SANDOZ' TAVIST-1 AND TAVIST-D RECOMMENDED FOR Rx-TO-OTC SWITCH APPROVAL: LABELING SHOULD INCLUDE HIGHLIGHTED DROWSINESS WARNING - - FDA ADVISORY CMTE.

Sandoz' Tavist-1 (clemastine) and Tavist-D (clemastine and phenylpropanolamine) should be approved for OTC status, FDA's Pulmonary-Allergy Drugs Advisory Committee voted unanimously at its March 23 meeting. Sandoz is seeking OTC status for the lower-dose Tavist formulations, 1.34 mg of clemastine fumarate. The company also markets Tavist formulations of 2.68 mg clemastine fumarate which were not reviewed by the committee. Tavist-related drowsiness was a major focus of discussion for the panel. In the company presentation to the committee, Sandoz Director of Regulatory Affairs Michael Silverman, MD, said that of a "large body of data on the safety of Tavist products," Tavist- induced "somnolence turns out to be the most frequently reported event." Drowsiness was reported with "frequency ranges of 5.7% in foreign studies and 14.6% in domestic controlled" studies, Silverman said. He added that these results are "not unexpected ...and the frequency seems to be in line with many of the [antihistamines] with which we are familiar." FDA Pulmonary Drugs Medical Officer Susan Johnson concurred with Silverman's assessment, stating that the agency's review concludes "that adverse reactions associated with Tavist products are similar to those reported for marketed OTC antihistamines." Advisory Committee Chairman Leonard Bernstein, MD, University of Cincinnati Medical Center, relayed concerns voiced by the National Transportation Safety Board at a meeting that he had attended. The NTSB meeting addressed the potential dangers of antihistamine use among drivers, in particular truck drivers, Bernstein said. Sandoz Director of Registration and Regulatory Affairs Gregory Torre, PhD, pointed out that "labeling contraindicates the use of antihistamine and operating machinery, driving cars, etc." Bernstein responded that the drowsiness "warning should be highlighted." Committee member Joann Blessing-Moore, MD, Palo Alto, Calif. agreed, proposing that the warning be moved to the "second line." FDA Pulmonary Drugs Group Leader Eileen Leonard, MD, asked if the agency should "interpret this recommendation as one which would follow for all sedating antihistamines." Bernstein suggested that FDA "check with" the NTSB, which has issued "strong recommendations that truck drivers should not take antihistamines." The committee did not vote to recommend revised labeling for all antihistamines, although members emphasized the need for a highlighted drowsiness warning in Tavist labeling. Sandoz' Torre responded that "there is no reason why we couldn't put it [the warning] higher up." The drowsiness issue has created a problem for Sandoz in the past in its relations with FDA. The company ran ads in September 1987 that touted Tavist-1 as offering "unique, clinically-proven low drowsiness." The ads were canceled after FDA told the company that its claims were "false and misleading" ("The Pink Sheet," Oct. 26, 1987, p. 7). Sandoz consultant William Barr, PhD, presented information on the pharmacokinetics of Tavist-1 and Tavist-D, concluding that both the clemastine and the combination product with phenylpropanolamine are "very well suited for OTC use." In his analysis, Barr found that "there is no pharmacokinetic interaction between clemastine and [phenylpropanolamine]." FDA medical officer Johnson reported that the combination product does not have as "wide a safety margin" as Tavist-1. Despite these criticisms, she concluded that "the safety and effectiveness of Tavist-1 and Tavist-D have been adequately demonstrated for OTC use, and the risk/benefit ratio is appropriate." Sandoz' Silverman also noted that Tavist has accumulated a substantial record of market use, both as a prescription drug and an OTC. While "FDA has suggested that a three to five year threshold" of years on the market "is suitable" for Rx-to-OTC approval, Tavist-1 has been available for 26 years "since its original approval in Germany in 1966," Silverman said. Tavist-1 has been marketed in the U.S. for 13 years. Tavist-D "has 16 years of use, with nine of those being in the U.S.," the exec added. According to Silverman, FDA suggests that the distribution of over 500 mil. units "provides an adequate database in order to judge the safety" of an OTC candidate. Sandoz has sold 6 bil. units of Tavist-1 worldwide, including about 300 mil. in the U.S., Silverman said. For Tavist-D, approximately 800 mil. units have been sold worldwide, including more than 500 mil. in the U.S. Silverman added that outside the U.S. the "OTC distribution would also exceed three-quarters bil. units sold...over the last 15 years." According to physician use surveys, Tavist and Tavist-1 command a 5% market share of prescription antihistamines, Silverman said. For combination antihistamine and decongestant products, Silverman said that "Tavist-D was the most widely prescribed prescription cold medication distributed in this country, with an 18% market share in 1990." Silverman also noted that Tavist products already are available over-the-counter in several foreign countries. Tavist-1 was first approved for OTC use in Switzerland in 1971. The drug is currently available direct to consumer in eight countries, including Canada, Germany and Great Britain. Tavist-D is sold OTC in Canada, Japan, Switzerland, Germany and Great Britain. In Canada, the OTC labeling for Tavist handles the drowsiness issue by warning about initial use. "Drowsiness may occur initially," the Canadian package insert says, "but experience suggests this symptom should lessen or disappear after the first few tablets." The Canadian labeling also includes a statement "as is the case with other antihistamines" warning about alcohol interaction, operating machinery or driving a car.