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SYNTEX' SYNOREL (NAFARELIN) RECOMMENDED FOR APPROVAL IN THE TREATMENT OF ENDOMETRIOSIS - FDA ADVISORY COMMITTEE; BONE LOSS MAJOR SIDE EFFECT

Executive Summary

Synorel should be approved for the management of pelvic pain and reduction of lesions associated with endometriosis, FDA's Fertility and Maternal Health Drug Products Advisory Committee recommended on April 28. The committee voted nine to zero, with one abstention, to approve the gonad releasing hormone agonist. The Syntex NDA is based on two clinical studies, one U.S and one European. The two studies compare nafarelin to danazol (Sterling's Danocrine), the only drug currently approved for the treatment of endometriosis in the U.S. In Syntex clinical trials, nafarelin demonstrated about an 87% improvement in symptom severity compared to approximately 82% for danazol. Nafarelin was administered intranasally to 380 subjects in doses of 400 mcg per day and 800 mcg per day compared to 800 mg per day of orally administered danazol. In the patients treated for six months, "it is clear from the data submitted that nafarelin is as effective as danazol," FDA Medical Reviewer Vanaja Ragavan told the committee. Like danazol, nafarelin has a recurrence rate of endometriotic symptoms six months after therapy of approximately 20%. During the meeting, Syntex emphasized a reduction in adverse reactions with nafarelin compared to danazol. Fifty percent of patients on danazol experienced weight gain versus only 21% for nafarelin, Howard Judd, MD, University of California-Los Angeles reported. Whereas danazol has been shown to decrease High Density Lipoproteins (HDL) by 34% and increase Low Density Lipoprotein (LDL) by 22%, nafarelin maintains a stable LDL to HDL ratio, Judd noted. However, about 90% of patients on nafarelin experienced hot flashes during therapy compared to 70% of patients on danazol. The committee's primary concern with nafarelin adverse events was the average 4% reduction in bone mass during therapy caused by estrogen depletion. Committee members recommended that labeling include warnings and that a patient pamphlet describing the risks of bone loss accompany prescriptions of nafarelin. Depsite the bone loss during the six month treatment period with nafarelin, the "risk/benefit ratio seems to be acceptable," committee member Charles Chesnut, MD, University of Washington, said. "Although bone loss did occur," he said, "it remained above a hypothetical fracture threshold." However, if approved, nafarelin treatment will probably be limited to a six-month regimen. The committee felt it could only recommend approval of the drug as a single treatment limited to six months duration based on the clinical data. Studies show that 60% of the bone loss experienced during nafarelin therapy occurs during the first three months. Syntex had initially proposed to include a claim of increased fertility post-treatment with nafarelin in the labeling but withdrew the claim after FDA determined that such claims were unsubstantiated by the studies. Committee member Arthur Haney, MD, Duke University Medical Center, insisted that labeling include a disclaimer that "there is no evidence that pregnancies are enhanced by Synorel."
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