Pharmacology Update

Rizatriptan Benzoate for Migraine

By William T. Elliott, MD, and James Chan, PharmD, PhD

On june 29, 1998, the fda approved rizatriptan, the fourth "triptan" approved for the treatment of acute migraine with or without aura. Rizatriptan, marketed as Maxalt by Merck & Co., is available in two formulations-conventional tablets and a lyophilized orally disintegrating tablet (Maxalt-MLT), which disintegrates within seconds on the tongue. The Maxalt-MLT delivery system, which was developed by R.P. Scherer using its Zydis technology, does not offer a faster onset of action than the conventional tablets but may offer a more easily administered dosage form (i.e., can be taken without water), especially in the midst of a migraine headache.

Rizatriptan is a selective agonist at 5-hydroxytryptamine 1D/1B (5HT1D/1B) receptors. Its pharmacologic profile is similar to that of other "triptans," such as sumatriptan, zolmitriptan, and naratriptan. Rizatriptan does not appear to possess any significant activity at other 5HT receptor subtypes including adrenergic, dopaminergic, muscarinic, or benzodiazepine receptors.1 Its mechanisms of action may involve inhibition of dural neurogenic inflammation, constriction of intracranial, extracerebral blood vessels, and direct attenuation of excitability of cells in the trigeminal nuclei1.2

Potential Advantages

Rizatriptan is well absorbed after oral administration either as the conventional tablets or the oral disintegrating tablets (Maxalt-MLT). The average oral bioavailability is about 40-45%. Peak plasma concentrations are achieved in 1-1.5 hours with the conventional tablets and a slower 1.6-2.5 hours with the oral disintegrating tablets.1 This compares to bioavailability and time to peak concentrations of 10-25% and 1.25-2.29 hours, respectively, for oral sumatriptan.4 In a recent review, an author tentatively concluded that rizatriptan may have better intra-patient consistency compared to sumatriptan.2

Some data suggest that rizatriptan 5 mg and 10 mg conventional tablets may have a faster onset of action than sumatriptan 25 mg and 50 mg.9,10 For example, patients receiving rizatriptan 5 mg and 10 mg were 16% and 14% more likely to gain pain relief within two hours than sumatriptan 25 mg and 50 mg, respectively.10

In vitro data suggest that rizatriptan has greater differential in the therapeutic concentration needed to produce a therapeutic response vs. an adverse response (coronary artery constriction) compared to sumatriptan. For example, there is a 12-fold difference for rizatriptan and four-fold difference for sumatriptan.5,6

Potential Disadvantages

The headache recurrence rates for rizatriptan 5 mg and 10 mg are 44% and 47%, respectively.7 In a comparative trial, the recurrence of headache was found to be 41% for both rizatriptan 10 mg and sumatriptan 100 mg.8 The median times from initial doses to the onset of headache recurrence were 14 hours (3-21) and 19 hours (6-23), respectively. This may be related to rizatrptan's short elimination half-life of 2-3 hours. The estimated probability of remedication 24 hours after the initial dose was 55-70% for rizatriptan compared to placebo (70-75%).1 The report values for naratriptan and zolmitriptan, in noncomparative trials, were 40-60% vs. 78% and 35-59% vs. 60%, respectively.11,12 The most common side effects compared to placebo were asthenia/fatigue (4-7% vs 2%), somnolence (4-8% vs 4%), pain/pressure sensation (6-9% vs 3%), and dizziness (4-9% vs 5%).1

Dosing Information

Rizatriptan is available as 5 mg and 10 mg tablets, both as conventional tablets and orally disintegrat-ing/rapidly dissolving tablets. The recommended dose is 5 or 10 mg. Clinical trials indicate a higher response rate for the 10 mg dose. The choice of dose should be made on an individual basis, balancing effectiveness and side effects. If the headache recurs, a second dose may be taken anytime after two hours of the initial dose. No more than 30 mg should be taken in a 24-hour period.1 Patients taking propranolol should use the 5 mg tablets only and a maximum of 15 mg in 24-hours.1 Food delays the rate of absorption of rizatriptan; the time to peak concentration is delayed by an hour.1,3

Patients who do not respond to the first dose should not take a second dose without consulting with their physician, as the diagnosis of migraine should be reevaluated.1

Comments

Rizatriptan is the fourth "triptan" to be approved by the FDA. Clinical trials report the end points of headache relief (improved from moderate or severe to mild or no headache) and complete headache relief (no pain). The headache relief rates for the conventional tablets, 5 mg and 10 mg, compared to placebo at two hours were 60-62% and 52-77% compared to 18-47%.1 Complete pain relief rates were 26% and 26-49% compared to 3-15% for placebo.7,8 The rate for the oral 10 mg disintegration tablets was 66% compared to 47% for placebo.1 Headache recurrence rate appears to be similar to sumatriptan and also similar to other "triptans." Rizatriptan is generally well tolerated. The oral disintegrating tablet is a novel formulation, but efficacy data are limited, and it actually has a slower rate of absorption and a numerically lower estimated probability for response at two hours compared to the conventional tablets.1

Clinical Implications

Rizatriptan offers another "triptan" for the treatment of migraine headaches. It appears to be at least as effective as sumatriptan with similar headache recurrence rates. Limited data have compared rizatriptan 5 mg to 25 mg of sumatriptan and 10 mg to 50 and 100 mg of sumatriptan. Merck may promote the oral disintegrating tablets for its convenience, although it offers no clinical advantage (i.e., onset of action or response rate) over the conventional tablets. Comparative trials are needed to determine if one of the new triptans will emerge as a "better" agent.

The average wholesale cost of rizatriptan is $14 per tablet for all strengths and forms. The drug is priced competitively with sumatriptan 50 mg tablets.

References

    1. Maxalt Product Information. Merck & Co., Inc. June 1998.

    2. Ferrai MD. Lancet 1998;351:1043-1051.

    3. Cheng H, et al. Biopharm Drug Dispos 1996;17:17-24.

    4. Perry GM, Markham A. Drugs 1998;55(6):889-922.

    5. Longmore J, et al. Funct Neurol 12(1):3-9.

    6. Longmore J, et al. Br J Clin Pharmacol 1996;42:431-441.

    7. Teall J, et al. Headache 1998;38:281-287.

    8. Visser WH, et al. Arch Neurol 1996;53:1132-1137.

    9. Goldstein J. American Academy of Neurology 50th annual meeting. April 30, 1998.

    10. Norman BA, et al. Neurology 1998;50(4, Supp 4):A341.

    11. Amerge Product Information. Glaxo Wellcome Inc. January 1998.

    12. Zomig Product Information. Zeneca Pharmaceuticals. November 1997.