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LEDERLE’s ONE-A-DAY BETA BLOCKER ZEBETA (BISOPROLOL) APPROVED ON JULY 31 FOR HYPERTENSION; LABELING INDICATES SAFETY/EFFICACY IN ELDERLY AND BLACK POPULATIONS

Executive Summary

Lederle's once-a-day beta blocker Zebeta (bisoprolol) was approved on July 31 after three years of review as a treatment for hypertension either alone or in combination with other antihypertensive agents. Zebeta will be available in 5 mg and 10 mg tablets for oral administration. The recommended starting dose is 5 mg, but approved labeling states that "the dose of Zebeta must be individualized to the needs of the patients." Lederle is not yet disclosing marketing plans or pricing for the new beta blocker. The company announced in March the formation of a new 500-person sales force, Advantus Pharmaceuticals, which participated in the launch of the ProStep nicotine patch ("The Pink Sheet" March 16, T&G-11). The Advantus logo appears on the Zebeta labeling. The new sales force provides Lederle with the opportunity to use separate sales forces to launch Zebeta while continuing to detail the sustained release calcium channel blocker Verelan (verapamil), which Lederle co-promotes with Wyeth-Ayerst. Zebeta received a unanimous approval recommendation for the management of hypertension from FDA's Cardio-Renal Drugs Advisory Committee over a year ago on June 6, 1991 ("The Pink Sheet" June 10, 1991, p. 5). The committee also recommended approval for Lederle's fixed combination of bisoprolol and low dose hydrochlorothiazide as single-agent treatment. The combination product is still pending at FDA. Lederle filed the bisoprolol fumarate NDA (19-982) in July 1989 and the combination product NDA (20-186) in April 1991. The company also filed for approval of Zebeta for use in treating angina and coronary artery disease. Zebeta is the third brandname Lederle has tagged on the bisoprolol during the drug's development; the beta blocker also has been referred to as Probeta and Monocor. The FDA-approved labeling describes Zebeta as "a beta- selective (cardioselective) adrenoceptor blocking agent without significant membrane stabilizing activity or instrinsic sympathomimetic activity in its therapeutic dosage range." The labeling points out that Zebeta's "cardioselectivity is not absolute, however, and at higher doses (greater than or equal to 20 mg) bisoprolol fumarate also inhibits beta-2-adrenoceptors, chiefly located in the bronchial and vascular musculature: to refrain selectivity it is therefore important to use the lowest effective dose." In a pivotal trial of bisoprolol as monotherapy, 276 patients were treated with either 5 mg, 10 mg, or 20 mg bisoprolol or placebo and measured for changes in blood pressure at four weeks. Results from the trial showed that bisoprolol reduced diastolic blood pressure to 90 mmHg or less in 50-70% of patients. Bisoprolol reduced diastolic blood pressure an average of 8.3 mmHg in the 5 mg group, 10.8 mmHg in the 10 mg group and 11.9 mmHg in the 20 mg group compared to a 3.4 mmHg reduction in the placebo group. Zabeta labeling also depicts a favorable profile in elderly patients. "Response rates and mean decreases in systolic and diastolic blood pressure were similar to the decreases in younger patients in the U.S. clinical studies," the labeling states. "Observed reductions in heart rate were slightly greater in the elderly than in the young and tended to increase with increasing dosage." Since there was no disparity in adverse experience reports or dropouts for safety reasons between older and younger patients, dose adjustment based on age is not necessary, according to labeling. "Overall, significantly greater blood pressure reductions were observed on bisoprolol than on placebo regardless of race, age, or gender," the labeling states. "There were no significant differences in response between black and non-black patients." Lederle's Zebeta is the first beta blocker approved by FDA since Abbott's Cartrol (carteolol) in December 1988. Lederle is expected to position Zebeta as a "third generation" beta blocker in the relatively mature beta blocker field.
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