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Executive Summary

ASTRA's TOPROL XL SUSTAINED-RELEASE METOPROLOL APPROVED JAN. 10 as a once-daily treatment for hypertension and angina. The immediate-release version of the beta blocker is marketed in the U.S. as Lopressor by Ciba-Geigy under license from Hassle, which, like Astra Pharmaceutical, is a subsidiary of the Swedish firm AB Astra. Toprol XL uses an Astra-developed polymer microencapsulation process to deliver metoprolol. Hassle filed an NDA for Toprol XL on Dec. 22, 1989. Ciba-Geigy's Lopressor OROS sustained-release metoprolol, developed by Alza, was approved in December 1989 but has never been marketed in the U.S. Ciba-Geigy sought a license from Hassle but says it currently has no plans to market the product. Toprol XL will be the first product marketed in the U.S. by Astra's Rx Division. Shipments will begin during the last week of January, Astra said, with full-scale detailing commencing in February. Astra announced the formation of a cardiovascular sales force in February 1991 ("The Pink Sheet" Feb. 25, T&G-4). The division now has 150 people, including 121 sales reps, Astra said. Foscavir (foscarnet), Astra's first product marketed in-house in the U.S., is detailed by a separate hospital division and anti-viral sales force that numbers about 100 people. Astra will discount Toprol XL slightly to Lopressor. Toprol XL will cost .35 per 50 mg tablet, .53 per 100 mg tab and $1.06 per 200 mg tab, Astra said. "RedBook" price data shows an average wholesale price for Lopressor of .43 per 50 mg tab and .64 per 100 mg tab. Toprol XL labeling discusses pharmacological advantages of the sustained-release formulation. While once-a-day Toprol XL and Lopressor given once to four times per day "provided comparable total beta[1]-blockade over 24 hours" in the 100 mg to 400 mg dose range, "at a dosage of 50 mg once daily, Toprol XL produced significantly higher total beta[1]- blockade over 24 hours than immediate-release metoprolol," approved labeling states. Immediate-release metoprolol "given at a dose of 50-100 mg once a day produced a significantly larger peak effect on exercise tachycardia" than Toprol XL, the label says. Lopressor had to be given three or four times a day "to match the peak to trough ratio obtained with Toprol XL over the dosing range of 200 mg to 400 mg," labeling notes. FDA's Cardio-Renal Drugs Advisory Committee recommended approval of Astra's sustained-release metoprolol (formerly tradenamed Toprolol LA) in June 1990 ("The Pink Sheet" June 18, 1990, T&G-4). The committee was critical of the 50 mg Toprol XL trials but ultimately recommended approval of that dose for use in hypertension. Approved labeling states that "the usual initial dosage is 50 to 100 mg daily" for hypertension. Lopressor labeling indicates an initial dose of 100 mg only. A Jan. 13 Astra press release suggests another advantage the company may promote for Toprol XL over Lopressor: "The delivery system makes Toprol XL less sensitive to the effects of food than immediate-release metoprolol tablets, allowing patients to take Toprol XL without regard to food or meals." The "Patient Information" section of labeling notes that Toprol XL should be taken "preferably with or immediately following meals." Lopressor labeling does not include the "preferably." Toprol XL labeling does not suggest any side effect advantage for the sustained-release formulation. Toprol XL and Lopressor have identical contraindications, adverse events, precautions and warnings sections. Lopressor is indicated for use in treating myocardial infarction in addition to hypertension and angina.

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