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Executive Summary

Pfizer's Cardura (doxazosin) should be approved for once-daily treatment of hypertension "alone or in combination with other antihypertensive agents," FDA's Cardio-Renal Drugs Advisory Committee unanimously recommended at its May 4 meeting. The committee recommended that doxazosin dosing could range from an initial dose of 1 mg to a maximum well-tolerated dose of 16 mg. The panel concluded that the only limiting factors with respect to dose escalation are postural side effects such as dizziness, somnolence and fatigue, which occurred in up to 23% of the patients at the 16 mg dose. Data presented by Pfizer showed responder rates to doxazosin therapy were 50% to 60%, "which is in the ballpark of what we know from the literature for antihypertensive monotherapies," Pfizer Drug Regulatory Affairs Director Joan Leader, PhD, told the committee. Efficacy data from multi-center placebo-controlled trials found that doxazosin significantly reduced blood pressure in four areas: standing diastolic blood pressure by an average 8.5 mm Hg; standing systolic by 9.5 mm Hg; supine diastolic by 6 mm Hg; and supine systolic by 7 mm Hg. In separate studies doxazosin was compared to once-daily atenolol (ICI's Tenormin), nadolol (Squibb's Corgard), and metoprolol (Ciba-Geigy's Lopressor). According to Leader, the studies found that "in the standing position doxazosin was comparable to all agents." However, "doxazosin was somewhat less effective in the supine position from the generally comparable control agents," Leader noted. The committee rejected a proposal to include lipid reduction data presented by Pfizer in Cardura labeling. FDA indicated it was being cautious in allowing marginal data which could be possibly used in claims that doxazosin lowers cholesterol. "I guess there is some concern in the agency about how this would be marketed if actually written that there was a certain percent change [in lipids]," committee Chairman Craig Pratt, MD, Baylor College of Medicine, commented. Pfizer presented retrospective data from their studies that demonstrated that doxazosin lowers total cholesterol by 5%, low density lipoproteins by 9%, triglycerides by 5% and raises high density lipoproteins by .3%. Preliminary prospective data from a Phase I portion of the large Treatment of Mild Hypertension Study (TOMHS), presented by James Pool, MD, Baylor College of Medicine, showed statistically significant reductions in total cholesterol and LDL during treatment with doxazosin. However, FDA statisticians found only a statistically significant change in LDL, leading Lipicky to conclude that the clinical significance of lipid reduction by doxazosin "clearly requires extrapolating outside the range of any knowledge that anyone has. And it would be over my dead body that anything other than "no adverse effects" on lipids would ever get into labeling [for doxazosin]."

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