A joint FDA advisory committee voted 18-to-8, with one abstention, that the benefits of Opana ER (oxymorphone hydrochloride) do not outweigh its risks to public health, following outbreaks of HIV, hepatitis C, and vascular issues related to intravenous abuse of the drug.
While the question was not directly posed to joint panel, most agreed that the drug should be removed from the market given its high potential for intravenous abuse and related consequences. The 2-day meeting, which carried on despite a snowstorm, involved members of the Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) and the Drug Safety and Risk Management Advisory Committee (DSARM).
"This formulation of oxymorphone has unintended consequences that deserve its removal from market," said panelist , of Columbia University in New York City, who voted against the drug.
, of the University of California San Francisco (UCSF), agreed that the "risks outweigh the benefits. Oxymorphone has a limited place in the repertoire. The weak abuse-deterrence formulation is not good at this point and needs more innovation ... The best thing moving forward is to go back to the lab. Microbeads, irritants ... should be strongly considered by this company."
Opana has had a long and tumultuous regulatory history at the FDA. It was approved in 2006 for treatment of chronic pain, but drugmaker Endo Pharmaceuticals upped the ante in 2011 with a reformulated version it said would be harder to abuse.
The company never won any abuse-deterrent labeling for the new formulation, and lost a battle to get the FDA to ban generic versions of the original formulation, claiming the new version was much safer. Purdue Pharma had succeeded at both strategies with its reformulated abuse-deterrent version of OxyContin (oxycodone) in 2010 and banned generics in 2013.
Opana had originally come to market in 1959 as Numorphan, but earned a reputation for severe abuse, and was eventually removed from the market in the 1970s, as detailed in a 51˶/Milwaukee Journal Sentinel investigation.
Several public health issues have appeared since the reformulated version came to market. In 2013, the CDC reported 15 cases of thrombotic thrombocytopenic purpura (TTP) tied to intravenous abuse of Opana ER. Since that time, additional case reports have appeared in the literature.
An outbreak of HIV in Scott County in Indiana was also tied to intravenous abuse of Opana, and many of those patients also had co-infection with the hepatitis C virus due to needle sharing, according to the CDC.
The meeting appears to have originated from the FDA's Office of Surveillance and Epidemiology, with a letter from, leading the FDA's meeting materials. Staffa presided over the meeting. , director of FDA's division of anesthesia, analgesia, and addiction products, was in attendance.
Officials from Endo Pharmaceuticals presented efficacy data on the drug, as well as post-marketing data on abuse and misuse from its NAVIPPRO and RADARS monitoring systems. FDA reviewers also analyzed epidemiologic and animal data to fully characterize the risks and benefits of the drug.
Overall, many panelists acknowledged the lack of data, and said the available data were limited. But most said they felt confident enough to conclude that Opana did carry increased risks tied to injection abuse. While its new formulation made it hard to abuse intranasally, panelists said, it became easier to abuse via injection.
Other characteristics of the drug made it particularly susceptible to problems like TTP and HIV infection, they agreed. For instance, the drug has a short half-life, which forced users to inject more frequently. Also, the gelling property that was intended to diminish injection abuse was easily defeated but it still led to thickening that was likely tied to TTP, they said. The culprit behind the TTP issues was thought to be the use of polyethylene oxide (PEO) in the reformulated version.
During the vote, panelists debated whether other strategies, rather than complete withdrawal from the market, could improve the risk profile tied to abuse of Opana ER.
"I do think we should take steps to limit prescribing, such as using labeling to make it a second-line drug, because it does have unique properties that make it more effective for those who failed other therapies," said panelist , of Banner University Medical Center in Phoenix, who voted that the drug's benefits outweighed its risks. "I would support changing the label, or the prescribing pattern, and a warning on misuse."
Many panelists, however, thought a better idea would be to improve the drug.
, also of UCSF, voted that the drug's benefits outweighed its risks, said he would advocate revising and resubmitting the drug NDA for Opana ER.
"We've got a good start, but it needs improvement, and we need to address the issue of what happens when you put it in a syringe," Mendelson said. "One milligram of Narcan would change our discussion today. I voted a qualified 'yes,' and I would revise and resubmit the application."
, of the University of Maryland in College Park, who cast the lone abstention vote, said he heard plenty of data regarding the complications of abusing the drug, but not enough about its efficacy.
"Almost all of [the data] was about the risk of this drug. To make a decision, I need another binder on the receptivity of the drug by patients and physicians, and how effective it is," Wish said. "If the FDA could do anything, it would be to require physicians to institute random drug testing of patients, to make sure they're taking the drugs properly and not using a panoply of other drugs, which would indicate they need other types of treatment."