http://www.drugs.com/nda/nebido_080630.html
The FDA has expressed a concern about a relatively small number of patients in European post-marketing use who have experienced respiratory symptoms immediately following the intramuscular injection of Nebido 1000 mg, 4 cc injection volume, (versus the 750 mg, 3 cc injection volume used in the United States). The Company believes and the FDA concurs that the reaction is likely the result of a small amount of the oily solution immediately entering the vascular system from the injection site, a known, rare complication of oil-based depot injections.
The phenomenon is characterized by short-term reactions involving an urge to cough, coughing episodes or a shortness of breath. In rare cases the reaction has been classified as serious or the patient experiences other symptoms such as dizziness, flushing or fainting. In the Company's U.S. clinical trials of Nebido 750 mg (3 cc injection volume), the proposed dose in the U.S., there was a single, mild, non-serious case of oil-based cough observed. In addition, the FDA believes that four cases in the European post-marketing experience may have an allergic, anaphylactoid component, although the Company believes these cases were improperly classified and represent the same oil-based phenomenon.
The FDA has requested the Company address these clinical deficiencies by providing detailed safety information from clinical studies to determine the precise incidence of serious post-injection oil-based reactions and allergic reactions. Specifically, the FDA has requested follow-up data from the on-going U.S. and European studies in which patients are being treated with Nebido on an extended basis. A majority of these trials are scheduled to be completed within twelve months. The FDA stated that depending on the findings, the number of subjects and the number of injections of testosterone undecanoate from the studies listed above, the safety database may need to include data from additional clinical studies. They have requested that the Company propose the size of the safety database (i.e., total number of subjects exposed to testosterone undecanoate intramuscular injection and total number of injections) and the rationale for the size of the proposed safety database.
FDA has also requested the Company provide a plan to minimize the risks associated with the clinical use of testosterone undecanoate intramuscular injection, namely, to reduce the incidence and/or severity of the serious oil-based reactions and has requested certain in vitro and skin-testing data to exclude an allergic component to the drug or some of its excipients.
