A long-acting intramuscular formulation of testosterone has been approved by the Food and Drug Administration for treating hypogonadism, with a label that includes a boxed warning about the risks of pulmonary oil microembolism and anaphylaxis associated with treatment.
The depot formulation of testosterone undecanoate (TU), in castor oil and benzoyl benzoate, has been approved for treating adult men with primary hypogonadism or hypogonadotropic hypogonadism, congenital or acquired. The indications section includes the statement that it "should only be used in patients who require testosterone replacement therapy and in whom the benefits of the product outweigh the serious risks of pulmonary oil microembolism and anaphylaxis."
The drug will be available, with restrictions, through the Aveed Risk Evaluation and Mitigation Strategy (REMS), according to the manufacturer, Endo Pharmaceuticals, which is marketing the product as Aveed. Under the REMS, prescriber education and certification will be required and distribution of the product will be restricted, according to the company.
The product is available in single-use vials; the recommended dosing is 3 mL (750 mg) at the start of treatment, at 4 weeks, and then at 10-week intervals. After each injection, patients are observed for symptoms of pulmonary oil microembolism (POME) or anaphylaxis for 30 minutes in the physician’s office, clinic, or hospital, the only places where the drug can be administered. Symptoms of serious POME reactions include an urge to cough, dyspnea, throat tightening, chest pain, dizziness, and syncope.
Since Endo filed for approval in 2007, approval of TU has been held up for safety reasons, namely reports of anaphylaxis and POME during or shortly after injections were administered, in clinical and postmarketing studies in countries where the product was approved. At a meeting in April 2013, the FDA’s Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee split on the safety issue, voting 9-9 on whether they believed the drug had an acceptable safety profile for the proposed use.
Approval was based on the results of a phase III, 84-week, single-arm study of 130 hypogonadal men (mean age, 54 years), which determined that TU was an effective testosterone replacement therapy, based on serum testosterone levels. There was one case of a patient who had mild coughing after the third injection, which was later attributed to POME, according to the prescribing information.
But more cases have been reported after approval in countries outside the United States and in a review of 18 clinical studies; where possible cases of POME were adjudicated, of about 3,500 patients there were 9 cases of POME in 8 patients and 2 cases of anaphylaxis.
The product has been available since 2003 outside the United States, where it is marketed by Bayer Pharma and its subsidiaries.
The company is providing information about the REMS at www.AveedREMS.com and 855-755-0494.
Serious adverse events associated with testosterone undecanoate should be reported to the FDA’s MedWatch program at 800-332-1088 or www.fda.gov/medwatch.