Dose ranging with ELE

By two hours, the severity of migraine headache decreased to mild or none from moderate to severe in 54% of the patients given a single 20-mg dose compared with 24% after placebo. The relief and overall improvement in functioning resembled that seen with 100 mg SUMA. Sponsor data show 66% of the ELE patients wanted to take 20 mg again as a treatment for migraine.

The 40- and 80-mg ELE doses led to 38% and 41% of the patients respectively, to respond by one hour compared with 20% for the 100 mg SUMA group. Patient desire to treat a second attack with ELE rose to 74% with the 40-mg tablet and to 84% with the 80-mg tablet.

Adverse drug events (ADEs) with ELE dosing

Similar percentages of patients reported ADEs after single doses of 20 and 40 mg ELE. ADEs occurred in 34% and decreased to 26% and 23% respectively, when assessed as treatment-related.

Thirty-seven percent of the 80-mg ELE group had ADEs. As reference, 100 mg SUMA led to an all causality incidence of 40% and treatment-related, 29%. Asthenia developed in 10% and paresthesia in 7% of the patients treated with 80 mg ELE.

A single 2.5 mg dose led to 60% to 68% of the patients reporting headache relief (pain scores of moderate to severe reduced to mild or none) over a 4-hour period. Relief was reported with this dose of NARA at the 24-hour time point in 43% to 52% of the patients. A 1.0-mg dose was less effective but also superior to placebo. The observed headache recurrence rate after a single 2.5 mg dose of NARA was 19% to 28% between 4 hours and 24 hours post-dose.

Data on 3,920 patients in controlled clinical trials showed that the frequency and types of adverse drug events (ADEs) with NARA did not differ significantly from placebo. Please consult the accompanying information on sumatriptan, Imitrex^® Tablets.

Efficacy of oral NARA

Over 2,500 patients with severe to moderate migraine pain participated in three double-blind, well-controlled Phase III trials. One study involved single NARA doses of 0.1, 0.25, 1.0, and 2.5 mg for comparison with placebo. A three-attack evaluation compared the same doses of NARA with 100 mg sumatriptan (SUMA) and placebo. Another study in patients with four attacks of migraine used a crossover design comparing placebo and three dose levels of NARA.

Analysis of the results showed:

• 0.1 and 0.25-mg doses were ineffective as studied

• 1.0 mg was effective and 2.5 mg rated optimal based on 4-hour and 24-hour headache relief; both doses were significantly superior to placebo

• significantly more patients reported headache relief, compared with placebo, beginning at one hour with percentages of responders increasing over the first 4 hours; thereafter, the relief was maintained at all time points for 24 hours

• recurrence was 19% in one study on 1,222 patients for the 2.5-mg dose of NARA vs 36% for SUMA over a period of 24 hours

• consistent antimigraine activity followed 1.0- and 2.5-mg doses in the three- and four-attack studies

Safety of NARA tablets

The incidence of adverse events with NARA does not increase with multiple dosing nor does it differ from placebo. Cardiovascular and chest symptoms occurred in one per cent or less of the patients treated with 1.0 or 2.5 mg. One per cent or less of the patients medicated with 1.0 or 2.5 mg NARA reported a tingling sensation. Vital signs, ECG, and clinical laboratory results were comparable to those seen with placebo.

Comparison with SUMA tablets

Single doses of placebo, 5 and 10 mg RIZA, and 100 mg SUMA were evaluated in a double-blind, well-controlled parallel design study. Data on 1,100 patients showed:

• time to pain relief fastest with 10 mg RIZA

• relief from pain significant at one hour only with 10 mg RIZA; at 1.5 hours to 2 hours, RIZA was superior to SUMA in providing freedom from pain

• improved functionality at two hours with both doses of RIZA and 100 mg SUMA noted superior to placebo; 10 mg RIZA was better than 5 mg RIZA and 100 mg SUMA

Low dose comparison

Five mg RIZA, 50 mg SUMA, and placebo were compared in a well-controlled study on 933 migraine patients. Both active medications proved to be comparable in the percentage of patients reporting mild or no pain at 4 hours and were significantly better than placebo.

RIZA vs usual care

In three single-dose extension studies totalling 1841 migraine patients, RIZA led to higher response rates than seen with usual care. Although not blinded, data covering 40,000 attacks showed median pain relief response rates of: usual care,70%; 5 mg RIZA,80%; and 10 mg RIZA,90%. About 76% of the usual care patients had been treated previously with SUMA, according to the presenter.

Safety of RIZA tablets

Experience with RIZA in controlled and open studies show the usual 5-HT type 1 agonist adverse events. Generally, the ADEs were mild to moderate, transient, and resolved spontaneously. Chest pain, tightness, or heaviness occurred in 3% of the patients on placebo, 1% with 5 mg and 3% with 10 mg RIZA, 5% with 50 mg and 6% with 100 mg SUMA, respectively. Because propanolol increases RIZA blood levels by 70%, it is contraindicated as a comedication with the 10-mg RIZA tablet.

Is it too early to compare the newer triptans with the original member of the class, sumatriptan (SUMA)? Recent development of a SUMA nasal spray eases patient use and hastens pain relief which are improvements over the currently available subcutaneous and oral preparations.

Recurrence of pain within two to three hours after a single triptan dose, occurs in about 40% to 50% of migraine patients, according to Campbell. Will the improved bioavailability and longer half-life of elimination seen with NARA result in a decrease in pain recurrence? These and other questions prompt Campbell to suggest holding a second symposium on new triptans in 1999 which would include clinical investigator comments and possible debate.