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SILVER SPRING, Md. -- An FDA advisory committee was split Thursday on the safety of an injectable form of testosterone replacement, but voted overwhelmingly against a proposed risk mitigation plan.
In a joint meeting of the FDA's Reproductive Health Drugs Advisory Committee and its Drug Safety and Risk Management Advisory Committee, panelists voted 9-9 that Endo Pharmaceuticals' testosterone undecanoate injection (Aveed) was safe to treat low testosterone in men.
The FDA and committee members expressed concern over a small number of severe cases of post-injection reactions from the testosterone. The reactions, classified as either pulmonary oil microembolism (POME) or anaphylaxis, were believed to be a result of the castor oil used in the product's formulation or the excipient benzyl benzoate.
"We may be holding Endo to a higher standard looking at other formulations that are out there," said panelist Robert Zaayer, PA-C, director of physician extended services at Premier Physician Services in Dayton, Ohio, who voted that the product was safe. "Virtually all of them list anaphylaxis as one of their side effects."
Patients receiving the Aveed injection suffered 3.71 cases of post-injection reactions per 10,000 treatment years, the FDA said. The reactions were sometime so severe that they required hospitalization. The proposed product, 750 mg in 3mL solution, is injected 4 weeks after the initial dose and then every 10 weeks thereafter.
Malvern, Pa.-based Endo noted the product has been used for 9 years in other countries, and 3.7 million doses have been administered. In fact, multiple committee members noted the long track record of use in Europe with no serious events.
But the FDA's concerns, expressed in briefing documents released before Thursday's meeting, resonated with panelists.
"For them to have noted the seriousness of this, I paid attention to that," said Elaine Morrato, DrPH, professor of health management and policy at the University of Colorado, Anschutz Medical Campus in Aurora, Colo., who voted against the safety.
Bart Clarke, MD, of the Mayo Clinic College of Medicine in Rochester, Minn., expressed concern over long-term use in patients and the worse safety profile compared with other formulations.
Testosterone replacement is already approved in formulations of transdermal patches, gels, tablets, subcutaneous implants, solution, and two products for intramuscular injection similar to Endo's proposed product.
A representative of the American Association of Clinical Endocrinologists, who spoke during the meeting's public hearing, said the organization doesn't support the approval of any one product, but added that there is a need for new drugs to help decrease the burden of low testosterone.
The Endocrine Society's representative, Allan Glass, MD, of Bethesda, Md., suggested that cough related to injected testosterone was an order of magnitude more prevalent than the injection reactions the committee discussed at length, and should not be overlooked.
Panelists also on Thursday voted 17-1 against recommending a proposed risk evaluation and mitigation strategy (REMS) for the drug.
Because many of the infections occurred within minutes of the injection, the FDA suggested adding instructions in the product's label that Aveed be administered using a slow injection lasting from 30 seconds to 60 seconds. Also, providers would be strongly advised to keep patients in their office for 30 minutes after receiving an injection to see if any post-injection reactions occur.
"Doing these things makes sense, but I don't think it'll actually make a difference in the number of injection reactions," Clarke said.
He and others expressed doubt that simply injecting the product slowly -- rather than all at once -- would prevent reactions from occurring.
"We don't know the mechanism of the severe adverse events we're discussing, so how can we possibly know the solution?" asked Richard Bockman, MD, PhD, head of endocrine service at the Hospital for Special Surgery in New York City.
Endo's proposed REMS plan also includes issuing a "Dear Doctor" letter in its communication plan, but the FDA said there is little incentive for prescribers to review materials that are not required, given demands on their time.
The path to obtain approval for Endo and Aveed has been long. The company first submitted its new drug application to the FDA in August 2007 with a similar dosing regime. However, the FDA raised the same concerns about severe post-injection reactions. The application was deemed not approvable in June 2008.
Endo submitted additional safety data in March 2009, but the FDA continued to be concerned with the risk-benefit profile and issued a complete response letter in December 2009.
There are few questions over the product's efficacy, and the FDA didn't ask for the advisory committee to offer its opinion in that area, nor did it ask the panel to vote on whether it would recommend approval.
Of 130 patients enrolled in an efficacy trial with an extension, 89% completed the 24-week study, and 94% of subjects had serum total testosterone values within normal range (95% CI 90% to 99%). The FDA concluded that this result met the requirement for efficacy.
The FDA is due to render its decision on Aveed by mid-May. The agency isn't required to follow the advice of its advisory committees but usually does.