Frovatriptan

Frovatriptan (Migard®; Frova®) is an orally administered triptan approved for the acute treatment of adults with migraine, with or without aura. This article reviews the pharmacology of frovatriptan, focusing on its efficacy and tolerability.

The precise mechanism of action of frovatriptan is unknown, but is thought to stem from agonism at serotonin 5-HT_1B and 5-HT_1D receptors, resulting in inhibition of intracranial and extracerebral artery vasodilation, along with possible anti-inflammatory and pain inhibiting effects. Frovatriptan appears to be functionally selective for 5-HT receptors in human basilar arteries over coronary arteries, which could translate into a low cardiovascular risk. In contrast to other triptans, frovatriptan has a long terminal elimination half-life in blood of ≈26 hours, which can be expected to be associated with a sustained treatment effect.

Oral frovatriptan 2.5 mg was efficacious in patients with moderate to severe migraine attacks; in randomized, double-blind trials the proportion of patients with headache response at 2 hours (primary endpoint) was consistently significantly higher in frovatriptan than placebo groups. Frovatriptan was generally well tolerated in short-term clinical trials and when used over the longer term. The most frequent treatment-emergent adverse events occurring at a frequency ≥1% higher in frovatriptan than placebo recipients were dizziness, fatigue, headache, paraesthesia, flushing, skeletal pain, hot or cold sensation, dry mouth, chest pain and dyspepsia. In a study in patients with coronary artery disease, or who were at high risk of coronary artery disease, there was no increase over placebo in the occurrence of clinically significant ECG changes or in cardiac rhythm disturbances. In a further trial, frovatriptan administered early in a migraine attack was more efficacious than placebo followed by later administration of frovatriptan as pain progressed.

Three crossover trials compared early administration of frovatriptan 2.5 mg with almotriptan 12.5 mg, rizatriptan 10 mg and zolmitriptan 2.5 mg in patients with migraine. There were no significant between-group differences in patient drug preference scores (primary endpoint) or in other endpoints, except for headache recurrence, which favoured frovatriptan in two of the trials. The trials did not test noninferiority of frovatriptan to the comparator. In a placebo-controlled trial that included a sumatriptan active treatment arm, sumatriptan 100 mg was significantly more efficacious than frovatriptan 2.5 mg for this primary endpoint. Frovatriptan was generally better tolerated than all four triptan comparators.

In summary, frovatriptan was an efficacious acute treatment for moderate to severe migraine attacks and had a favourable tolerability profile, although in a single trial, it was not as efficacious as sumatriptan. Administration of frovatriptan early in an attack while the attack was at a mild level of intensity was more efficacious than late administration. Furthermore, in clinical trials adopting this early administration strategy, frovatriptan was not significantly less efficacious than almotriptan, rizatriptan and zolmitriptan, appeared to have a more sustained treatment effect, and was better tolerated than the comparators. Frovatriptan provides an alternative treatment for migraine, especially in patients who have had adverse events or frequent headache recurrences with triptans or other anti-migraine drugs, and who are amenable to adopting an early administration strategy.