CGRP Receptor Antagonists

CGRP receptor antagonists (gepants) are small molecules that block the calcitonin gene-related peptide receptor on trigeminal and meningeal vessels and nerves. They treat acute migraine and prevent episodic and chronic migraine without causing vasoconstriction.

Classification. Acute gepants (rimegepant, ubrogepant, zavegepant) and preventive gepants (atogepant, and rimegepant every other day).

Pharmacokinetics. Oral and nasal absorption is rapid. Rimegepant, ubrogepant and atogepant are cleared mainly by CYP3A4, so interactions matter.

• Rimegepant 75 mg orally disintegrating tablet once as needed (maximum 75 mg in 24 hours); prevention 75 mg every other day.
• Ubrogepant 50 mg or 100 mg orally, repeated after 2 hours if needed; maximum 200 mg in 24 hours.
• Zavegepant 10 mg intranasally once; maximum 10 mg in 24 hours.
• Atogepant 10 mg, 30 mg or 60 mg once daily for prevention; 60 mg daily for chronic migraine.

Differences. Gepants do not constrict blood vessels, so they may be used when triptans are contraindicated, although safety data in cardiovascular disease are limited. Efficacy in acute attacks is slightly lower than triptans.

• Acute migraine: after failure of, or contraindication to, an NSAID and a triptan.
• Prevention: after at least 2 oral preventives have failed or been unsuitable.
• Medication overuse: limit acute gepant use to under 10 days a month until more data exist.

Selection. Cost and availability restrict use in many East African settings.

Contraindications. Hypersensitivity (dyspnoea, rash, anaphylaxis). Ubrogepant and rimegepant with strong CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir-boosted antiretrovirals) and strong inducers (rifampicin, carbamazepine, phenytoin).

Adverse effects. Nausea, somnolence, dry mouth, constipation (atogepant), decreased appetite and weight loss, rare hypertension and Raynaud phenomenon.

Interactions. Strong CYP3A4 inhibitors raise levels and strong inducers lower them. With moderate inhibitors, ubrogepant is reduced to 50 mg and a second dose is avoided; rimegepant is not repeated within 48 hours.

Special groups.

• Pregnancy and breastfeeding: limited data; avoid.
• Children: not licensed under 18 years.
• Older adults: no adjustment, limited data over 65.
• Kidney impairment: avoid rimegepant and atogepant at creatinine clearance under 15 mL/min.
• Liver impairment: avoid rimegepant and atogepant in severe impairment; ubrogepant 50 mg in severe.

Monitoring. Headache diary, blood pressure, bowel habit and weight.

Referral and escalation. Failure of a gepant after 3 attacks, headache on 10 or more days a month, or new neurological symptoms.