Rizatriptan

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Abstract
Rizatriptan is an orally active serotonin 5-HT1 receptor agonist selective for the 5-HT1b/1dsubtypes. The efficacy of oral rizatriptan (5 or 10mg) has been demonstrated in large (n = 309 to 1746) well designed comparative trials with placebo and oral sumatriptan. Two hours postdose, rizatriptan 5 or 10mg was more effective than placebo at producing pain relief or a pain free status, relieving migraine-associated symptoms and normalising functional ability. In general, rizatriptan 10mg appeared to be more effective than rizatriptan 5mg. However, recurrence rates with rizatriptan 5 and 10mg appeared to be similar to those with placebo. Patients were significantly more likely to achieve pain relief within 2 hours after receiving rizatriptan 5mg than sumatriptan 25mg and after rizatriptan 10mg than sumatriptan 50mg. This was also observed with rizatriptan 10mg compared with sumatriptan 100mg according to an age-adjusted and a prespecified per-protocol analysis. In general, rizatriptan was better than sumatriptan at relieving migraine-associated symptoms, particularly nausea, and in normalising functional ability depending on which doses were compared. The incidence of headache recurrence, time to onset of recurrence and the need for escape medication in nonresponders appeared to be similar between rizatriptan and sumatriptan. Over the 24 hours after the dose, rizatriptan 10mg improved the quality of life of patients with migraine compared with placebo. Rizatriptan 10mg also significantly improved work function compared with placebo and with sumatriptan 50mg. Rizatriptan appears to be well tolerated with most adverse events being mild and transient. The most commonly experienced events included general digestive complaints, general neurological complaints, dizziness, somnolence, asthenia/ fatigue and pain and pressure sensations. In clinical trials, the overall incidence of adverse events with rizatriptan 5 or 10mg was similar to that with sumatriptan 25 or 50mg but lower than that with sumatriptan lOOmg. Chest pain was reported by 1 to 3% of rizatriptan recipients and by 3 to 6% of patients receiving sumatriptan (25, 50 or lOOmg); clinically significant effects on ECG parameters, heart rate or blood pressure were not observed with rizatriptan. Conclusions: Rizatriptan produces pain relief and a pain free status, relieves associated symptoms of migraine, normalises functional ability and improves patient quality of life. Rizatriptan 10mg appears to be more effective than rizatriptan 5mg. In comparison with oral sumatriptan, rizatriptan may provide better relief from pain and nausea, with some evidence of a faster onset of action. Thus, rizatriptan 5 or 10mg is likely to establish a place as an effective and well tolerated agent for the management of acute migraine. Rizatriptan is an orally active serotonin 5-HT1 receptor agonist which selectively acts at the 5-HT1b/1d subtypes. In vitro, at supra-therapeutic doses, rizatriptan produced greater maximum contraction of human cranial arteries and less vasoconstriction of human coronary arteries than sumatriptan. Rizatriptan inhibited electrically-induced, but not neuropeptide-induced, vasodilation of the durai blood vessels in rats, possibly by reducing neuropeptide release. Durai plasma protein extravasation was also inhibited by rizatriptan and this action may contribute to the drug’s antimigraine effect. Rizatriptan inhibited electrically-induced firing of neurons from the trigeminal nucleus caudalis in rats, suggesting a central antinociceptive effect. In small studies in healthy volunteers or patients with controlled hypertension, rizatriptan (0.5 to 80mg as a single dose or 10mg every 2 hours for 3 doses per day for 4 days) generally produced only small, transient increases in blood pressure and did not alter heart rate, or affect the increases in blood pressure and heart rate in response to sympathetic stimulation. However, it is important to note that, as with other 5-HT1b/1d agonists, rizatriptan is contraindicated in patients with coronary artery disease or uncontrolled hypertension. In a small study in healthy volunteers, no additive effects on systolic blood pressure were observed when rizatriptan 10mg was added to intravenous ergot-amine 0.25mg. Oral rizatriptan in single doses of 20 to 60mg produced a transient increase in growth hormone levels similar to that after sumatriptan 100mg, but had no effect on prolactin levels. Oral Administration: After single dose oral rizatriptan 5 to 60mg in healthy male volunteers, the maximum plasma concentration (Cmax) ranged from 7.8 to 90.8 µg/L, the area under the plasma concentration-time curve (AUC) ranged from 17.4 to 394.5 µg/L · h. The mean time to achieve Cmax (tmax) was 0.7 to 2.1 hours after single dose rizatriptan 2.5 to 60mg. The median tmax of rizatriptan (5 to 60mg) was significantly lower than the tmax of oral sumatriptan 100mg (1.3 vs 2.5 hours). The elimination half-life (t½) of rizatriptan was about 2 to 2.5 hours. The main route of elimination of rizatriptan is metabolism via the monoamine oxidase A enzyme; the major indole-3-acetic acid metabolite is inactive at 5-HT1b/1d receptors but a minor N-monodesmethyl metabolite has similar activity to the parent drug. The presence of food increased the extent and decreased the rate of rizatriptan absorption without altering t½ values. Multiple rizatriptan doses increased values for absorption (Cmax, tmaxand AUC) but not elimination (t½ and renal clearance) parameters, and there was no unexpected accumulation. Pharmacokinetic parameters (Cmax, AUC and t½) appear similar in adolescent migraineurs compared with healthy volunteers. It is unclear whether rizatriptan pharmacokinetics differ between men and women....