Gepants Examples: Nurtec, Ubrelvy, Qulipta, and Zavzpret

Gepants are a class of small-molecule drugs that block the calcitonin gene-related peptide (CGRP) receptor, and four are currently approved for migraine in the United States: ubrogepant (Ubrelvy), rimegepant (Nurtec ODT), atogepant (Qulipta), and zavegepant (Zavzpret). Each fills a slightly different role, from stopping a migraine attack in progress to preventing one from starting, and one is even delivered as a nasal spray rather than a pill. Understanding which gepant does what, how they compare, and where they fall short gives you a much clearer picture of how this drug class fits into modern migraine care.

How Gepants Work

CGRP is a signaling molecule heavily involved in migraine. During an attack, CGRP levels rise in the brain’s blood vessels and surrounding tissues, promoting inflammation, blood vessel dilation, and pain signaling. Gepants work by sitting in the binding pocket of the CGRP receptor, which is formed by two protein subunits called RAMP1 and CLR, and physically preventing CGRP from latching on.¹ This is fundamentally different from the other major class of CGRP-targeting therapies, the monoclonal antibodies (like erenumab, fremanezumab, and galcanezumab), which are large injected proteins that either grab the CGRP molecule itself or block the receptor from the outside. Gepants are small enough to be taken as pills or sprayed into the nose, and they clear the body within hours rather than weeks.

The Failed First Generation

The idea of blocking the CGRP receptor with a small molecule is not new. Two earlier gepants, telcagepant and MK-3207, proved effective at treating migraine attacks in clinical trials but were pulled from development because they caused liver damage.² Telcagepant in particular showed clear hepatotoxicity when used repeatedly.³ Those failures cast a long shadow over the entire class, and the four gepants that eventually reached the market had to demonstrate convincingly that they did not share that problem. They appear to have succeeded: liver-related side effects have been rare across all four approved gepants in post-marketing surveillance, and modeling studies predict none of them would cause the severe liver injury seen with telcagepant.⁴ That said, because all four gepants are cleared primarily through the liver, they are not recommended for people with severe liver disease.⁵

Ubrogepant (Ubrelvy)

Ubrogepant was the first gepant to win FDA approval, in December 2019, for the acute treatment of migraine in adults. It is taken as a tablet when a migraine attack begins, and a second dose can be taken at least two hours later if the headache has not resolved. In pooled data from two large phase 3 trials (ACHIEVE I and ACHIEVE II), about one in five people taking the 50 mg dose were pain-free at two hours, compared with about one in eight on placebo. Freedom from the most bothersome accompanying symptom, such as nausea or light sensitivity, occurred in roughly 39% of the ubrogepant group versus 28% on placebo.⁶ Side effects were mild and occurred at rates nearly identical to placebo, with nausea being the most commonly reported at under 2%.⁷

A more recent trial, PRODROME, tested whether ubrogepant could work even earlier, during the warning phase (prodrome) before head pain starts. People who took ubrogepant during the prodrome were significantly more likely to avoid developing moderate or severe headache within 24 hours: 46% succeeded versus 29% on placebo.⁸ This is a meaningful finding for people who can reliably recognize their prodrome symptoms, such as mood changes, neck stiffness, or food cravings, before a full attack develops.

Rimegepant (Nurtec ODT)

Rimegepant stands out among the four approved gepants because it is the only one cleared for both acute treatment and prevention of episodic migraine. For acute use, it comes as an orally disintegrating tablet (the “ODT” in its brand name) that dissolves on the tongue without water. Phase 3 trials showed it outperformed placebo for both pain freedom and relief from the most bothersome symptom at two hours. For prevention, the same tablet is taken every other day, and trials demonstrated it reduced the number of monthly migraine days over 12 weeks, with benefits holding up through a year of treatment.⁹

Real-world data have been encouraging. In a prospective multicenter study, 45% of people were pain-free two hours after taking rimegepant for an acute attack. Interestingly, the odds of being pain-free were significantly better when the tablet was taken within the first hour of pain onset, reinforcing the common advice to treat migraine attacks early. Side effects were mild in roughly 16% of treated attacks, mostly fatigue, stomach symptoms, and drowsiness, and tolerability was rated good to excellent in 85% of cases.¹⁰

Atogepant (Qulipta)

Atogepant is the only gepant approved exclusively as a preventive. You take it daily (or twice daily at a lower dose for chronic migraine), and it is not meant for treating an attack once it starts. In a pivotal trial published in the New England Journal of Medicine, the 60 mg once-daily dose reduced monthly migraine days by about 4.2 over 12 weeks, compared with 2.5 for placebo, a difference of roughly 1.7 fewer migraine days per month.¹¹ In a separate trial focused on chronic migraine (15 or more headache days a month), the reductions were larger: the 30 mg twice-daily dose cut monthly migraine days by 7.5 versus 5.1 for placebo.¹² A recent meta-analysis pooling multiple trials confirmed these reductions were consistent across studies.¹³

Real-world data from a multicenter Italian study (GIANT) also showed substantial benefits even in patients who had failed multiple prior preventive treatments. Monthly migraine days dropped by an average of 6 at 12 weeks, and about two-thirds of participants achieved at least a 50% reduction in migraine frequency. Improvements were detectable as early as the first week.¹⁴ Among side effects, severe constipation has been flagged as a relatively specific issue with atogepant in post-marketing reporting.¹⁵

Zavegepant (Zavzpret)

Zavegepant is the only gepant delivered as a nasal spray, which makes it a useful option for people who experience severe nausea or vomiting during attacks and cannot reliably keep a pill down. It was approved in 2023 for the acute treatment of migraine. In its phase 3 trial, 24% of people who used the 10 mg nasal spray were pain-free at two hours, compared with 15% on placebo, and 40% were free of their most bothersome symptom versus 31% on placebo.¹⁶ The earlier dose-ranging trial also showed that both 10 mg and 20 mg doses were effective with a favorable safety profile.¹⁷ The most distinctive side effect is an altered taste (dysgeusia), which is unsurprising given that nasal sprays can drip into the back of the throat; post-marketing analysis found this side effect was strongly linked to zavegepant specifically among the gepants.¹⁸

Gepants Versus Triptans for Cardiovascular Safety

Triptans have been the go-to acute migraine treatment for decades, but they work partly by constricting blood vessels, which makes them off-limits for people with a history of heart attack, stroke, or uncontrolled high blood pressure. Gepants do not cause vasoconstriction.¹⁹ Current evidence has not found that gepants should be ruled out for people with cardiovascular disease, though long-term data are still accumulating.²⁰ This matters quite a bit, because migraine itself is associated with higher cardiovascular risk, so many migraine patients are exactly the people who were previously stuck without a targeted acute treatment.

Gepants Versus CGRP Monoclonal Antibodies

Both gepants and CGRP monoclonal antibodies target the same pathway, but they do it differently and come with different practical trade-offs. Monoclonal antibodies are injected monthly or quarterly and stay in the body for weeks; gepants are taken as needed or daily and wash out within hours. A systematic review of post-marketing safety data found that injection-site reactions, hair loss, and constipation were more commonly flagged with certain antibodies, while nausea and fatigue were more characteristic of gepants. A more concerning finding was that some monoclonal antibodies showed signals for rare but serious cerebrovascular events, while no such signals were detected for any gepant as of the latest analysis.²¹

Some clinicians are now combining the two: a preventive monoclonal antibody injection alongside an as-needed gepant for breakthrough attacks. The theoretical rationale is that the antibody works outside the brain in the peripheral nervous system while gepants can cross the blood-brain barrier and act centrally, potentially creating complementary coverage. Whether this combination truly produces a synergistic effect is still uncertain, and researchers have acknowledged the outcomes are hard to predict.²²

The Medication Overuse Headache Advantage

One of the trickiest problems in migraine management is medication overuse headache (MOH), a cycle where using acute pain medications too frequently actually causes more headaches. Triptans, NSAIDs, and combination analgesics are all well-known triggers when used on too many days per month. Gepants appear to be different. Current evidence suggests they do not cause medication overuse headache, which could be a game-changer for people who have frequent attacks and need to treat many of them.²³ This is one reason some headache specialists are starting to favor gepants for patients who are at high risk of slipping into an overuse pattern.

Drug Interactions Worth Knowing About

Most gepants are processed by the same liver enzyme, CYP3A4, and are also substrates for certain transport proteins. This means drugs that strongly inhibit or rev up that enzyme can change how much gepant ends up in your bloodstream. No clinically significant interactions have been found with common migraine preventives like topiramate or amitriptyline.²⁴ But stronger CYP3A4 inhibitors, such as the antifungal itraconazole, can substantially raise blood levels of atogepant, while CYP3A4 inducers like the antibiotic rifampin can lower them.²⁵ Rimegepant shows a similar pattern and also mildly inhibits the metabolism of midazolam (a sedative), so there is some potential for rimegepant to raise levels of other drugs that go through the same pathway.²⁶ The practical takeaway is that if you are starting a gepant while already taking strong CYP3A4 inhibitors or inducers, your doctor may need to adjust the dose.

Cost and Access

Gepants are expensive, and this remains a real barrier. A cost-effectiveness analysis found that none of the three acute gepants (ubrogepant, rimegepant, zavegepant) met standard cost-effectiveness thresholds compared with usual care. Among the three, rimegepant came out as the most cost-effective option, and zavegepant the least. The authors noted gepants may be a more reasonable economic choice for people who have only one or two migraines a month, where the per-attack cost does not add up as steeply.²⁷ Insurance coverage varies widely, and many plans require step therapy, meaning you have to try and fail on cheaper treatments like triptans before a gepant will be approved.

Gepants in Children and Teenagers

None of the gepants are formally approved for pediatric use, but some headache specialists have started prescribing them off-label for children and adolescents who have not responded to standard treatments. A multicenter chart review found that about 58% of young patients given rimegepant for prevention saw at least some benefit, compared with 42% on atogepant. Side effects were generally mild, including nausea, fatigue, and constipation, though a few patients on atogepant reported depressed mood. Discontinuation rates due to side effects were low for rimegepant but somewhat higher for atogepant.²⁸ These are early and small data, but they give a preliminary sense that gepants can be tolerated in younger patients.

Special Populations and Dosing Adjustments

Because gepants are processed by the liver and kidneys, their use in people with organ impairment needs some care. For atogepant, a phase 1 study found no clinically meaningful changes in drug levels in people with mild, moderate, or even severe liver impairment after a single dose.²⁹ However, as noted above, the broader pharmacovigilance picture has led to a recommendation against using gepants in severe liver disease, given that liver clearance is their main elimination route.³⁰ For kidney disease, gepants are considered safe in mild and moderate renal impairment.³¹

For breastfeeding, data are still very thin. A small phase 1 study of atogepant in healthy lactating women found it was generally well tolerated, with only mild stomach-related side effects in two of twelve participants and no new safety signals.³² That study was designed to characterize how much drug passes into breast milk, not to provide a definitive safety clearance, so conversations with a prescriber are still essential.

Beyond Migraine

Researchers are starting to explore whether gepants might be useful for other headache disorders. Cluster headache, a condition even more painful than migraine but with fewer approved preventive options, is one candidate. A small case series described four patients with cluster headache who had not responded to other preventives but improved on daily atogepant at 60 mg. Two had episodic cluster headache and two had chronic cluster headache.³³ Four patients is far too few to draw firm conclusions, but it signals interest in the idea that CGRP receptor blockade could help in cluster headache, where CGRP is also known to play a role. Larger trials will be needed before this becomes anything close to a standard practice.