FDA Panels Say Risks of Opana ER Outweigh Benefits

Fran Lowry

March 17, 2017

A panel of US Food and Drug Administration (FDA) experts has advised the agency that the risks of an abuse-deterrent extended-release formulation of oxymorphone (Opana ER, Endo Pharmaceuticals) for relief of severe pain now outweigh its benefits.

The vote by experts on the FDA's Drug Safety and Risk Management Advisory and Anesthetic and Analgesic Drug Products Advisory committees was 18 "yes" to 8 "no," with one abstention, with the yes votes indicating that the risk-benefit ratio has changed and not for the better.  

The committees were asked to discuss safety issues with the product for the indication of management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Several oxymorphone products are on the market, including original immediate-release Opana, and multiple generic immediate-release and extended-release products, but only the reformulated Opana ER is designed to deter abuse by intranasal or injection routes, the FDA briefing document notes.

The reformulated version of Opana ER was approved by the FDA in 2011. It incorporated physiochemical properties designed to make it more difficult to snort or inject. However, the FDA did not approve a supplemental application in 2013 by the company requesting approval of labeling describing these properties, so that language does not appear in the label, the briefing document points out.  

At the meeting, the committees heard and discussed pre- and postmarketing data on the abuse of Opana ER and the overall risk-benefit of this product.

Data presented showed that nasal abuse was reduced with the reformulation, but intravenous abuse increased, and with it, reports of a fatal bleeding disorder resembling thrombotic thrombocytopenic purpura. In addition, what the document calls an "unprecedented outbreak" of HIV occurred in a rural Indiana county in association with intravenous abuse of Opana ER.

In their internal review, FDA staff noted that it was unclear whether that rise in intravenous use was tied directly to the reformulation.

"When the drug was approved, it was approved based on the conditions and the labeling that it was proposed for, and at that point the risk-benefit ratio was considered favorable. Now the ratio is no longer considered to be favorable," Almut Winterstein, RPh, PhD, professor and Crisafi Chair, Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, told Medscape Medical News.

"The majority of advisory committee members felt that the risk-benefit was not favorable anymore. That basically means something needs to be done," Dr Winterstein, who chaired the meeting, said.

"Several advisory committee members said explicitly that they thought the drug should be withdrawn from the market in the discussion after the vote was taken, but I did not count the number," she added. "There were certainly some, but even among the people who voted that they felt the risk-benefit ratio was still good, even those members agreed that something needs to be done to curb the abuse potential, so I think the general consensus was that it cannot continue the way it has."

There was debate, she said, "but the majority of advisory committee members felt that there needs to be a very significant restriction put in place which cannot be as simple as a medication guide but perhaps should include something like restrictions to certain types of physicians or certain types of patient populations, something that would make it harder to prescribe…as first line treatment if other treatment choices are available adequate and appropriate."

"The question put before us was 'Do the benefits of Opana ER still outweigh the risks?'" Suzanne B. Robotti, founder and president of MedShadow.org, New York, New York, and the consumer representative on the Drug Safety and Risk Management Advisory Committee, told Medscape Medical News. "That was the original vote and years ago the answer was yes. I voted no, it no longer does."

She said she felt that although the research studies were not of the highest quality, "the pattern seemed clear, that the abuse of the drug had moved from nasal abuse, from snorting, to intravenous abuse," she noted.

"The additional problems with snorting are not so great, so large a threat to your health, but the additional problems with IV starts with sepsis and moves on to HIV and hep C and other complications that make recovery from addiction much, much harder," Robotti said. "When considering the effect of the medication in the entire community — that seemed like an unacceptable shift to me."

She agreed that finding pain control that does not have abuse potential is a problem.

"Absolutely. In fact, you have to be able to give the drug to people who are in terrible pain, who often need to crush it because they can't swallow it otherwise, so it is almost impossible to make a complete abuse deterrent. And that's a phrase that…almost all of us [on the committee] agreed is a confusing term and a misleading term," she said. "This drug is crush resistant, but an addicted person will be able to figure out how to use it intravenously."  

"Endo remains confident that the body of evidence established through clinical research demonstrates that Opana ER has a favorable risk-benefit profile when used as intended in appropriate patients," said Matthew W. Davis, MD, RPh, senior vice president, research & development, branded pharmaceuticals, at Endo, in a statement.

"Our top priorities include patient safety and ensuring that patients with chronic pain have access to safe and effective therapeutic options," he added. "We plan to work collaboratively with the FDA as the Agency completes its evaluation of Opana ER, while advocating to preserve the important benefits of the medicine for patients."

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