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Executive Summary

Schering-Plough's nonsedating antihistamine Claritin is being launched at an average wholesale price of $1.64 per tablet, comparable to the AWP for one day of therapy with Marion Merrell Dow's Seldane, Schering-Plough said April 13. Claritin (loratadine) is recommended for dosing of one 10 mg tablet per day. Seldane (terfenadine) 60 mg tablets are labeled for twice-daily dosing and sell for about 85 cents per tab AWP. Seldane is occasionally prescribed for use once a day or as needed, although Marion Merrell Dow said it has no information to quantitate such use. Johnson & Johnson's Hismanal (astemizole) 10 mg once-a-day tablets list for $1.69 per tab AWP. Claritin was approved by FDA April 12 and shipping began April 15. The antihistamine will be available in pharmacies by May 1, Schering-Plough said. Claritin will be sold in bottles of 100, unit of use packages of 14 and 30, and a 10 X 10 unit dose- hospital pack. Claritin is indicated "for the relief of nasal and non-nasal symptoms of seasonal allergic rhinitis." In placebo-controlled trials involving more than 10,700 patients, "10 mg once daily of Claritin was superior to placebo and similar to [Sandoz' Tavist] clemastine (1 mg b.i.d) or terfenadine (60 mg b.i.d.) in effects on nasal and nonnasal symptoms of allergic rhinitis," labeling states. "Somnolence occurred less frequently with Claritin than with clemastine and at about the same frequency as terfenadine or placebo," labeling states. "In studies with Claritin at doses two to four times higher than the recommended dose of 10 mg, a dose- related increase in the incidence of somnolence was observed. Therefore, some patients, particularly those with hepatic or renal impairment and the elderly, may experience somnolence." The recommended starting dose for patients with liver failure is 10 mg every other day. Patients are advised to take Claritin on an empty stomach, although food effects seen in pharmacokinetic studies "would not be expected to be clinically important," labeling states. The safety database referenced in labeling includes approximately 90,000 patients who received 10 mg loratadine once daily in controlled and uncontrolled trials. Use ranged from two weeks to six months. "The rate of premature withdrawal from these trials was approximately 2% in both the treated and placebo groups," labeling states. Adverse events most frequently reported, including headache, somnolence, fatigue and dry mouth, did not differ significantly from placebo in controlled trials. Claritin's approval comes six-and-one-half years after the NDA was submitted Oct. 31, 1986 and more than five years after it was recommended for approval by FDA's Pulmonary-Allergy Drugs Advisory Committee in October 1987. Approval was first delayed by bioequivalence concerns raised by Schering-Plough's decision to market a tablet dosage form after conducting clinical studies using capsules. After Schering-Plough began gearing up for launch of Claritin in late 1989, carcinogenicity concerns based on animal studies emerged. A second review by the Pulmonary-Allergy committee in June 1991 concluded that Claritin is "not likely" to be carcinogenic in humans ("The Pink Sheet" June 24, 1991, p. 7). The protracted review of Claritin prevented it from becoming the second nonsedating antihistamine available in the U.S. The drug is now the third approved in the class, and two others -- Pfizer's Reactine (cetirizine) and Burroughs-Wellcome's Semprex-D (acrivastine/pseudoephedrine) -- are scheduled for advisory committee review April 26. The timing of Claritin's approval, however, could prove fortuitous. Domestic sales of Seldane and Hismanal declined sharply in the U.S. in the second half of 1992 after the two products were relabeled with boxed warnings citing the potential for cardiovascular side effects. Seldane was relabeled to warn of possible interactions with erythromycin and ketoconazole in July ("The Pink Sheet" July 13, 1992, p. 9). Two weeks later, Hismanal was relabeled to warn of overdoses ("The Pink Sheet" July 27, 1992, p. 3). Marion Merrell Dow has renewed its direct-to-consumer advertising for the terfenadine-decongestant combo product Seldane D for the spring allergy season. Consumer ads carrying the new warnings ran during the week of April 12 (see following story). Schering-Plough said it is considering direct-to-consumer ads for Claritin. Claritin labeling suggests that it is free of serious cardiovascular side effects. "In a study in which Claritin was administered at four times the clinical dose for 90 days, no clinically significant increase in the QTc was seen on ECGs," labeling states. Both Seldane and Hismanal have been shown to prolong the QT interval. In "more than 600 mil. patient days of use" internationally, Schering-Plough said, Claritin has "not been associated with any reports to date of torsades de pointes," the life-threatening arrhythmia seen with Seldane and Hismanal. Tachycardia has been reported with overdoses of Claritin, labeling states. Schering-Plough has committed to "conduct interaction studies with erythromycin, ketoconazole and cimetidine," FDA's approval letter states. Labeling notes that "the number of subjects who concomitantly received macrolide antibiotics, ketoconazole, cimetidine, ranitidine or theophylline along with Claritin is too small to rule out possible drug-drug interactions." Schering-Plough's efforts to demonstrate that Claritin is free of the side effects seen with Seldane and Hismanal could ultimately place Claritin in a position to become the first nonsedating antihistamine to move over-the-counter in the U.S. In the wake of the relabeling of Seldane and Hismanal, however, FDA will likely proceed cautiously with any OTC switch in the class. Claritin is available over-the-counter in 13 countries worldwide, including Canada and the U.K. Schering-Plough has agreed to four other postmarketing requirements, FDA's approval letter states. These include: "to further study the efficacy of loratadine at lower doses"; "to initiate development of a more sensitive analytical method for the detection of impurities"; "to identify the specific enzyme systems responsible for the metabolism of loratadine"; and "to conduct studies to evaluate the pharmacokinetics and pharmacodynamics of loratadine based on sex and race." The "Precautions" section of labeling references the animal carcinogenicity data reviewed by the advisory committee. "Male mice given 40 mg/kg [of loratadine] had a significantly higher incidence of hepatocellular tumors than concurrent controls," labeling states. "The clinical significance of these findings during long-term use of Claritin is not known." "We are confident that Claritin will attain a significant share of the nonsedating antihistamine market in its first year," Schering-Plough said, citing its once-a-day dosing as an advantage over Seldane and its "fast onset" as an advantage over Hismanal. The latter "may take days to show optimal effects," Schering- Plough maintained. Hismanal labeling states that "clinical trials have not been conducted to show whether Hismanal is effective for short courses of therapy." Claritin is patented until August 1998 and the company plans to apply for a two-year patent extension, Schering-Plough said. The firm is developing other dosage forms of loratadine. A pediatric suspension has completed clinical trials, FDA said. Schering-Plough also has an NDA pending for a loratadine/pseudoephedrine combination (Claritin D). Claritin is approved in 70 countries worldwide. In Canada, where it is available both by prescription and OTC, Claritin is the market leader with 30.2% of the combined antihistamine market, Schering-Plough said. It is also the market leader in Italy with 25.6% of antihistamine sales. With 1992 sales of $139 mil., Claritin is second overall to Seldane in international sales of nonsedating antihistamines, Schering-Plough said. The firm estimates the U.S. nonsedating antihistamine market at $600 mil. in 1991.

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