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7/20/2001

Almotriptan Joins Migraine Market

Cheryl A. Thompson

The May decision by FDA to approve the marketing of almotriptan malate (Axert, Pharmacia) brings to five the number of available migraine treatments that act by selectively binding to serotonin type 1 receptors.

FDA made its decision about the efficacy of almotriptan on the basis of three multicenter, randomized, double-blind, placebo-controlled studies conducted in Europe involving 1586 adults, primarily white women. Two hours after taking 6.25 or 12.5 mg of almotriptan to treat a moderate to severe migraine, 55.5–64.9% of the study participants reported that their headache pain had disappeared or decreased in severity to mild. That level of relief was reported by <40% of placebo users. Among the patients whose migraine episodes were normally accompanied by photophobia, phonophobia, nausea, and vomiting, almotriptan users reported fewer of these symptoms than did placebo users.

Almotriptan use is contraindicated in patients with ischemic heart disease and those with symptoms of or findings consistent with ischemic heart disease, coronary artery vasospasm, or another serious cardiovascular disease. The labeling strongly recommends that first-time administration of the drug to patients with risk factors predictive of coronary artery disease occur in the physician's office or a medically staffed and equipped facility.

The drug should not be taken by patients with uncontrolled hypertension or within 24 hours of treatment with another serotonin type 1-receptor agonist or an ergotamine-containing or ergot-type medication. Patients with hemiplegic or basilar migraine should not take almotriptan.

Nausea, somnolence, headache, paresthesia, and dry mouth were the most common adverse effects reported during almotriptan use in the clinical studies. The labeling notes that almotriptan was found to bind to melanin-containing tissues in animals and, therefore, clinicians should be aware of the possibility that the drug might have long-term effects on patients' eyes.

After oral administration, almotriptan is well absorbed. The peak plasma concentration is reached one to three hours after ingestion, regardless of food intake. The mean half-life of almotriptan is three to four hours, with about 75% of the dose eliminated by renal excretion, some of it by an active mechanism. Monoamine oxidase (MAO) type A and cytochrome P-450 (CYP) isoenzymes 3A4 and 2D6 serve as the major routes of metabolism for almotriptan; flavin monooxygenase is a minor route. Total drug exposure is 25% greater in people ages 65–76 than in persons 19–34 years; the labeling states that this difference does not seem to be clinically important.

Patients' concomitant use of a selective serotonin-reuptake inhibitor and almotriptan should be monitored. Administration of verapamil (a CYP 3A4 inhibitor) or moclobemide (an MAO inhibitor) increases the plasma concentration of almotriptan by about 25% but does not necessitate a decrease in dosage. Ketoconazole, however, increases the peak plasma concentration of almotriptan by 60%; the labeling notes that increased exposure to the drug should be expected in patients who also take a potent CYP 3A4 inhibitor.

The recommended dosage of almotriptan for the acute treatment of migraine is 6.25 or 12.5 mg. A second dose may be taken two hours after the first if the headache returns. No more than two doses should be taken in 24 hours. The labeling notes that the safety of using almotriptan to treat more than four migraines in a 30-day period is unknown.

Patients with hepatic impairment should use an initial dose of 6.25 mg and not take more than 12.5 mg in 24 hours. This recommendation is based on the estimation that hepatic impairment would decrease the clearance of almotriptan by, at most, 60%. The same dosage instructions should be used for patients with a creatinine clearance of 10–30 mL/min, in whom almotriptan clearance has been found to be 65% lower than in patients with normal renal function.

Axert is available as 6.25- and 12.5-mg tablets in blister packs containing six doses and a leaflet directed at patients.