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WYETH-AYERST’s ISMO (ISOSORBIDE MONONITRATE) FOR ANGINA WILL BE AVAILABLE IN MID-MARCH; BOEHRINGER-MANNHEIM WILL COPROMOTE TWICE-DAILY NITRATE COMPOUND

Executive Summary

Wyeth-Ayerst's twice-daily anti-anginal nitrate compound ISMO (isosorbide mononitrate) will be available in pharmacies in mid- March and will be "priced competitively" with other long-acting nitrate compounds, Wyeth-Ayerst said Jan. 2. ISMO was approved by FDA on Dec. 30 after a review period that began with an initial NDA filing on Dec. 28, 1983. The NDA subsequently was resubmitted on April 14, 1987. ISMO is indicated for the prevention of chronic, stable angina pectoris "due to coronary artery disease" The nitrate compound is not approved for aborting acute anginal episodes due to its slow onset of action (one hour). The clinical pharmacology section of ISMO's approved labeling states that isosorbide mononitrate is the "major active metabolite of isosorbide dinitrate...and most of the clinical activity of the dinitrate is attributable to the mononitrate." ISMO was given FDA's "1C" designation (new molecular entity with little or no therapeutic gain over existing therapies). Wyeth-Ayerst licenses ISMO from Boehringer Mannheim GmbH. Boehringer Mannheim Pharmaceuticals Corp., the German company's newly spun-out U.S. pharmaceutical arm, will copromote ISMO as one of its first U.S. commercial operations. Former Beecham President Ted Wood is joining Boehringer Mannheim's U.S. pharmaceutical business on Jan. 13 as president ("The Pink Sheet" Dec. 23, T&G- 6). ISMO is the first nitrate compound for the prevention of angina approved in 30 years, Wyeth-Ayerst said. Isosorbide dinitrate has been on the market for a number of years. The company's brand is Isordil. ICI Pharma markets an isosorbide dinitrate product under the Sorbitrate brand and more than a half- dozen generic versions also have been approved. On Dec. 26, Roberts Pharmaceuticals announced the completion of an agreement in principle with Wyeth Labs-U.K. to acquire four prescription products for sale in the U.K., including Isordil (see related T&G). The recommended dosing regimen for ISMO tablets is 20 mg (one tab) twice daily, seven hours apart. The anti-anginal effect begins one hour after dosing and reaches its peak from one-to-four hours after administration. Dosing adjustments are not necessary for elderly patients or those with "altered renal or hepatic function," labeling notes. Discussing ISMO's pharmacodynamics, labeling states that "the drug-free interval sufficient to avoid tolerance...has not been completely defined." The only dosing regimen for the twice- daily drug that did not show tolerance development was two doses given seven hours apart. "The same twice-daily regimen of ISMO tablets successfully avoided significant rebound/withdrawal effects," labeling states. ISMO was studied in placebo-controlled clinical trials lasting two to three weeks where the drug was administered in asymetric regimens (dosing intervals of seven and 17 hours) designed to avoid tolerance, labeling states. One trial tested 10 mg and 20 mg doses twice daily; another study tested 20, 40 and 60 mg doses two times a day; and three trials looked only at 20 mg doses twice daily. For at least three weeks into the trials, exercise tolerance in patients treated with ISMO 20 mg tabs "was significantly greater" than with placebo, "although there was some attentuation over time," labeling states. FDA's Dec. 30 approval letter notes that Wyeth-Ayerst, in a Dec. 27 letter to the agency, agreed to meet with FDA's Cardio- Renal Drug Products Division "to identify a study design that would enhance the current instructions for use." FDA noted that "it is understood that this study would be designed to obtain additional dose-ranging data." Labeling points out that in clinical trials, ISMO has not been "adequately" studied "in single doses less than 20 mg...while single doses greater than 20 mg have demonstrated no greater efficacy than doses of 20 mg."

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