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Executive Summary

Merck's Vasotec (enalapril) is entering the U.S. market as a first-line antihypertensive which can be administered to some patients on a once-a-day dosing schedule. Vasotec, joining Squibb's Capoten (captopril) as the only approved angiotensin-converting enzyme inhibitors in the U.S., was cleared by FDA on Dec. 24, classified by the agency as a 1B agent (new molecular entity with modest therapeutic gain). In a press release on the approval, Merck said that the FDA approved labeling will allow Vasotec to be used in "hypertension of all degrees of severity." The across-the-board use is reflected by the unqualified package insert indication statement that Vasotec "is indicated for the treatment of hypertension." Merck said in the release that "Merck believes Vasotec will become an important addition to the drugs physicians use for first line therapy in treating hypertension." The firm also said that Vasotec is the only U.S.-approved ACE inhibitor "that may be prescribed once a day." The package insert states that "the recommended initial dose in patients not on diuretics is 5 mg once a day . . . The usual dosage range is 10 to 40 mg per day administered in a single dose or two divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients, an increase in dosage or twice daily administration should be considered." Initial labeling indications will allow Vasotec the same across-the-board approval for hypertension therapy which was only recently received by Squibb's Capoten. During its first three years on the market, Capoten carried a restricted, last resort, labeling due to the unknown extent of neutropenia/agranulocytosis risk. Capoten labeling was expanded to permit use of the drug as a first choice antihypertensive in normal renal function patients only after a three-year supplemental NDA review ("The Pink Sheet" July 8, p. 3). Vasotec labeling notes: "In using Vasotec, consideration should be given to the fact that another angiotension-converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show that Vasotec does not have a similar risk." At FDA's Cardio-Renal Drugs Advisory Cmte. meeting in June 1984, members agreed that enalapril data did not "indicate a risk that [warranted label] restrictions at this time" ("The Pink Sheet" June 25, 1984, p. 8). The advisory cmte. reviewed Merck's 2,164-patient studies, which showed only 11 cases (.51%) of proteinuria. At the meeting, Merck said that in overall enalapril clinicals, involving over 4,000 patients, not a single neutropenia/agranulocytosis event occurred. One cmte. member, Robert Goldstein, MD, Uniformed Services University of the Health Sciences, remarked: "It seems to me that the problem lies with the current restrictions on captopril and I don't think we should perpetuate the mistake with enalapril." Unlike Capoten, however, U.S. labeling indications for Vasotec do not include the treatment of congestive heart failure. According to Merck, studies on enalapril for congestive heart failure have been conducted, and this use has been approved abroad. At $106 mil. (retail acquisition cost) 1985 sales through November, Pharmaceutical Data Services (PDS) predicted that Capoten would become Squibb's number one selling U.S. retail product by early 1986. When asked by securities analysts last April how the introduction of enalapril would impact upon Squibb's Capoten business, Squibb President and CEO Dennis Fill responded that in the U.S. "another product is going to broaden the marketplace overall" ("The Pink Sheet" April 22, T&G-7). The most recent PDS figures (through November 1985) show Capoten prescriptions up 54% since the same time last year. The 1.2 mil. new Rxs and 3 mil. refills bring the 11-month 1985 total to 4.2 mil. prescriptions dispensed from retail pharmacies. Increasing research interest in ACE inhibitors is reflected by four new listings in the 1986 USAN and USP Dictionary of Drug Names ("The Pink Sheet" Aug. 19, p. 3). Parke-Davis and USV are among companies with ACE inhibitors in clinical trials. Ciba-Geigy's pentopril is in preclinical evaluation, and both Merck and Squibb are developing second generation ACE inhibitors to add to their original market entries. Merck, which has a history of getting simultaneous major approvals, will begin 1986 with two significant new products for its sales force: the broad spectrum antibiotic Primaxin (imipenem/cilastin) and Vasotec. This year's situation, a downscaled repeat of 1981 when the company introduced five new drugs at once, is backed by a specialized sales force that the firm said has "been built up in recent years in anticipation of new products." In preparation for its new generation of drugs, Merck repositioned its sales force in 1980 ("The Pink Sheet" March 17, 1980, p. 10) into geographic areas and therapeutic categories. The mid-atlantic, southeastern and southwestern regions are divided into two sales groups specializing in cardiovascular and musculoskeletal products. In addition, according to the firm, some territories now include a hospital-directed sales force. Merck will begin distribution of Vasotec "the second on third week in January." According to the standard Merck policy, the drug will be available to wholesale and retail accounts at the same price, terms and conditions. Vasotec already is available in 20 countries, including France, Germany, U.K., Argentina and Spain.

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