The efficacy of frovatriptan was assessed in men and women aged 18 to 55 at 2, 4, and 6 hours after administration of the dose using the International Headache Society’s four-point scale of 0 to 3 (0 indicating no headache and 3 indicating severe headache). At two hours, the lowest effective dose, 2.5 mg, was observed to provide an effect of 40%, compared to an effect of 23% with placebo. The effect was defined as a change from severe or moderate (3 or 2 on the four-point scale) to mild or no headache (1 or 0).
Doses ranging from 5 to 40 mg were also given but were no more effective than the dose of 2.5 mg; similarly, 0.5-mg and 1-mg doses proved no more effective than placebo.
Headache recurrence was defined as taking place in patients who had a 1 or 0 response and whose headache recurred to grade 2 or 3 in a 24-hour period after administration of 2.5 mg of frovatriptan. The rate of recurrence was significantly less with frovatriptan than with placebo—9% to 16% in contrast to 27%. The smaller recurrence rate may be due to the long duration of action of frovatriptan as a result of its 26-hour half-life.
SAFETY AND TOLERABILITY
All doses of frovatriptan given in the studies, from 0.5 mg to 40 mg, were well tolerated. The most common adverse events reported were dizziness, nausea, and fatigue. It should be noted that these effects are commonly experienced during migraine attacks and are also dose-related effects, zolmitriptan, nara-triptan, (Maxalt®, Merck). These effects are also dose-related in frovatriptan, with the highest incidence seen at doses of 10 mg and above. Most of the adverse events were of mild to moderate intensity and of short duration. Other adverse events with low incidence (at least 1%) were paresthesia, flushing, chest pain, dyspepsia, and skeletal pain.
All doses of frovatriptan, except for 0.5 mg and 1 mg, were more efficacious than placebo at relieving nausea, photophobia, and phonophobia associated with migraines, but 2.5 mg was shown to be the lowest effective dose. In a single study (VML 251/96/09, study 4) frovatriptan 2.5 mg was better tolerated than suma-triptan 100 mg. Patients experienced adverse events at a rate of 36% with frova-triptan and at 43% with sumatriptan. The total number of adverse events reported was 50% higher for sumatriptan canadian.
In vitro, frovatriptan is not an inhibitor of human MAO enzymes or cytochrome P-450 (isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, 3A4). No induction of drug metabolizing enzymes was observed.
The recommended dosage is one 2.5-mg tablet, up to three tablets a day, at no less than two-hour intervals.
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Overdosage. The maximum single dose given to men and women was 40 mg (16 times the recommended dose), and the maximum single dose given to men was 100 mg, without significant effect. Therefore, the possibility of overdose is very slim, because several times the recommended dosage was consumed without adverse effects. In addition, patients receive only nine tablets per carton of frovatriptan.
Frovatriptan is available as a round, white, film-coated 2.5-mg tablet. Tablet markings show a 77 on one side and an “e” logo on the other. The drug is available in a card of nine tablets with one blister pack per carton.
In general, it is clear that the triptans are an effective means of providing abortive migraine therapy. From a pharmacoeconomic standpoint, the higher cost of the triptans can be offset by the overall reduction in cost of medical care. Arguably, sumatriptan has been the standard of care since its approval. Its limitations—its high incidence of adverse effects, its short duration of action, its short half-life, and the high recurrence rates of migraine—has led to the need for more well tolerated and efficacious agents. The addition of frovatriptan to the market significantly increases the choices for the effective treatment of a disabling health condition that affects many people in the U.S.
Frovatriptan’s potency as a cerebral vasoconstrictor, its dual elimination by the kidneys and liver, and its selectivity make frovatriptan a unique agent for the treatment of acute migraines. Its selectivity for cerebral vessels lessens the potential for undesirable peripheral effects. In addition, frovatriptan’s 26-hour half-life provides the possibility of reducing migraine recurrence and decreasing the need for repeated dosing.
Frovatriptan may be taken without regard to meals. There appears to be no need to adjust the dose in patients with renal or hepatic impairment, in older adults, or in women taking COCs, because frovatriptan is well tolerated in these individuals. Frovatriptan provides an option for migraine sufferers with long-lasting or frequently recurring headaches.