Gepants, an Expensive New Class of Migraine Drugs: Do Not Use for Seven Years

Migraines are recurrent throbbing or pulsating headaches that are often debilitating and are frequently accompanied by nausea, sensitivity to light or sound, and other bothersome symptoms.[1] “Gepants,” more formally known as small-molecule calcitonin gene-related peptide receptor antagonists, are a new and expensive class of migraine drug that works by blocking the transmission of pain signals caused by migraines.[2],[3]

Between 2019 and 2023 the Food and Drug Administration (FDA) approved four gepants. This article discusses three of these drugs: rimegepant (NURTEC ODT),[4] ubrogepant (UBRELVY)[5],[6] and zavegepant (ZAVZPRET).[7] All three drugs are approved for the acute treatment of migraine in adults with or without aura (a sensory phenomenon or visual disturbance). Rimegepant is also approved for the prevention of episodic migraines in adults. A fourth gepant, atogepant (QULIPTA), is only approved for the prevention of migraines.[8]

Because adequate long-term data are not available on the safety of gepants and no study has directly established that gepants are safer and more effective than other types of migraine drugs,[9],[10] Public Citizen’s Health Research Group has designated these gepants as Do Not Use for Seven Years. Gepants are also expensive.

Treatment of migraine headaches

Mild to moderate migraine attacks should first be treated with over-the-counter drugs such as acetaminophen (TYLENOL and generics) and nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (ADVIL, MIDOL, MOTRIN and generics), as discussed in more detail in the February 2025 issue of Worst Pills, Best Pills News.[11]

If over-the-counter medications fail to provide relief, triptans (such as sumatriptan [IMITREX and generics]) can be tried. Public Citizen’s Health Research Group has designated triptans as Limited Use. Triptans are associated with important adverse effects, including nausea, dizziness, chest tightness or pain, and overuse headaches (the exacerbation of headaches caused by the overuse of drugs used to treat migraines).[12] Less frequent adverse events include heart attack or stroke. Triptans may cause blood vessels in the brain and heart to narrow (vasoconstriction),[13] which is why triptans are not recommended for patients with a history of heart conditions.

Gepants

Rimegepant is an oral disintegrating tablet, ubrogepant is an oral tablet and zavegepant is a nasal spray. The average cost for six to eight doses of these drugs ranges from $1,085 to $1,316.

Because gepants do not cause vasoconstriction, they are sometimes prescribed as an alternative to triptans.[14] It is not yet known whether gepants have any clinical advantages over triptans. To date, no study has directly compared these two classes of migraine drugs to determine which has a better efficacy and safety profile.[15] However, two network meta-analyses that indirectly compared different classes of migraine drugs found that gepants might not be as effective as triptans.[16],[17]

Evidence of efficacy of gepants

The efficacy of gepants on a single migraine attack was demonstrated for each of the three gepants in randomized, double-blind trials; two trials compared either 50 mg or 100 mg of ubrogepant with placebo,[18],[19] two studies compared 10 mg of zavegepant with placebo,[20],[21] and one study compared 75 mg of rimegepant with placebo.[22],[23] In all trials, participants who had received a gepant were significantly more likely than those who had received a placebo to achieve freedom from pain and a significant reduction of their most bothersome migraine symptoms (such as nausea or sensitivity to light or sound) after two hours.

For example, in one of the ubrogepant trials, 19% of participants who received 50 mg of the drug and 21% of those taking 100 mg were pain free after two hours, compared with 12% of those who had received placebo, a difference of 7-9% between the ubrogepant and placebo groups. In the second ubrogepant study, the difference was 8% between the groups. Moreover, significantly more drug-treated participants were free of bothersome symptoms two hours post-dose compared with placebo, with a difference of 10-12% between groups across both studies. Similarly, in the studies that assessed zavegepant, at two hours the difference in freedom from pain was 7-9% and the difference in relief from bothersome symptoms was 8-9%. For rimegepant, the difference between groups at two hours for freedom from pain was 10% and 8%, respectively.

All studies also evaluated gepants on other endpoints, including sustained freedom from pain between 2 to 24 hours after dosing. For most but not all of the gepant-dose studies, there were significant differences with placebo. Studies also found that the efficacy of gepants may be lower for certain groups of patients, such as men or adults aged 65 years or older.

Evidence of safety of gepants

Ubrogepant, rimegepant and zavegepant are second- and third-generation gepants that are chemically different from the first generation of these drugs.[24],[25] The development of earlier gepants was stopped over concerns about liver damage.

The safety of ubrogepant, rimegepant and zavegepant was evaluated in randomized, double-blind and placebo-controlled trials and one-year open-label extension studies.[26],[27],[28] Overall, compared with placebo, treatment with any gepant was associated with several adverse events, including nausea and somnolence (sleepiness). For example, 2% of participants who received rimegepant reported nausea, as compared with 0.4% of those who received placebo.

Compared with placebo, treatment with the oral drugs ubrogepant and rimegepant was more commonly associated with dizziness and abdominal pain. More participants who received the nasal spray zavegepant than those in the placebo group had taste disorders, nasal discomfort and vomiting. Moreover, treatment with gepants has been associated with severe hypersensitivity reactions, including anaphylaxis, trouble breathing, and swelling of the mouth, tongue and throat.

Importantly, although the gepants that have been approved are safer than the first-generation drugs, there are still concerns about cardiovascular and cerebrovascular adverse events, as well as liver damage.[29],[30],[31]

In this context, it is important to note that most participants in all the clinical trials were young and healthy; people with major cardiovascular diseases were excluded. Even though the FDA stated that none of the studies showed a “clear safety signal,” sufficient long-term data on the safety of gepants (that is, data for use over a seven-year period) are not yet available. Moreover, not enough is known about the safety of gepants during pregnancy, which is salient because of the prevalence of migraine among women of childbearing age.

What You Can Do

If you have migraine attacks, Public Citizen’s Health Research Group recommends that you do not use gepants for seven years. Adequate information about their safety and effectiveness as compared to other migraine drugs is not yet available. To relieve acute migraine symptoms, try acetaminophen or NSAIDs first. If these drugs do not adequately relieve pain, discuss with your clinician triptans and other treatment options.
 

References

[1] Schwedt TJ, Garza I. Acute treatment of migraine in adults. UpToDate. Updated October 7, 2024.

[2] Laohapiboolrattana W, Jansem P, Anukoolwittaya P, et al. Efficacy of lasmiditan, rimegepant and ubrogepant for acute treatment of migraine in triptan insufficient responders: systematic review and network meta-analysis. J Headache Pain. 2024;25(1):194.

[3] Kissoon NR, Steel S. Patient education: migraine in adults (beyond the basics). UpToDate. Updated October 18, 2024.

[4] Pfizer. Label: rimegepant (NURTEC ODT). April 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/212728Orig1s025Correctedlbl.pdf. Accessed February 4, 2025.

[5] Allergan. Label: ubrogepant (UBRELVY). February 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/211765s007lbl.pdf. Accessed February 4, 2025.

[6] Food and Drug Administration. FDA approves new treatment for adults with migraine. December 23, 2019. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-adults-migraine. Accessed February 4, 2025.

[7] Pfizer. Label: zavegepant (ZAVZPRET). March 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216386s000lbl.pdf. Accessed February 4, 2025.

[8] AbbVie. Label: atogepant (QULIPTA). April 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215206s004lbl.pdf. Accessed February 4, 2025.

[9] Schwedt TJ, Garza I. Preventive treatment of episodic migraine in adults. UpToDate. Updated October 7, 2024.

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

[11] New drugs for migraine symptoms are not always more effective than old ones, study finds. Worst Pills, Best Pills News. February 2025. https://www.worstpills.org/newsletters/view/1645. Accessed February 4, 2025.

[12] Review of the triptan drugs for treating migraines. Worst Pills, Best Pills News. June 2022. https://www.worstpills.org/newsletters/view/1468. Accessed February 4, 2025.

[13] Vu M, Jarrett TL, Newsom LC. Consider cardiovascular risk factors before prescribing triptans for migraine. Am Fam Physician. 2018;98(6):342.

[14] Schwedt TJ, Garza I. Acute treatment of migraine in adults. UpToDate. Updated October 7, 2024.

[15] Moreno-Ajona D, Villar-Martínez MD, Goadsby PJ. New generation gepants: migraine acute and preventive medications. J Clin Med. 2022;11(6):1656.

[16] Yang CP, Liang CS, Chang CM, et al. Comparison of new pharmacologic agents with triptans for treatment of migraine: a systematic review and meta-analysis. JAMA Netw Open. 2021;4(10):e2128544.

[17] Karlsson WK, Ostinelli EG, Zhuang ZA, et al. Comparative effects of drug interventions for the acute management of migraine episodes in adults: systematic review and network meta-analysis. BMJ. 2024;386(September 18):e080107.

[18] Allergan. Label: ubrogepant (UBRELVY). February 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/211765s007lbl.pdf. Accessed February 4, 2025.

[19] Food and Drug Administration. Center for Drug Evaluation and Research. Clinical review(s) for application number: 211765Orig1s000. Ubrogepant (Ubrelvy). December 2019. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211765Orig1s000MedR.pdf. Accessed February 4, 2025.

[20] Pfizer. Label: zavegepant (ZAVZPRET). March 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216386s000lbl.pdf. Accessed February 4, 2025.

[21] Food and Drug Administration. Center for Drug Evaluation and Research. Clinical review(s) for application number: 216386Orig1s000. Zavegepant (Zavzpret). March 2023. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216386Orig1s000MedR.pdf. Accessed February 4, 2025.

[22] Pfizer. Label: rimegepant (NURTEC ODT). April 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/212728Orig1s025Correctedlbl.pdf. Accessed February 4, 2025.

[23] Food and Drug Administration. Center for Drug Evaluation and Research. Clinical review(s) for application number: 212728Orig1s000. Rimegepant (Nurtec ODT). February 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212728Orig1s000MedR.pdf. Accessed February 4, 2025.

[24] Moreno-Ajona D, Villar-Martínez MD, Goadsby PJ. New generation gepants: migraine acute and preventive medications. J Clin Med. 2022;11(6):1656.

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

[26] Allergan. Label: ubrogepant (UBRELVY). February 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/211765s007lbl.pdf. Accessed February 4, 2025.

[27] Pfizer. Label: rimegepant (NURTEC ODT). April 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/212728Orig1s025Correctedlbl.pdf. Accessed February 4, 2025.

[28] Pfizer. Label: zavegepant (ZAVZPRET). March 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216386s000lbl.pdf. Accessed February 4, 2025.

[29] Food and Drug Administration. Center for Drug Evaluation and Research. Clinical review(s) for application number: 212728Orig1s000. Rimegepant (Nurtec ODT). February 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2020/212728Orig1s000MedR.pdf. Accessed February 4, 2025.

[30] Food and Drug Administration. Center for Drug Evaluation and Research. Clinical review(s) for application number: 216386Orig1s000. Zavegepant (Zavzpret). March 2023. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216386Orig1s000MedR.pdf. Accessed February 4, 2025.

[31] Food and Drug Administration. Center for Drug Evaluation and Research. Clinical review(s) for application number: 211765Orig1s000. Ubrogepant (Ubrelvy). December 2019. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211765Orig1s000MedR.pdf. Accessed February 4, 2025.