Safety and tolerability of short-term preventive frovatriptan: a combined analysis.

Objective: To assess the safety and tolerability profile of the 5-HT(1B/1D) agonist frovatriptan (Frova(R), Endo Pharmaceuticals Inc., Chadds Ford, PA, USA) when used as a 6-day regimen for the short-term prevention of menstrual migraine scheduled over multiple perimenstrual periods.

Background: Two randomized controlled trials have established the efficacy of a 6-day regimen of frovatriptan for reducing the incidence and severity of menstrual migraine over 1 to 3 perimenstrual periods; long-term data are needed to further assess the safety and tolerability profile of this regimen.

Methods: Two multinational trials were included in the analysis: Study 1 was a randomized, placebo-controlled double-blind parallel trial (3 perimenstrual periods treated) with an open-label extension (3 additional perimenstrual periods treated), and Study 2 was a long-term (12 perimenstrual periods treated over 12-15 months) open-label study. Enrolled women experienced menstrual migraine defined as predictable migraine attacks that started -2 days to +3 (Study 1) or +4 (Study 2) days relative to the first day of menses and that occurred in at least 2 out of 3 menstrual cycles. Frovatriptan or placebo was given 2 days before anticipated menstrual migraine and continued for 6 days. Adverse events, serious adverse events, vital signs, cardiovascular events, electrocardiograms, and laboratory parameters were assessed and recorded periodically and summarized using descriptive statistics. Adverse event data from Study 1 and Study 2 were compared using event rates.

Results: The demographic characteristics of the 2 study populations were similar: the mean age was approximately 38 years, > or =94% of participants were white, and 85% reported menstrual migraine began on days -2 to +1 of the menstrual cycle. The mean reported history of menstrual migraine was approximately 11 years. A large percentage of the respective safety populations completed each study or study period: 87% (362/416) and 88% (273/309) completed the double-blind period and open-label periods of Study 1, respectively, and 59% (308/525) completed treatment of 12 perimenstrual periods in Study 2. Major reasons for discontinuation in Study 1 included adverse events (5%, double-blind period) and "other" (10% double-blind period and 5% open-label period). In Study 2, major reasons for discontinuation included patient request (17.3%) and adverse event (10.2%). The most common treatment emergent adverse events in the double-blind period of Study 1 (placebo vs frovatriptan twice daily) were upper respiratory infection (9% vs 9%), nausea (6% vs 8%), dizziness (7% vs 7%), fatigue (4% vs 7%), dysmenorrhea (3% vs 7%), influenza (3% vs 6%), neck pain (4% vs 6%), and migraine (4% vs 4%). With the exception of migraine (which was reported using a different method in each study), prevalence rates for Studies 1 and 2 were numerically similar. The most frequently reported cardiovascular adverse events during double-blind treatment (placebo vs frovatriptan twice daily) were chest discomfort (2% and 3%), chest pain (2% and 2%), and hypertension (0 and 2%). The corresponding adverse event rates in Study 2 were 2% (chest pain), 3% (chest discomfort), and 3% (hypertension). In both studies, most adverse events were of mild or moderate intensity and their incidence numerically declined with each perimenstrual period/cycle, as did the incidence of menstrual migraine. The observed rate of intercurrent migraine in Study 2 over 12 perimenstrual periods was 1.5 per month, compared with 1.7 at baseline. There was no observable increase in the first occurrence of migraine in the 5 days following the perimenstrual period, indicating a lack of rebound headache.

Conclusions: During treatment of up to 12 perimenstrual periods over a 12- to 15-month period, the safety and tolerability of frovatriptan for short-term prevention of menstrual migraine was similar to that observed with acute use of triptans. Adverse events were generally mild or moderate in severity, there was no evidence of an increased risk of cardiovascular adverse events relative to acute treatment, and rebound headache was not evident. A short-term regimen with frovatriptan presents a safe and viable treatment option for preventing predictable migraine such as menstrual migraine.