The following article is from Pain Medicine News. Among other considerations, it explains the necessity for PFE to perform a second abuse liability study on the "tweaked" formulation of Remoxy.
FDA Approves One Citizen Petition, Rejects Another, Clouding Picture for Abuse-Deterrent Opioid Developers
When in April, the FDA granted approval to Purdue Pharma’s supplemental new drug application (NDA) for its reformulated, abuse-deterrent version of controlled-release oxycodone hydrochloride (OxyContin), many in the field of pain medicine, as well as political and media pundits, surmised that they had figured out a method to the FDA’s madness regarding the development of abuse-deterrent formulations of opioids. By agreeing with the principles of Purdue’s Citizen Petition, namely that the original version of OxyContin was removed from the market because of safety and efficacy reasons, and furthermore that the new abuse-deterrent version was superior in terms of risks and benefits, the agency set a new benchmark that all generic versions of OxyContin would be required to meet. This, many decided, was how the FDA was going to handle the prickly issue of generic opioids, which given their lack of abuse-deterrent properties, likely would make them a target for abusers, misusers and diverters of opioid analgesics as more abuse-deterrent agents enter the market.
Then, on May 10, Endo Pharmaceuticals, the maker of Opana ER (oxymorphone HCl), which also was reformulated with abuse-deterrent properties that made it crush resistant, received a denial for its own Citizen Petition. That petition made many of the same arguments for Opana ER that were made for OxyContin—specifically, that the non–abuse-deterrent formulation was withdrawn from the market for reasons of safety, and the new abuse-deterrent version was therefore safer and should be the measuring stick used for all potential generic versions. This time, however, the FDA did not agree.
Thumbs Up for OxyContin …
In April, the FDA approved updated labeling for reformulated OxyContin (oxycodone hydrochloride controlled-release) tablets. The new labeling states that reformulated OxyContin is imbued with “physical and chemical properties that are expected to make abuse via injection difficult and to reduce abuse via the intranasal route (snorting),” according to a press release from the FDA, announcing the approval.
The FDA further announced that the reformulated OxyContin is therapeutically equivalent to original OxyContin, which ceased delivery to pharmacies in August 2010, because of safety concerns. (The abuse-deterrent version of the agent was introduced in April 2010.) The agency added that given the original version’s higher risk for some forms of abuse and misuse, “the FDA has determined that the benefits of original OxyContin no longer outweigh its risks and that original OxyContin was withdrawn from sale for reasons of safety or effectiveness.” Thus, the FDA stated at the time of the new approved labeling that it would not consider for approval new drug applications for generic opioids based on the approval of the original, discontinued version of OxyContin. The original formulation of OxyContin was approved by the FDA in 1995.
“Purdue Pharma is pleased with the FDA’s approval of this new language for the OxyContin label, which will provide important information to health care professionals,” said Gary L. Stiles, MD, senior vice president of research and development at Purdue Pharma. He added, “Prescriber and patient education remains critically important to ensuring the proper use of opioid analgesics. We strongly encourage prescribers to take advantage of the professional education resources developed as part of the Risk Evaluation and Mitigation Strategies (REMS) for extended-release and long-acting opioids.”
… but Not for Opana ER
Endo maintained in a press release, following the ruling on its petition with the FDA, that the original formulation of Opana ER also was withdrawn from the market for safety reasons. The company stated that its stance is in part supported by ongoing epidemiologic research. Specifically, Endo stated that the research showed the 30-day abuse rates for the crush-resistant version of Opana ER per 100,000 prescriptions was 79% lower than for generic, non–abuse-deterrent versions of oxymorphone.
Based on these data, the company asked the FDA to reject any abbreviated NDAs for generic versions of oxymorphone that referenced the non–abuse-deterrent version of Opana ER. Furthermore, it requested the suspension of any approved generic formulations of Opana ER currently on the market. Both requests were turned down by the FDA.
According to Endo, the FDA decided that the original formulation of Opana ER was not withdrawn from the market for safety or effectiveness reasons. Because of this, the agency will continue to allow existing generic versions of the original formulation of oxymorphone to remain on the market and allow new products to be submitted for FDA approval.
In a statement regarding the rejection of Endo’s petition, the FDA stated that while the new version of Opana ER better resisted attempts to crush it than the older version, “study data show that the reformulated version’s extended-release features can be compromised when subjected to other forms of manipulation, such as cutting, grinding or chewing, followed by swallowing.” The agency also maintained that reformulated Opana ER could still be manipulated easily for injection, “despite Endo’s claim that these tablets have ‘resistance to aqueous extraction (i.e., poor syringeability).’” The FDA added that the reformulated drug “can be prepared for snorting using commonly available tools and methods.”
“We are extremely disappointed and disagree with today’s decision, and believe that the approval of non–abuse-deterrent formulations of long-acting opioids will contribute to a significant increase in prescription drug abuse,” said Rajiv De Silva, president and CEO of Endo Health Solutions. “With the approval and expected launch of additional non–abuse-deterrent generic versions of Opana ER, we will carefully assess Endo’s position in the competitive landscape and explore all options, including those intended to mitigate the effect of this decision. Endo remains committed to patient safety, including appropriate use of our products, as a top priority.”
News of the two rulings was met with confused reactions by several thought leaders in pain medicine.
“The OxyContin approval sends a very positive message for developers of other [potential] oxycodone extended-release abuse-deterrent formulations,” said Joseph Pergolizzi, Jr, MD, adjunct assistant professor at Johns Hopkins University School of Medicine, in Baltimore, adjunct faculty member in the Department of Anesthesiology at Georgetown University School of Medicine, in Washington, D.C., and senior partner in the Naples Anesthesia and Physician Associates Group, in Naples, Fla. Dr. Pergolizzi is also a Pain Medicine News editorial board member.
“It [the OxyContin approval] is a great win for public health policy,” he said. “Unfortunately, the negative ruling on Endo’s Citizen Petition last week related to Opana ER with Intac technology is somewhat concerning, because now non–[abuse-deterrent formulations] of this potent opioid analgesic could be more readily available.”
American Academy of Pain Medicine (AAPM) President Lynn Webster, MD, said pushing for extending tamper-resistant requirements for all opioid analgesic drugs is a chief focus of the AAPM for 2013.
“It would be ironic and counterproductive if the FDA allows generics without tamper-resistant properties to compete with branded tamper-resistant formulations since they also have mandated a comprehensive REMS for the same long-acting/extended-release opioid formulations,” Dr. Webster told Pain Medicine News. “Since abuse-deterrent technology is now available, all new formulations should be required to have abuse-deterrent properties. Failure to require abuse-deterrent properties in new formulations or generics would be a setback in the battle to fight prescription drug abuse and unintentional overdose deaths.”