The evolution of gepants in migraine treatment highlights an important safety difference between the first and second generations. First-generation gepants, evaluated over 15 years ago, were discontinued due to liver toxicity, a concern not seen with today's second-generation gepants. In clinical trials, supranormal doses of atogepant did not increase alanine aminotransferase levels (ALT) above 1.5 times the upper limit of normal (ULN).¹ Only 1.0% of patients receiving rimegepant had liver enzymes above 3 times the ULN. No Hy’s Law cases were seen.² With ubrogepant, there were 20 cases of liver enzymes above 3 times the ULN. Of these, 4 were in the usual care arm, 13 were deemed unlikely medication-related, 2 were possibly related, and 1 was probably related.³ Rimegepant, zavegepant, and atogepant use should be avoided in patients with severe liver disease.^4,5,6

Gepants are processed through the CYP3A4 pathway, which can impact the effectiveness of medications using the same pathway. Rimegepant and ubrogepant use should be avoided when taking strong CYP3A4 inhibitors.^4,7 Atogopant dose should be limited to 10 mg once daily when treating episodic migraine.⁴ No restrictions were placed on zavegepant usage when taking CYP3A4 inhibitors or inducers.⁶

Unlike triptans, gepants do not constrict blood vessels. Post hoc analysis of ubrogepant and rimegepant clinical studies found that efficacy and treatment emergent adverse events did not differ based on cardiovascular risk.^8,9

Gepants are primarily metabolized in the liver, excreted in bile and stool, with less than one-fourth excreted in the urine. However, zavegepant use should be avoided in patients with severe renal disease or end-stage renal disease, atogepant dosage should be limited in patients with severe renal impairment and use should be avoided in patients with severe hepatic impairment, ubrogepant dosage should be limited in patients with severe renal disease and end-stage renal disease, and rimegepant use should be avoided in patients with severe hepatic impairment.^4,5,6,7

References:
1. Min KC, et al. Clin Transl Sci. 2021;14(2):599-605;
2. Croop R, et al. Neurology. 2020;94(15_supplement):4829;
3. Ailani J, et al. Headache. 2020;60(1):141-52;
4. Qulipta. Package insert. AbbVie; 2023;
5. Nurtec ODT. Package insert. Pfizer Inc.; 2023;
6. Zavzpret. Package insert. Pfizer Inc.; 2023;
7. Ubrelvy. Package insert. AbbVie Inc.; 2023;
8. Hutchinson S, et al. Cephalalgia. 2021;41(9):979-90;
9. Hutchinson S, et al. Neurology. 2021;96(15_supplement).