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LEDERLE's PROBETA (BISOPROLOL) AND DIURETIC COMBO RECOMMENDED FOR APPROVAL FOR HYPERTENSION BY FDA's CARDIO-RENAL DRUGS ADVISORY COMMITTEE

Executive Summary

Lederle's once-a-day beta blocker Probeta received a unanimous approval recommendation for the management of hypertension from FDA's Cardiovascular and Renal Drugs Advisory Committee on June 6. The committee also recommended approval for Lederle's fixed combination of bisoprolol and low-dose hydrochlorothiazide as a first line treatment. Lederle filed the bisoprolol fumarate NDA (19-982) in July 1989 and the combination product NDA (20-186) in April. Lederle recently changed the brand name for bisoprolol from Monocor to Probeta. The company said it has not yet decided on a brandname for the combination product. Although labeling for the bisoprolol monotherapy will be similar to other beta blockers, the committee recommended that labeling for the combination product forego the standard FDA requirement that each drug in the combination be titrated to individual patients needs. The elimination of the requirement would allow physicians to administer the combination product as they would a single agent. "Removing the requirement for individual titration makes it indistinguishable from other single drug antihypertensives," noted committee member Milton Packer, MD, Mount Sinai Medical Center. "Therefore one would look at this as being first line therapy." Labeling of other beta blocker/diuretic combinations, such as ICI's Tenoretic, discourage use as initial therapy. The panel appeared impressed by the results of the combination therapy study. "I found the analysis of the way that the effects were elucidated for each dose and the argument that the effects were truly additive across doses for both drugs to be very, very compelling," Packer commented. In the pivotal trial of bisoprolol as a single agent, 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, presented by Lederle Cardiovascular Clinical Research Director Brian Bryzinski, MD, 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 3.4 mmHg in the placebo group. An analysis of black versus non-black patients showed no significant difference in efficacy between the two groups when treated with Probeta. In the combination study, 512 patients received 0, 2.5, 10, and 40 mg of bisoprolol plus 0, 6.25 or 25 mg of hydrochlorothiazide. Patients receiving 40 mg bisoprolol/25 mg hydrochlorothiazide and 40 mg bisoprolol/6.25 mg hydrochlorothiazide showed the greatest response to therapy, 84% and to 83%, respectively, compared to 75% of patients receiving 40 mg bisoprolol alone. Patients receiving 10 mg bisoprolol/6.25 mg hydrochlorothiazide had a similarly large response rate at 80%. The committee suggested that the starting dose for combination therapy be 2.5 mg bisoprolol/6.25 mg hydrochlorothiazide. In that group, 61% of patients showed a response while experiencing few adverse reactions. "It is important to give credit to the sponsor for exploring that 6.25 mg of hydrochlorothiazide," Packer said. Dosages of thiazide diuretics usually have been too high, leading to "little incremental antihypertensive efficacy but a lot problems of a metabolic nature," Packer observed. Lederle will likely promote the improved side effect profile of the low-dose hydrochlorothiazide combination over existing combinations which use 12.5 mg or more of the diuretic. The company plans to market bisoprolol 2.5 mg, 5 mg, and 10 mg with 6.25 mg of hydrochlorothiazide. Hypokalemia, a significant reduction in serum potassium often seen with diuretics, occurred less frequently in the 5 mg bisoprolol/6.25 hydrochlorothiazide group than in patients receiving 25 mg hydrochlorothiazide, 0.7% compared to 6.5%. The major side effect of bisoprolol was fatigue in about 6% of the patients. In addition, 2.8% of patients suffered from diarrhea.
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