OTC QUININE SULFATE EFFICACY FOR LEG CRAMPS IS NOT ESTABLISHED

OTC QUININE SULFATE EFFICACY FOR LEG CRAMPS IS NOT ESTABLISHED by data so far submitted to FDA, OTC Division Director William Gilbertson, PharmD, told Ciba-Geigy and Scholl in Dec. 6 letters. In response to two studies submitted by Ciba-Geigy, manufacturer of Q-vel, and three studies submitted by Legatrin manufacturer Scholl, Gilbertson concluded that "quinine sulfate remains a nonmonograph condition for the treatment and/or prevention of nocturnal leg cramps." The division head objected to a number of design and analysis elements of the Scholl studies, including the possibility of bias in two of the studies and the lack of raw data for independent analysis in the third published study. However, in reference to one of the studies, Gilbertson noted that "a parallel trial with a larger sample size [greater than 75 patients] and of longer duration (i.e., longer than two weeks) might be capable of showing the efficacy of quinine sulfate." He suggested that Scholl submit a protocol to the agency before conducting such a study. Responding to Ciba-Geigy's studies on Q-vel, a combination of quinine sulfate and vitamin E, Gilbertson pointed out that one of the studies did not contain a vitamin E arm and was, therefore, incapable of demonstrating the contribution of both ingredients in the product. The statistical analysis in the second study, according to FDA, "is inadequate for review because the model used does not separate the carry-over effect from the treatment effect." Gilbertson told the firm that the study could be evaluated if a new analysis of the data were submitted. Ciba-Geigy is also in the process of conducting a 1,080 patient study with Q-vel that compares the combination product to placebo and to both of the individual ingredients. FDA is conducting an expedited review of quinine sulfate, presumably because of concerns relating to the safety of the agent. The agency held an internal meeting in mid-December to discuss safety and efficacy of the drug, including reports of two recent fatal hypersensitivity reactions ("The Pink Sheet" Dec. 5, T&G-13). Safety of the ingredient was also questioned in a Dec. 1 petition from Health Research Group requesting a ban on OTC sales of the product. In his letters to Ciba-Geigy and Scholl, Gilbertson noted that safety issues relating to quinine sulfate "will be addressed in a future communication." Scholl, in a Dec. 15 letter to FDA, maintained that HRG's allegations about the safety of quinine sulfate, particularly cinchonism, are not applicable to the doses used for leg cramps. HRG's petition "fails to mention that cinchonism usually occurs only after continued use at daily doses significantly higher than 325 mg," the maximum daily dose for leg cramps, the Schering subsidiary asserted. The firm noted that the internal analgesic panel only expressed concern about cinchonism and other side effects at analgesic doses of up to 1,300 mg.