Merck Maxalt 30-Minute Onset Of Action Cited In Dutch Labeling

Merck's Maxalt has a 30-minute onset of action, Dutch labeling for the migraine therapy states.

Maxalt (rizatriptan) was approved in the Netherlands Feb. 12 for "acute treatment of the headache phase of migraine attacks with or without aura." Merck's entry into the 5-HT1D agonist class is pending at FDA with a user fee review deadline in June.

A 30-minute onset of action claim would differentiate Maxalt from other oral therapies in the U.S. Glaxo Wellcome's Imitrex (sumatriptan) tablet labeling cites onset of relief (defined as little or no migraine pain) within one to one-and-a-half hours. Sumatriptan is also available in injectable and nasal spray formulations with a more rapid onset of relief.

Glaxo's follow-on Amerge (naratriptan) tablets are being positioned based on duration of action: labeling does not reference a specific onset time. Similarly, Zeneca's Zomig (zolmitriptan) labeling does not cite an onset time shorter than two hours.

Maxalt will be available in 5 mg and 10 mg strengths in tablet and rapidly dissolving wafer formulations.

Maxalt's Dutch labeling cites response rates of 67%-77% for the 10 mg dose and 60%-63% for the 5 mg dose, compared to 23%-40% for placebo. Maxalt was approved in the Netherlands based on four pivotal studies in more than 2,000 patients.

Merck did not study repeat dosing of Maxalt in nonresponders, Dutch labeling states. "Although patients who did not respond to initial treatment with Maxalt were not redosed for the same attack, they were still likely to respond to treatment for a subsequent attack."

At the June 1997 meeting of the International Headache Society in Amsterdam, Merck reported results from a pivotal multiple attack study. "Of the patients who did not respond in the first attack, 70% responded to rizatriptan during the second attack, which indicated that nonresponse in the first episode did not predict nonresponse during a subsequent episode," Merck said.

Only 4% of patients failed to respond to Maxalt in any of four attacks, the company said ("The Pink Sheet" June 16, 1997, T&G-9).

Maxalt has a plasma half-life comparable to that of Imitrex and Zomig. The rizatriptan plasma half-life "averages 2-3 hours," the label states. Imitrex' half-life is 2.5 hours, and Zomig's is three hours.

Amerge has a half-life of six hours, and is being positioned as an alternative to patients who require repeat dosing for efficacy. However, Zomig labeling in the U.S. suggests comparable single-dose efficacy ("The Pink Sheet" Feb. 16, p. 3).

Rizatriptan is contraindicated in patients with previous cerebrovascular accidents or transient ischemic attacks. Like Amerge, Maxalt is contraindicated in patients with severe hepatic insufficiency.

Maxalt also carries a class contraindication for patients with uncontrolled hypertension, "established" coronary heart disease or peripheral vascular disease.

The "special warnings" segment of the Maxalt label refers to "rare reports of serious coronary events with another drug in this class." Although "such events were not observed in clinical trials with Maxalt," the labeling recommends a cardiovascular assessment in patients before prescribing the drug.

Maxalt carries a propranolol drug interaction warning because both drugs are metabolized via monoamine oxidase, resulting in increased plasma concentrations of rizatriptan.

As a result, the 5 mg dose is recommended for patients taking propranolol. The Maxalt label notes that no pharmacokinetic interaction was observed in patients taking the beta-blockers nadolol or metoprolol, and that none is expected in timolol or atenolol patients.

The 5 mg dose is also recommended for patients with mild, moderate or severe renal insufficiency or mild-to-moderate hepatic insufficiency. Labeling notes, however, that the "efficacy of the 2.5 mg dosage did not differ significantly from placebo."

The most common Maxalt side effects were dizziness, somnolence and asthenia/fatigue, labeling states.

Merck expects to launch Maxalt in the Netherlands in about three months, pending the resolution of pricing and reimbursement negotiations. The dossier is undergoing mutual recognition review in the remaining European Union member states.