US regulatory officials today approved Endo Pharmaceuticals' testosterone replacement therapy drug Aveed (testosterone undecanoate), ignoring a petition submitted last week by a consumer group that claimed the agency should first conclude a safety review of alternative products.

Background

FDA recently initiated a safety review of testosterone replacement therapy drugs-more commonly known as "Low-T" drugs-after several studies raised concerns about their cardiovascular safety in certain male subgroups.

The studies, in the Journal of the American Medical Association (JAMA) and in the journal Public Library of Science: Medicine (PLoS Medicine), both showed an elevated risk of cardiovascular events. The JAMA study suggested a 30% increase in risk of stroke, heart attack and death in those taking products intended to treat low-T, while the PLoS study showed that older men (ages 65 and older) exhibited a two-fold increase of heart attack and younger men with a history of heart disease had a two- to three-fold increased risk of the same.

Based on those studies, FDA said it would reassess the risks of testosterone treatment, but stopped short of asking physicians to alter their current prescribing habits.

The drugs are already subject to a number of serious safety warnings, including that accidental exposure to testosterone (such as by family members) may cause health problems. The drugs also contain warnings that patients should tell their doctors if they have prostate cancer, heart problems, kidney or liver problems or urinary problems.

A Petition

Based on those concerns, the public advocacy group Public Citizen petitioned FDA to add Black Box Warnings to all Low-T drugs, and to delay the approval of Endo's Aveed until its safety review had been completed.

Public Citizen said in light of the new risks, introducing a new product to the market could exacerbate harms by impacting additional patients. Four Low-T drugs are already on the market: Androgel, Axiron, Testim and Fortesta. Those drugs were prescribed more than five million times in 2013, according to Public Citizen's petition.

Read more about Public Citizen's petition in Focus' 26 February 2014 article, "Consumer Group Calls for New Warnings for Low-T Products, Delay of Endo's Aveed."

Regulatory Concerns

Those safety concerns were certainly not unwarranted. A joint meeting of two FDA advisory committees had called into question the safety of Aveed during an April 2013 meeting,  and ultimately denied approval to the drug in May 2013 in a Complete Response Letter (CRL) to Endo. At the time, FDA said the company's Risk Evaluation and Mitigation Strategies (REMS) and Elements to Assure Safe Use (ETASU)-both used to restrict access to the medication and ensure its safe use-needed to be strengthened based on the risks of post-injection reactions.

The drug had twice before been denied by regulators.

Endo's Aveed is injected into patients, unlike other Low-T drugs, which are applied topically. In theory, this would mitigate some of the more common risks associated with topical application of the drug, most notably the transfer of the hormone to others, which can cause adverse reactions.

Fourth Time is the Charm

For Endo, though, a subsequent review-its fourth-was sufficient to placate regulators to the safety of Aveed. On 6 March 2014, Endo announced that the drug had been approved by FDA for the treatment of adult men with hypogonadism, or Low-T.

The safety concerns associated with the drug are notable in the company's approval notice. Patients are only able to obtain the drug at a doctor's office, clinic or hospital, and patients are advised to stay at the those locations for 30 minutes after being injected with Aveed in case they suffer a serious allergic reaction or serious pulmonary oil microembolism (POME).

Both warnings are contained within the drug's Boxed Warning. The drug is also approved under a REMS requiring prescriber education and certification, as well as restricted distribution.

Public Citizen Response

News of the approval immediately caused Public Citizen to send a letter of protest to FDA Commissioner Margaret Hamburg.

The approval "will likely greatly expand the use of testosterone, now found to increase the risk of heart attacks and other cardiovascular diseases," wrote Sidney Wolfe, founder of Public Citizen's Health Research Group.

Public Citizen also raised the prospect that FDA's approval of the drug, based in part on the findings of its advisory committee, might have reached a different conclusion had the advisory committee known about the potential cardiovascular risks associated with the drug.

"It is likely, if not certain, that the vote against safety would have been even greater had there been a presentation and discussion of the cardiovascular risks known at that time," Wolfe wrote.

The group urged FDA to reverse its approval, calling it "unsafe and unreasonable."