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Conrad Notes
a timely medical meeting newsletter
NEW TRIPTANS FOR TREATING MIGRAINE
J.K. Campbell, MD, Mayo Clinic, Rochester, Minn, moderated the symposium on the triptan class of drugs. Triptans are selective serotonin (5-HT) receptor agonists. At present, the class includes sumatriptan (SUMA) marketed as US Imitrex® and Imigran® and four US investigational triptans. Naratriptan (NARA) and zolmitriptan (ZOLI) are probably closer to FDA approval and marketing than eletriptan (ELE) and rizatriptan (RIZA). The symposium, a medical meeting first, had pharmaceutical companies present research status reports to experts on migraine.

Eletriptan (ELE) Clinical Pharmacology Data on ELE tablets show linear pharmacokinetics. The time to maximum blood concentration (Tmax) is one hour and the half-time of elimination (T1/2) is 5 hours. A single ELE tablet of 20 mg approximates 100 mg SUMA in producing pain relief at two hours, improved functioning, and patient agreement to again take the assigned medication. The 40- and 80-mg ELE doses appear to work more quickly than the SUMA reference. All drug doses proved significantly superior to placebo. Recurrence of migraine in patients who responded within two hours was about 33% for all treatment groups.

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.

Naratriptan (NARA) Efficacy and Safety Experience with sumatriptan helped guide the development of an improved congener having a half-life of 6 hours and oral bioavailability of 63% to 74%. Phase III studies showed a dose-related, statistically significant increase in the proportion of patients with relief of migraine headache, compared with placebo, using 1.0- and 2.5-mg NARA tablets.

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

In addition, use of 2.5 mg NARA in an open-label, 12-month study on 417 patients (15,301 migraine attacks) resulted in 70% of the patients reporting relief.

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.

Rizatriptan (RIZA) Supporting Data Dose-finding studies (Phase II) prompted clinical evaluation of 5- and 10-mg tablets. RIZA showed a 45% bioavailability in healthy volunteers. In Phase III studies, compared with placebo, 5 mg and 10 mg doses were significantly better in providing pain relief at two hours. About 50% of the RIZA patients reported pain relief within one hour and 80% by two hours postdose. With 4 attacks, 75% to 80% responded with 48% to 55% attaining a pain-free status at two hours. Double-blind, single dose comparative studies with sumatriptan (SUMA) show that 5 mg RIZA and 50 mg SUMA are comparable and 10 mg RIZA is superior to 100 mg SUMA. RIZA is well-tolerated. The usual 5-HT agonist adverse drug events (ADEs) occurred with RIZA and were related to the administered dose. Propanolol increases RIZA blood levels by 70%. Please consult the accompanying information on sumatriptan, Imitrex® Tablets.

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.

Clinical Experience with Zolmitriptan (ZOLI) This 5-HT receptor agonist is absorbed up to 75% using 2.5- and 5.0-mg tablets. The onset of migraine headache relief occurs within one hour and continues to improve over the next three hours. Some pain relief was reported by 60% of the patients at two hours postdose. About 44% experienced complete pain relief, free of recurrence within 24 hours of dosing, with either ZOLI tablet compared with 16% in the placebo group. In general, headache recurrence after ZOLI was about 30% and similar to that of other triptans. Safety data on 25,000 ZOLI-treated migraine headaches show no significant changes in blood pressure or ECG even with long-term use. According to the presenter, administration of ZOLI tablets leads to a well-defined dose-response curve, a rapid onset of action, and predictable efficacy.

Comments This symposium on four new 5-HT type 1 receptor agonist drugs represents a first in medical meeting history. Inclusion of data on sumatriptan (SUMA), the only US-marketed medication of the triptan class, gave the audience an opportunity to compare the newcomers with a reference besides placebo. See "Treatment of Migraine Headache: Sumatriptan (SUMA)" in this issue of CONRAD NOTES.

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.

For professional correspondence, please contact the publisher at: conradnotes@worldnet.att.net

Eugene A. Conrad

Presented at Thirty-ninth Annual Scientific Meeting, American Association for the Study of Headache (AASH), June 19-22, 1997
Copyright © 1997 Conrad Group, Inc. All Rights Reserved
Eugene A. Conrad, PhD, MPH / ISSN 1078-2230 / September 1997

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