Rizatriptan

Rizatriptan is an orally active serotonin 5-HT₁ receptor agonist that potently and selectively binds to 5-HT_1B/1D subtypes.

Earlier clinical trials demonstrated that rizatriptan 5 or 10mg is more effective than placebo at providing pain relief and a pain-free state, relieving associated symptoms of migraine, normalising functional ability and improving patient quality of life, and showed that rizatriptan provides faster freedom from pain and reduces nausea to a greater extent than oral sumatriptan.

More recently, rizatriptan 10mg was shown to be more effective than zolmitriptan 2.5mg or naratriptan 2.5mg at producing a pain-free state 2 hours postdose. Furthermore, compared with naratriptan, significantly more patients who received rizatriptan were pain free or had pain relief from 1 hour onwards. The number of patients with normal functional ability at 2 hours was significantly higher after rizatriptan than after naratriptan or zolmitriptan. Rizatriptan was also generally more effective than zolmitriptan or naratriptan at relieving migraine-associated symptoms.

Rizatriptan is generally well tolerated and adverse events are usually mild and transient. The most common adverse events associated with rizatriptan in recent randomised trials were asthenia/fatigue, dizziness, somnolence and nausea. There was a trend towards a lower incidence of adverse events with rizatriptan compared with zolmitriptan (31.2 vs 38.8%). However, rizatriptan was associated with a significantly higher incidence of adverse events than naratriptan (39 vs 29%). The incidence of chest pain was similar after the administration of rizatriptan, zolmitriptan or naratriptan (2 to 4%).

Rizatriptan is an orally active serotonin 5-HT₁ receptor agonist that potently and selectively binds to 5-HT_1B/1D subtypes.

Rizatriptan, sumatriptan and zolmitriptan induce vasoconstriction and reduce (albeit to a different extent) compliance of conduit arteries, suggesting that 5-HT_1B/1D agonists should be used with caution in patients with an increased risk for cardiovascular events. In a double-blind study in 16 patients with migraine, rizatriptan, sumatriptan and zolmitriptan caused similar decreases in the diameter of the carotid and brachial arteries (by about 4 to 10%); there were no significant differences between active treatments. Distension, vascular resistance, and isobaric cross-sectional compliance of the carotid artery were not affected by any of the active drugs. Unlike sumatriptan or zolmitriptan, rizatriptan did not significantly affect the isobaric compliance of the brachial artery. Rizatriptan had no effect on the diameter or vascular resistance of the temporal artery.

Rizatriptan generally produces only small and transient increases in BP and does not affect heart rate or the increases in heart rate or BP in response to sympathetic stimulation. However, rizatriptan is contraindicated in patients with uncontrolled hypertension.

In guinea pigs, intravenous rizatriptan 0.01 to 1 mg/kg dose-dependently inhibited electrically stimulated neurogenic dural vasodilation, but had no effect on rat-α-calcitonin gene-related peptide (αCGRP)-induced vasodilation, indicating that rizatriptan has an inhibitory action on the release of CGRP via an action at receptors located on the trigeminal sensory fibres.

In rats, intravenous rizatriptan 100 and 1000 μg/kg inhibited dural plasma protein extravasation induced by electrical stimulation of the trigeminal ganglion (by about 57 and 89%). Rizatriptan inhibited electrically induced central nociceptive neurotransmission, suggesting a central antinociceptive effect.

Rizatriptan 20 to 60mg does not affect serum prolactin concentrations, and produces transient increases in growth hormone concentrations similar to those seen after sumatriptan 100mg.

The bioavailability of rizatriptan after oral administration is about 45%. Maximum plasma concentration (C_max) and area under the plasma concentration-time curve (AUC) values for rizatriptan were generally dose-proportional after single-dose rizatriptan 5 to 60mg. Studies evaluating single-dose rizatriptan 10mg in healthy volunteers showed C_max and AUC values of between 17.7 and 32.1 μg/L and 49.6 and 97.0 μg · h/L, respectively. The mean time to achieve Cmax (t_max) was 0.7 to 1.5 hours after rizatriptan 10mg; the elimination half-life (t½) was 1.7 to 2.6 hours.

After multiple-dose rizatriptan (10mg every 2 hours for three doses on 4 consecutive days), the AUC was approximately 3-fold higher, C_max was 2-fold higher and t_max was 5-fold higher than after single-dose rizatriptan 10mg; t½ and the rate of renal clearance (CL_R) were not significantly affected.

C_max, AUC, t_max and t½ values after single-dose rizatriptan 10mg in healthy elderly volunteers (aged between 65 and 78 years) were similar to those found in younger adults; however, CL_R was somewhat lower in the elderly (11.8 vs 17.6L/h).

Rizatriptan is predominantly metabolised by monoamine oxidase A (MAO-A) in the liver; the major metabolites are triazolomethyl-indole-3-acetic acid and rizatriptan-N-oxide (both inactive). The minor metabolite N-monodesmethyl-rizatriptan is active at 5-HT_1B/1D receptors. 82.4 and 15.2% of an administered dose of rizatriptan 10mg is excreted in the urine and faeces, predominantly within the first 24 hours.

Coadministration of rizatriptan with moclobemide (which is contraindicated) or propranolol (but not nadolol or metoprolol) causes an increase in plasma concentrations of rizatriptan; patients receiving propranolol should be prescribed rizatriptan 5mg. Results from a study in women taking oral contraceptives showed that rizatriptan has no effect on the pharmacokinetics of ethinylestradiol or norethisterone (norethindrone).

The efficacy of rizatriptan [standard tablets and orally disintegrating tablets (wafers)] in the treatment of migraine has been demonstrated in large well designed, placebo-controlled studies and comparative trials with oral sumatriptan, zolmitriptan and naratriptan.

Earlier comparative studies with sumatriptan demonstrated that at 2 hours postdose, rizatriptan 5 and 10mg were more effective than sumatriptan 25 and 100mg, respectively, at producing a pain free state, and that rizatriptan 5mg was more effective than sumatriptan 25mg at providing pain relief. Rizatriptan 5 or 10mg also provided faster freedom from pain than sumatriptan 25 to 100mg. Rizatriptan 10mg has also been shown to be more effective than rizatriptan 5mg at providing freedom from pain within 2 hours of the dose.

More recent randomised, double-blind, placebo-controlled studies showed that more patients who received rizatriptan 10mg for the acute treatment of a single migraine attack were free of pain 2 hours postdose than patients who received zolmitriptan 2.5mg or naratriptan 2.5mg. Compared with zolmitriptan recipients, more rizatriptan recipients had pain relief after 1 hour (but not at 2 hours). Compared with naratriptan recipients, more patients who received rizatriptan were pain free or had pain relief from 1 hour onwards. More patients receiving rizatriptan were likely to be free of pain or experience pain relief sooner than patients receiving naratriptan [odds ratios (ORs) 2.68 and 1.62] but not with zolmitriptan (1.26 and 1.22).

In the earlier comparative studies with sumatriptan, 32 to 48% of patients receiving rizatriptan 5 or 10mg were functioning normally 2 hours postdose, compared with 33 to 43% of sumatriptan 25 to 100mg recipients. In one trial, more patients who received rizatriptan 10mg had normal functional ability at 2 hours than those who received sumatriptan 100mg or rizatriptan 5mg. The effects of rizatriptan 5 or 10mg at 2 hours on most migraine associated symptoms, except nausea, were similar to the respective comparative doses of sumatriptan. The incidence of nausea at 2 hours was lower after rizatriptan 5 and 10mg than after sumatriptan 100mg in one study. In another trial, the incidence of nausea at 2 hours was lower when rizatriptan 5mg was compared with sumatriptan 25mg, but not when rizatriptan 10mg was compared with sumatriptan 50mg.

In more recent studies, the number of patients with normal functional ability at 2 hours was higher after rizatriptan than after naratriptan or zolmitriptan. Compared with zolmitriptan, rizatriptan was associated with a lower incidence of nausea or photophobia at 2 hours. Rizatriptan was associated with a lower incidence of photophobia or phonophobia than naratriptan at 2 hours. The incidence of migraine recurrence within 24 hours of the initial dose was similar among patients treated with rizatriptan or zolmitriptan, but lower with naratriptan. A retrospective analysis of five double-blind trials concluded that rizatriptan 10mg was more effective than oral sumatriptan 25, 50 or 100mg or naratriptan 2.5mg, but not zolmitriptan 2.5mg, at eliminating nausea within 2 hours of a migraine attack in patients with nausea at baseline. In another retrospective analysis of five clinical trials that compared the same treatment regimens, more rizatriptan recipients had a 24-hour sustained pain-free response than patients who received sumatriptan 25 or 50mg, naratriptan or zolmitriptan. Although 24-hour sustained pain-free rates were higher in rizatriptan recipients than in sumatriptan 100mg recipients, the difference did not achieve statistical significance.

In a large noncomparative trial involving 25 501 evaluable patients who treated up to three attacks, the proportion of patients who reported feeling the first effects (a definition of pain relief was not provided) of rizatriptan within 30 minutes during the first and third attacks was 32.3 and 43.9%. Corresponding values for pain relief between 30 minutes and 1 hour were 43.1 and 38.5%.

The efficacy of rizatriptan was not affected by long-term administration. In a nonblind extension study, 458 patients with migraine treated multiple attacks (a total of 8229) with rizatriptan 5 or 10mg or usual therapy [85% of patients in the usual therapy group used sumatriptan (dose not specified) either alone or in combination with other agents to treat most of the attacks (77%)] over a 6-month period. The median percentage of attacks in which rizatriptan 10mg recipients reported pain relief or an absence of pain 2 hours after the dose was 82 and 46%; corresponding values among recipients of rizatriptan 5mg (72 and 25%) or usual therapy (73 and 30%) were lower. ORs showed rizatriptan 10mg was more likely to provide pain relief or an absence of pain at 2 hours than rizatriptan 5mg (1.60 and 1.93) or usual therapy (1.63 and 1.50).

In a meta-analysis of 53 double-blind clinical trials (involving rizatriptan, sumatriptan, eletriptan, almotriptan, zolmitriptan and naratriptan), rizatriptan 10mg, eletriptan 80mg and zolmitriptan 2.5mg were better at providing headache relief within 2 hours than sumatriptan 100mg, against which all the triptans were compared. Although headache recurrence rates were higher with rizatriptan 5 or 10mg than with sumatriptan 100mg, 24-hour sustained pain-free rates were higher with rizatriptan 10mg, almotriptan 12.5mg and eletriptan 80mg than with sumatriptan 100mg. In an analysis of multiple-attack studies (data were not available for rizatriptan 5mg, sumatriptan 25 or 50mg or zolmitriptan 2.5 or 5mg) rizatriptan 10mg was shown to provide the highest consistent therapeutic response when compared with sumatriptan 100mg.

In another meta-analysis of 28 clinical trials, in which the primary efficacy variable analysed was the proportion of patients who were pain free at 2 hours, rizatriptan 10mg was the only triptan associated with a higher therapeutic gain than oral sumatriptan 100mg, against which all the studied triptans (oral sumatriptan 50mg, zolmitriptan 2.5 or 5mg, naratriptan 2.5mg, eletriptan 20, 40 or 80mg or almotriptan 12.5mg) were compared.

Two retrospective analyses have demonstrated that rizatriptan is effective in the treatment of menstrual migraine (i.e. migraine that is exacerbated around the time of menses). Rizatriptan 5 and 10mg were more effective than placebo at relieving a single migraine attack that occurred within 3 days of menstruation according to a retrospective subgroup analysis of two double-blind studies. Furthermore, a retrospective analysis of a long-term extension study showed rizatriptan 10mg to be as effective in the treatment of multiple menstrually associated migraine attacks as it was in the treatment of multiple nonmenstrual attacks.

Rizatriptan is generally well tolerated and adverse events are usually mild and transient. Earlier studies showed that the incidence of drug-related adverse events in patients who received rizatriptan 5 or 10mg or oral sumatriptan 25 or 50mg were similar, but lower with both doses of rizatriptan than with sumatriptan 100mg, and that the most common adverse events associated with rizatriptan were CNS-or gastrointestinal-related.

More recent studies showed that rizatriptan 10mg was also well tolerated in the two double-blind trials with zolmitriptan and naratriptan. The most common adverse events associated with rizatriptan, zolmitriptan or naratriptan were CNS-or gastrointestinal-related, and included asthenia/fatigue, dizziness, somnolence and nausea. These adverse events were, however, reported by relatively small percentages of patients (≤8%). There was a trend towards a lower incidence of adverse events with rizatriptan compared with zolmitriptan (31.2 vs 38.8%). However, rizatriptan was associated with a higher incidence of adverse events than naratriptan (39 vs 29%).

Rizatriptan 10mg was well tolerated in a large noncomparative study in 33 147 patients who treated up to three moderate or severe migraine attacks. 304 patients (0.9%) reported at least one adverse event. The most frequent were dizziness, asthenia/fatigue and nausea which occurred in 0.21, 0.17 and 0.11% of patients, respectively.

In the two recent double-blind studies, the incidence of chest pain (a feeling of tightness or pressure in the chest) was similar after the administration of rizatriptan, zolmitriptan or naratriptan (2 to 4%). In the noncomparative study in 33 147 patients, chest pain was reported by only 0.05% of patients.

Rizatriptan is indicated for the treatment of migraine with or without aura in adults. It is available in 5 or 10mg doses in standard tablet form or as orally disintegrating tablets (wafers).

The recommended initial dose is 5 or 10mg, and dose selection should be made on a per patient basis. If required, additional doses for headache recurrence should be separated by at least 2 hours; no more than 30mg should be taken during a 24-hour period. The use of rizatriptan for the treatment of more than four migraines in a 30-day period has not been established. Dose adjustments based solely on age are not considered necessary in elderly patients.

Rizatriptan, like all 5-HT_1B/1D receptor agonists, is contraindicated in patients with ischaemic heart disease, any other significant underlying cardiovascular disease, uncontrolled hypertension or hemiplegic or basilar migraine. It should be used with caution in patients on dialysis, with moderate hepatic impairment or those reporting signs or symptoms of angina.

Coadministration of rizatriptan with MAO inhibitors (within 2 weeks), ergot derivatives or other 5-HT_1B/1D receptor agonists (within 24 hours) is contraindicated. Coadministration with propranolol increases plasma concentrations of rizatriptan by 75%; therefore patients receiving propranolol should be prescribed rizatriptan 5mg. Observation of patients is advised if rizatriptan is coadministered with selective serotonin reuptake inhibitors, as symptoms of the serotonin syndrome have been reported.