Rizatriptan (Maxalt® | Maxalt-MLT™)

Classification:
» Neurological Agents
» Serotonin-Receptor Agonists

Description: Rizatriptan (MK-462) is a central serotonin-receptor 1B and 1D agonist. It is indicated for the treatment of acute migraine attacks with or without aura. Rizatriptan is not indicated for prophylactic therapy of migraine or for the treatment of hemiplegic or basilar migraines or cluster headaches. The efficacy and side effect profile of rizatriptan seems to be dose-dependent with the 10 mg dose being slightly more effective and causing a slight increase in adverse effects as compared to the 5 mg dose. Rizatriptan is more lipophilic than sumatriptan leading to a greater bioavailability and increased central nervous system penetration. When compared to those receiving sumatriptan 50 mg, more patients receiving rizatriptan 10 mg achieved headache pain relief within 2 hours (69.3% vs. 74.8%, respectively). In addition, rizatriptan 10 mg decreased the incidence of migraine-associated symptoms (nausea, photophobia, phonophobia) 0.5 - 1 hour postdose to a greater extent than sumatriptan 100 mg. Rizatriptan is not FDA approved for use in children. However, results from a double-blind, placebo-controlled, crossover trial demonstrated that rizatriptan was effective for the treatment of migraine attacks in pediatric patients 6 - 17 years of age. Studies comparing rizatriptan to other serotonin 1B/1D agonists have not been performed. Rizatriptan causes less sustained coronary artery constriction than dihydroergotamine and ergotamine. Rizatriptan was approved by the FDA in June 1998. Both tablets (Maxalt®) and orally disintegrating tablets (Maxalt-MLT™) are available.

Mechanism of Action: Rizatriptan is a selective 5-hydroxytryptamine 1B/1D (5-HT 1B/1D) receptor agonist. It has very weak activity at other 5-HT receptors, but has no activity at alpha, beta, dopaminergic, histaminergic, muscarinic, or benzodiazepine receptors. The pathophysiology of migraine is not completely understood, and therefore the action of the serotonin-agonists (i.e., ‘triptans’ ) in treating migraine is not completely certain. Multiple pharmacological actions have been derived that appear important for antimigraine effects. ‘Triptans’ stimulate presynaptic 5-HT1D receptors, an action that inhibits both dural vasodilation and inflammation. They directly inhibit trigeminal nuclei cell nociceptive neurotransmission via 5-HT1B/D receptor agonism within the trigeminocervical complex of the brainstem and upper spinal cord. Additionally, vascular 5-HT1B receptor agonism results in vasoconstriction of painfully dilated intracranial extracerebral vessels. Although rizatriptan has little effect on other 5-HT receptors, activation of coronary 5-HT 1B receptors could result in clinically significant cardiac events in patients with cardiac disease or risk factors for cardiac disease. However, it appears the cardiac effects of rizatriptan in vitro are less than those of sumatriptan. Maxalt MLT Orally Disintegrating Tablet (Tab Orally 10 mg)

Pharmacokinetics: Rizatriptan is administered orally; there are two distinct solid oral dosage forms. Rizatriptan is rapidly absorbed orally with a bioavailability of about 45%. The time to peak plasma concentrations is approximately 1 - 1.5 hours. Food does not affect the availability of rizatriptan but delays the time to peak concentration by an hour and increases AUC. The bioavailability and peak plasma concentrations are similar between Maxalt® tablets and Maxalt-MLT™ disintegrating tablets; however, the time to peak plasma concentration is longer with the Maxalt-MLT™ disintegrating tablets with a time to peak plasma concentration of 1.6 - 2.5 hours. The AUC and maximum plasma concentration of rizatriptan is 30% and 11%, respectively, higher in females than in males. There is no accumulation of rizatriptan with repeated dosing. Rizatriptan is metabolized via oxidative deamination by monoamine oxidase-A (MAO-A) to the inactive indoleacetic acid metabolite and to a small degree, to N-monodesmethyl-rizatriptan which has similar activity as the parent compound. Rizatriptan undergoes significant first pass metabolism with only 14% of the oral dose excreted in the urine as unchanged drug and 51% is excreted as the indole acetic acid metabolite. The half-life of rizatriptan averages 2 - 3 hours. Rizatriptan is a competitive inhibitor of cytochrome P450 2D6 but only at high, clinically irrelevant concentrations. Rizatriptan does not inhibit P450 isoforms 3A4/5, 1A2, 2C9, 2C19, or 2E1.

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References
_{. Norman BA, Block GA, Jiang K et al. Two-period crossover comparison of rizatriptan 5 mg and 10 mg to sumatriptan 25 mg and 50 mg for the acute treatment of migraine. Neurology 1998;50 (4 Suppl 4):A341.}

. Visser WH, Jiang K. Effect of rizatriptan versus sumatriptan on migraine-associated symptoms. Headache 1998;38:409.

. MaassenVanDenBrink A, Reekers M, Bax WA et al. Coronary side-effect potential of current and prospective antimigraine drugs. Circulation 1998;7:25 - 30.

. Longmore J, Hargreaves RJ, Boulanger CM et al. Comparison of the vasoconstrictor properties of the 5-HT1D-receptor agonists rizatriptan (MK-462) and sumatriptan in human isolated coronary artery: outcome of two independent studies using different experimental protocols. Funct Neurol 1997;12:3 - 9.

. Tepper SJ. Mechanisms of action of the 5-H1B/1D receptor agonists. Arch Neurol 2002;59:1084 - 8.

. Ahonen K, Hamalainen ML, Eerola M, et al. A randomized trial of rizatriptan in migraine attacks in children. Neurology 2006;67:1 - 6.

Rizatriptan (Maxalt® | Maxalt-MLT™)

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