FDA Panel Split on Safety of Long-Acting Testosterone

Megan Brooks

April 18, 2013

An advisory panel to the US Food and Drug Administration (FDA) was split today on the question of whether or not testosterone undecanoate intramuscular injection (Aveed, Endo Pharma Solutions) is a safe testosterone replacement therapy, given reports of severe post-injection reactions.

The vote was 9 for approval, 9 against. Many panel members acknowledged it was a tough decision and said that they were conflicted regardless of whether they voted yes or no to the question of safety.

The decision was far easier among panel members on whether the risk-management plan put forth by the company to ameliorate potential risks associated with the product was adequate. Only 1 panel member felt the risk-management plan was "sufficient."

Testosterone undecanoate is a long-acting depot formulation of testosterone in castor oil and benzyl benzoate. The proposed indication is for adult men with conditions associated with a deficiency or absence of testosterone. It is administered at a dose of 750 mg via intramuscular injection of 3 mLs of solution, followed by a repeat dose of 750 mg after 4 weeks, then 750 mg doses every 10 weeks thereafter.

Testosterone undecanoate intramuscular injection has been approved for marketing in more than 90 countries. The approved dosing regimen in Europe is 1000 mg via intramuscular injection of 4 mLs of solution.

The safety and risk-benefit profile of testosterone undecanoate injection was discussed today during a joint meeting of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee.

Post-Injection Reactions a Concern

The FDA first denied approval of the drug in 2008 citing safety concerns, and then again in 2009 for safety concerns and questions about the risk-benefit profile.

The concerns stem largely from immediate post-injection reactions, some severe, that have been reported in clinical trials and post-marketing experience with testosterone undecanoate injection, primarily pulmonary oil microembolism and anaphylactic reactions. No deaths have been reported after post-injection reactions, but resuscitations and hospitalizations have been required in some cases.

In general, panel members who felt the product is safe cited its long history of use in Europe and felt the risks were manageable, and there have been no reported deaths. "I voted a conflicted yes. I share concerns about safety but believe there is a strong need for a long-acting alternative," said panel member T. Mark Woods, PharmD, from Saint Luke's Hospital, Kansas City, Missouri.

During the open public hearing, all 8 speakers voiced support for the product and the need for a long-acting injectable testosterone product, given the limitations of currently available testosterone gels and patches and short-acting injectable testosterone.

Panel members who felt the product is not safe cited insufficient data and an unfavorable risk-benefit profile. Explaining his "no" vote, Lewis Nelson, MD, from New York University School of Medicine in New York City, said there is a "real absence of data to prove it's truly safe."

Brian Erstad, PharmD, of the University of Arizona College of Pharmacy, Tucson, said that while he appreciates the need for a long-acting product, he "felt obligated" to say no due to the risk-benefit profile.

Elaine H. Morrato, DrPH, from the University of Colorado, Aurora, said she was "persuaded by the FDA reviewers' concerns."

Suzanne Robottom, PharmD, senior risk management analyst at the FDA, who briefed the committee, said a concern she has is that there is "no way to predict who will develop a post-injection reaction" or prevent these reactions.

Risk-Management Plan Lacking

During the sponsor presentation, Frank Casty, MD, FACP, chief medical officer, Endo Pharma Solutions, said, "We take these events seriously and we've proposed a detailed risk-management plan."

Neil Shusterman, MD, FACP, from Endo Pharma, presented the company's risk-management plan, which is broadly based on "awareness, preparedness, and management of post-injection reactions which are infrequent, detectable, and manageable," he said.

The plan includes administering the drug using a slow (30 – 60 second) injection and having patients stay in the facility for 30 minutes after injection, akin to patients who get allergy shots. The reported post-injection reactions have occurred during or within minutes from the time of the intramuscular injection. The plan also includes a medication guide, a "Dear Health Care Provider Letter," and controlled distribution of the product, as well as other components.

However, by a vote of 17 to 1, the advisory committee did not feel the plan would be sufficient to ameliorate the risk for severe post-injection reactions.

The FDA is expected to make their decision next month, estimated to be around May 15.