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1/8/2002

Frovatriptan Approved as Migraine Treatment

Cheryl A. Thompson

Elan Pharmaceuticals received FDA approval to market frovatriptan succinate (Frova) for the acute treatment of migraines in adults. It is the sixth serotonin type 1 (5-HT1)-receptor agonist available in the United States for the treatment of migraines.

The efficacy of frovatriptan was shown in five randomized, double-blind, placebo-controlled studies involving more than 2300 adults, mostly white women. Participants were told to take one dose of their assigned treatment when they had a moderate to severe headache. Two hours after taking the assigned treatment, participants could use additional medications other than a 5-HT1 receptor agonist or ergotamine-containing product. In two of the studies, the participants could take a second dose of frovatriptan if the headache recurred within 24 hours.

Two hours after taking 2.5 mg of frovatriptan, 37–46% of 1508 patients reported that it had eliminated their headache or reduced its severity to mild; this level of relief was reported by 21–27% of placebo users. Relatively fewer users of frovatriptan 2.5 mg than of placebo took a second dose or used other headache relievers within 24 hours of the first dose.

Frovatriptan 0.5 and 1 mg were ineffective two hours after ingestion, and doses of 5–40 mg were as effective as 2.5 mg but had a higher frequency of adverse events. Migraine-associated nausea, photophobia, and phonophobia persisted in relatively fewer of the frovatriptan users than in the placebo group.

Because 5-HT1 receptor agonists can cause coronary vasospasm, frovatriptan should not be taken by patients with ischemic heart disease, cerebrovascular syndrome, peripheral vascular disease, or uncontrolled hypertension. Frovatriptan should also not be taken by patients who have used another 5-HT1 receptor agonist or an ergot-type medication in the previous 24 hours, have symptoms or test findings consistent with a diagnosis of ischemic heart disease or coronary artery vasospasm, or have hemiplegic or basilar migraine.

The product's labeling strongly recommends that the drug not be given to patients with a risk factor predictive of coronary artery disease unless a cardiovascular evaluation reveals clinical evidence to the contrary. In these patients, the first dose of frovatriptan should be administered in a medically staffed and equipped facility, such as a physician's office. Patients with a risk factor predictive of coronary artery disease and who are long-term intermittent users of any 5-HT1 receptor agonist should undergo periodic cardiovascular evaluation.

During four of the five placebo-controlled studies of frovatriptan, the most commonly reported adverse effects related to treatment were dizziness, paresthesia, headache, dry mouth, fatigue, flushing, a hot or cold sensation, and chest pain. Some of the older participants in the clinical studies had a small, transient increase in their systolic blood pressure.

The mean peak blood concentration of frovatriptan is reached two to four hours after ingestion of a single 2.5-mg dose. The absolute bioavailability of that dose is 30% in women and 20% in men. Food delays the time to peak blood concentration by one hour. About 15% of frovatriptan is bound to serum proteins.

The enzyme principally responsible for the metabolism of frovatriptan seems to be cytochrome P-450 isoenzyme 1A2. Less than 10% of an oral dose is excreted in the urine. The mean elimination half-life of frovatriptan is about 26 hours.

Total exposure to frovatriptan is up to twofold higher in healthy adults 65–77 years old than in young healthy people and about twice as high in patients with mild to moderate hepatic impairment. The product's labeling does not suggest adjusting the dosage in patients with mild to moderate hepatic impairment.

Frovatriptan does not inhibit or induce monoamine oxidase or CYP-450 enzymes. Total exposure to frovatriptan is 30% more than normal when taken during oral contraceptive therapy and 25% less when taken with ergotamine tartrate. Propranolol increases total exposure to frovatriptan by 60% in men and 29% in women.

Prescribers are advised in the product's labeling to be aware that frovatriptan and its metabolites may bind to melanin in the eye and, therefore, have long-term ophthalmologic effects.

The recommended dosage of frovatriptan is 2.5 mg, taken orally with a fluid. A second tablet may be taken two or more hours after the first dose if the migraine recurs, but a second dose should not be taken if the headache did not initially respond to treatment. No more than 7.5 mg should be taken in one day. The drug is not recommended for use by patients less than 18 years old.

Frova is manufactured by the Galen Group of Northern Ireland and available as white film-coated tablets containing the equivalent of 2.5 mg of frovatriptan base. The tablets are packaged in bottles of 100 or blister cards of 9, both accompanied by a patient package insert.