcome.6 So far, cardiovascular adverse events have not emerged in clinical trials, and specific warnings are not part of the current prescribing information. However, patients with cardiovascular contraindications were not included in the clinical trials.3 Recent approvals include lasmiditan (a serotonin 1F receptor agonist) and ubrogepant, which may be options for patients who are contraindicated to triptans or who have failed to respond to or are intolerant of at least two oral triptans. Patients with headaches that significantly interfere with daily routines despite acute treatment and with four or more headache days per month should be considered for preventive treatment.4 The cost for ubrogepant (50 mg or 100 mg) is $850 for 10 tablets.
- Allergan USA, Inc. Ubrelvy Prescribing Information, December 2019. Available at: http://bit.ly/2RsVPPb.
- Dodick DW, et al. Ubrogepant for the treatment of migraine. N Engl J Med 2019;381:2230-2241.
- Lipton RB, 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.
- American Headache Society. The American Headache Society position statement on integrating new migraine treatments into clinical practice. Headache 2019;59:1-18.
- Viana M, et al. Triptan nonresponders: Do they exist and who are they? Cephalagia 2013;33:891-896.
- Favoni V, et al. CGRP and migraine from a cardiovascular point of view: What do we expect from blocking CGRP? J Headache Pain 2019;20:27.