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Executive Summary

PFIZER's CARDURA (DOXAZOSIN) LAUNCH SET FOR JANUARY, following FDA approval on Nov. 2. The once-daily, cardioselective alpha blocker was given a "1-C" rating (new chemical entity with little or no therapeutic gain) by FDA. The compound gives Pfizer a new single-source entry into the alpha blocker class to supplement its 14-year-old Minipress product. Minipress (prazosin) has been available as a generic for two years. The product had reached about $120 mil. in annual sales for Pfizer before the loss of exclusivity. Pfizer has an Alza-developed formulation for prazosin pending approval at FDA. Cardura has a broad indication "for the treatment of hypertension." It "may be used alone or in combination with diuretics or beta-adrenergic blocking agents. There is limited experience with Cardura in combination with angiotensin-converting enzyme inhibitors or calcium channel blockers," the labeling states. Pfizer is preparing to put about 800 sales representatives behind the initial detailing for Cardura. The Roerig sales force and the cardiovascular specialty group of Pfizer Labs will handle the introduction ("The Pink Sheet," Nov. 5, p. 7). Pfizer got a break in the timing of FDA's final approval: coming one week before the major American Heart Association meeting in Dallas, permitting full promotion of the product to that group. Doxazosin is contraindicated "in patients with a known sensitivity to quinazolines (e.g. prazosin, terazosin)." Warnings on the package insert caution that "doxazosin, like other alpha-adrenergic blocking agents, can cause marked hypotension, especially in the upright position, with syncope and other postural symptoms such as dizziness." Labeling adds that "marked orthostatic effects are most common with the first dose but can also occur when there is a dosage increase, or if therapy is interrupted for more than a few days." Cardura was submitted to FDA as a computer-assisted NDA in March 1987, and Pfizer was informed that the drug was "approvable" on Aug. 8 of this year. The three-month delay between the approvable determination and final approval has been attributed to FDA budgetary restrictions that held up a mandatory pre-approval inspection of Pfizer's manufacturing processes. According to the company, that inspection did not occur until October ("The Pink Sheet" Nov. 5, p. 7). The package insert for Cardura includes a reference to the drug's effects on cholesterol levels. Clinical studies involving "about 300 patients" showed that "in these predominantly normocholesterolemic patients doxazosin produced small reductions in total serum cholesterol (2-3%), LDL cholesterol (4%), and a similarly small increase in HDL/total cholesterol ratio (4%). The clinical significance of these findings is uncertain," the labeling states. The inclusion of that reference to the drug's effects on lipids may be a significant marketing angle for Pfizer. In a Nov. 5 press release, the company noted that "while the clinical significance of these findings is unknown [the data] will be of interest to physicians who must consider the overall status of their patients' health." Pfizer Central Research President Barry Bloom, PhD, added that "the fact that Cardura does not negatively impact cardiovascular risk factors such as glucose tolerance or lipid levels is an important benefit." At its May 4, 1989 meeting, FDA's Cardio-Renal Drugs Advisory Committee recommended against Pfizer's proposal to include lipid reduction data in the final labeling. Committee Chairman Craig Pratt, MD, cited FDA concern about how the product would be marketed if the data were included. Cardio-Renal Drug Products Division Director Raymond Lipicky, MD, took a particularly strong position against the claim, saying that "it would be over my dead body that anything other than 'no adverse effects' on lipids would ever get into labeling" ("The Pink Sheet" May 8, 1989, p. 6). The statistics included in the final labeling suggest a more modest reduction in serum cholesterol levels than those presented to the committee. The data presented to the advisory committee were from selected studies in the NDA submission. Pfizer says it is conducting follow-up studies involving hypertensive patients with abnormally high cholesterol levels. One of the predecessors to Cardura in the alpha-blocker field, Abbott's Hytrin (terazosin) already contains similar labeling language on lipid profile data: "patients receiving terazosin monotherapy had a small but statistically significant decrease (a 3% fall) compared to placebo in total cholesterol and the combined low-density and very-low-density lipoprotein fractions. No significant changes were observed in high-density lipoprotein fraction and triglycerides compared to placebo." Abbott, however, was taken to task by FDA for promoting Hytrin's lipid profile in a manner that the agency believed suggested that Hytrin could be used for treating hypercholesteremia. Abbott revised its claims earlier this year ("The Pink Sheet" March 12, T&G-8). Dizziness is the most frequent side effect, according to clinical trials. Nineteen percent doxazosin recipients experienced dizziness versus 9% of those on a placebo. There were also increased incidences of vertigo, postural hypotension, somnolence, and fatigue/malaise among those receiving doxazosin. However, of 1,679 patients overall who were involved in the clinical development program, discontinuation of treatment as a result of side-effects occured "in only 7% of patients." Dosages of Cardura range from 1 mg to 16 mg, but the initial dosage should be 1 mg given once daily, and then increased as needed. The labeling warns that dosages above 4 mg "increase the likelihood of excessive postural effects including syncope, postural dizziness/vertigo, postural hypotension." Cardura has an added commercial potential outside the cardiovascular class in the treatment of benign prostatic hypertrophy, an indication that Pfizer is pursuing. The company reportedly will be receiving data from four international trials evaluating Cardura for the treatment of BPH within "the next few months." Once Pfizer evaluates that data, it will decide when to file for the new indication. The company is also conducting ongoing tests in nonhypertensive people in order to satisfy FDA's concerns about the potential for Cardura-induced hypotension in BPH patients.

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