Tolerability profile of zolmitriptan (Zomig™ 311C90), a novel dual central and peripherally acting 5HT1B/1D agonist

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Abstract
Zolmitriptan (Zomig™, formerly 311C90) at doses of 0.5–50 mg was administered to 316 unique volunteers in clinical pharmacology studies and 2,750 unique patients in eight clinical studies of acute migraine treatment. Overall, subjects received almost 50,000 doses; 97% of exposures were at doses >2.5 mg. In the clinical pharmacology studies, the overall incidence of subject exposures experiencing at least one adverse event was 52% with zolmitriptan 2.5 mg (28% with placebo). In placebo-controlled studies, the overall incidence of patients with at least one adverse event was dose-dependent for zolmitriptan over the 1–15 mg dose range, e.g. 42% and 46% with 1 and 2.5 mg, respectively and 58% with 5 mg (29% with placebo). Only four serious adverse events attributable to zolmitriptan were reported. In a long-term study, during which 2,058 outpatients treated a total of 31,579 migraine attacks with either one or two zolmitriptan 5 mg doses over a period of up to 1 year, the number of attacks associated with at least one adverse event was similar after one (26%) and two (24%) doses. The majority (59%) of the adverse events reported in this study (59%) occurred within 2 h of dosing, were predominantly mild (59%) or moderate (35%) in intensity, of ≦4 h duration (58%), required no further action (94%). In placebo-controlled studies, the percentage of patients who reported severe adverse events was similar with zolmitriptan 2.5 mg (4%) and placebo (5%). The most frequently reported adverse events with zolmitriptan in the placebo-controlled clinical studies were asthenia, heaviness (other than chest or neck), dry mouth, nausea, dizziness, somnolence, paresthesia and warm sensations. The type and severity of the adverse events was not influenced by gender (although the frequency of reported adverse events was higher in females, as was the case in the placebo group), age, presence of aura prior to the attack, association of migraine with menstruation, concurrent medication, or by the addition of a second zolmitriptan dose. Zolmitriptan showed a similar tolerability profile in the long-term study, in which a low withdrawal rate due to adverse events of 8% was observed. Zolmitriptan was not associated with an increased frequency of central nervous system-related adverse events in a comparative study of sumatriptan, despite pre-clinical and neurophysiological evidence of a dual peripheral and central action of zolmitriptan. Moreover, zolmitriptan doses of 5–20 mg produced no statistically significant effects on objective assessments of psychometric function. Zolmitriptan had no clinically significant effects on blood pressure (even in patients with controlled mild to moderate hypertension or impaired renal function), ECGs (e.g. there was no evidence of ischemic events) or clinical chemistry, hematological or urinalysis measurements. In summary, zolmitriptan is well tolerated, particularly at the recommended dose of 2.5 mg. Zolmitriptan has a well-defined dose-response with 2.5 mg proving highly effective and optimizing the benefit/risk ratio of treatment. Thus, zolmitriptan is well suited as an acute oral treatment for migraine in the outpatient setting.