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KNOLL'S ISOPTIN SR CLEARS FDA WITH FULL NDA; THREE YEARS EXCLUSIVITY FOR DOSAGE AND HYPERTENSIVE INDICATION POSSIBLE; SEARLE'S CALAN-SR ALSO COVERED

Executive Summary

Knoll's full NDA for Isoptin-SR, sustained-release verapamil, should give the original branded versions of the calcium channel blocker a formulation advantage over generic competitors for three years. It also makes verapamil the first calcium channel blocker to have an approved indication for hypertension. A full NDA for the sustained release product was approved by FDA on Dec. 16. Searle's branded version Calan-SR was approved through the Knoll NDA as part of the verapamil licensing agreement. By going the full NDA route and presumably submitting clinical studies on the sustained release formulation, Knoll and licensee Searle are eligible for three years of exclusivity under the ANDA/patent law. The combination of the sustained-release dosage form and the new hypertension indication could give Knoll and Searle and opportunity to promote product differentiation vs. the generic forms of verapamil. Generic competition to the standard dosage forms of Isoptin and Calan began on Sept. 24, on the second anniversary of the signing of the ANDA/patent restoration law. Knoll also is close to FDA approval for a hypertension claim for the standard product. Isoptin (immediate release) recently received an "approvable" letter from FDA ("The Pink Sheet" Dec. 1, "In Brief"). Previous brand experience with protected indications has shown exclusive labeling claims to be of limited use in forestalling generic competition. The double-lock of labeling and a unique dose form, however, may create a stronger protection for Knoll and Searle. By being first to receive the hypertension claim and a one-a-day formulation, verapamil, which has been running third among calcium channel blockers, has a chance to gain ground on Pfizer's Procardia (nifedipine) and Marion's Cardizem (diltiazem). Knoll's I.V. verapamil has been on the market since 1981 for treatment of cardiac arrhythmias and the oral dosage has been available since 1982 for the treatment of angina. Knoll has an oral supplemental NDA pending for the anti-arrhythmia indication. The sustained release verapamil NDA for hypertension was filed in October 1983. Knoll estimates that currently about 15% of verapamil prescriptions written by physicians are for treatment of hypertension. The sustained release product, to be marketed by Knoll as Isoptin SR and Searle as Calan SR, was launched Dec. 18. The price to wholesalers for Isoptin SR is $47.40 for a bottle of 100; the average wholesale price for Calan SR is $28.44 for a bottle of 60. Knoll is manufacturing the supplies for both sustained release formulations in Germany. The 240 mg, capsule-shaped, scored sustained release tablet is indicated for once a day dosage in the morning. If adequate response is not obtained, the dose may be titrated upward to an additional half tablet in the evening or one tablet every 12 hours. The immediate-release oral verapamil is available in 80 mg and 120 mg tablets; the usual initial dose is 80 mg three or four times a day. Knoll and Searle press material compare verapamil with beta-blockers, specifically propranolol. For example, both firms cite a study of 142 hypertensive patients published in the Oct. 24/31 Journal of the American Medical Association by Luigi Cubeddu, MD/PhD, et al. The cubeddu study found "verapamil lowered blood pressure more effectively than propranolol in black and white patients." The press material also quoted the investigators' conclusion that "verapamil was equally effective in blacks and whites, whereas propranolol was more effective in whites." Knoll's press release also states that "unlike beta-blockers, Isoptin can be used in patients with chronic obstructive airway disease." It maintains that "Isoptin is also effective in elderly patients, while beta-blockers are often less effective in lowering blood pressure in persons over 40 years of age." Knoll further states that "Isoptin does not impair physical activity, as beta-blockers often do." Discussing verapamil's side effect profile, Knoll stated that the most frequently reported reaction is constipation, occurring in 8.4% of patients. In contrast, Knoll said diuretics are "known to have potentially serious side effects including potassium depletion" and beta blockers "are frequently associated with such side effects as fatigue, impotence, mental confusion, and depression." The approved labeling for sustained release verapamil does not compare the calcium channel blocker to beta blockers. Labeling mentions beta blockers solely with regard to concomitant use with verapamil. The labeling states that "controlled studies in small numbers of patients suggest that the concomitant use of Isoptin [Calan] and oral beta-adrenergic blocking agents may be beneficial in certain patients with chronic stable angina or hypertension, but available information is not sufficient to predict with confidence the effects of concurrent treatment in patients with left ventricular dysfunction or cardiac conduction abnormalities." Labeling adds that "the combination can have adverse effects on cardiac function." The labeling warns that verapamil "should be avoided in patients with severe left ventricular dysfunction (e.g., ejection fraction less than 30% or moderate to severe symptoms of cardiac failure) and in patients with significant ventricular dysfunction if they are receiving a beta adrenergic blocker." It also notes that "occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials was 2.5%."
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