SANDOZ Rx LAMISIL APPROVED FOR ATHLETE’s FOOT, JOCK ITCH AND RINGWORM: ONE-WEEK SYMPTOM IMPROVEMENT NOTED IN LABELING BUT SUPERIORITY CLAIMS NOT ALLOWED

Sandoz Pharmaceuticals' prescription topical antifungal Lamisil cream (terbinafine 1%), approved Dec. 30 for athlete's foot, jock itch and ringworm, will not be permitted to make claims of clinical superiority based upon its potential one-week dosing regimen pending submission of further data. Terbinafine was approved for the treatment of interdigital tinea pedis (athlete's foot), tinea cruris (jock itch) or tinea corporis (ringworm) due to Epidermophyton floccosum, Trichophyton mentagrophytes or Trichophyton rubrum. Lamisil was cleared after an 18-month FDA review (designated "1S" by FDA, which means a new molecular entity given standard review). Sandoz submitted the NDA on June 30, 1991. Approved labeling recommends that the synthetic allylamine derivative be applied twice daily for athlete's foot and once or twice daily for jock itch or ringworm "until clinical signs and symptoms are significantly improved," which occurs "in many patients...by day seven of drug therapy." Labeling further notes: "The duration of drug therapy should be for a minimum of one week and should not exceed four weeks." The usual approved dosage recommendation for other topical antifungals, e.g. Miles' OTC Mycelex (clotrimazole 1%) and Glaxo's Rx Oxistat (oxiconazole nitrate 1%), is four weeks for athlete's foot and two weeks for jock itch and ringworm. FDA's approval letter states: "There are no data from adequate and well-controlled trials in this NDA establishing the superiority of a one-week regimen over other approved therapies." Any advertisement or promotional labeling will be considered "false and misleading" if "it states or implies that the standard dosing regimen for this product is simply a one-week regimen" or if it implies or states "a superiority claim of the four-week therapy with terbinafine over the active comparator in your four- week trial," the agency cautioned. In a Dec. 23 letter to FDA, Sandoz acknowledged that Lamisil could not claim superiority to the active control based on the study data presented in the NDA alone. "Please note that we are not trying to receive a claim of superiority at this time," the company wrote. Product labeling provides data from three studies of Lamisil Cream used b.i.d. for athlete's foot. Two studies were vehicle- controlled evaluations of one week of treatment with Lamisil. The third was a four-week study with an active comparator. In the active comparator study, 94 of 133 patients (71%) receiving Lamisil and 84 of 133 patients (63%) using the active control had successful outcomes after four weeks of therapy. At week six, 73% of Lamisil patients and 59% of control patients were evaluated as having successful outcomes. In the two vehicle-controlled evaluations, at the end of the treatment week, 11 of 79 patients using Lamisil and five of 79 patients using the control had successful outcomes. Three weeks later, the figures were 51% of Lamisil patients and 13% of control patients. After six weeks, 65% of patients who had used Lamisil and 12% of patients who had used the control vehicle achieved successful outcomes. Labeling also gives the results of two studies comparing Lamisil to vehicle for jock itch and/or ringworm. Twenty-one percent (7/33) of ringworm patients using Lamisil and 43% (21/49) of jock itch patients using Lamisil had successful outcomes compared to 0/31 ringworm control patients and 5/58 jock itch control patients having successful outcomes at week one. Three weeks after the end of therapy, patients receiving Lamisil had success rates of 83% for ringworm and 92% for jock itch. FDA's approval letter notes that in these trials "microbiologic eradication alone and individual sign and symptom alleviation alone did not always correlate with successful therapy." Therefore the company must not "portray in isolation individual criteria...used to determine 'successful outcome' without concomitant balanced presentation of the overall 'successful outcomes,' as defined in the approved labeling." Lamisil received an approvable letter Sept. 30. In approving the drug, FDA noted a letter from Sandoz dated Nov. 3 stating that within one year of approval the company would submit data "to demonstrate adequately the validation of the analytical methods used for each of the four clinical studies conducted to assess the percutaneous penetration, accumulation, and excretion of the drug product." The company also agreed to submit studies of an "in vitro method for monitoring the release rate of terbinafine from the drug product." Of 2,265 patients treated with Lamisil during clinical trials, six (0.2%) discontinued therapy due to adverse events, and 52 (2.3%) reported adverse reactions "thought to be possibly, probably, or definitely related to drug therapy," approved labeling states. These reactions included irritation (1%), burning (.8%), itching (.2%) and dryness (.2%). Terbinafine's safety and efficacy in children under 12 have not been established.