Can a new crush resistant formulation of an opioid block FDA approval of a generic version of the non-crush resistant product?

That’s the question confronting FDA in a citizen petition submitted by Endo Pharmaceuticals Inc. The company requested that FDA refuse to approve any pending ANDA for a generic version of the non-crush resistant version of its Opana ER (oxymorphone HCl) extended-release tablets and suspend and withdraw approval of any ANDA referencing that formulation.

FDA approved Endo’s new drug application for Opana ER Crush-Resistant Formulation in December 2011. The company announced in June that it had completed the transition of Opana ER to the new formulation, and on Aug. 10 it submitted its citizen petition. Endo noted in its citizen petition that FDA had moved Opana ER to the discontinued list section of the agency’s Orange Book.

Endo also requested that FDA determine that the company had withdrawn the original Opana ER formulation from sale for reasons of safety and effectiveness.

Prior to the discontinuation of Opana ER, FDA approved two ANDAs for generic versions of the product, submitted by Impax Laboratories Inc. and Actavis South Atlantic LLC. Endo said that because both products are directed to the original Opana ER NDA they are not likely to have a crush resistant design. Endo noted that it has a patent license agreement with Impax that prevents Impax from launching its non-crush-resistant formulation until Jan. 1, 2013.

“The potential widespread availability of non-tamper-resistant generics of all strengths of Opana ER in early 2013 calls into question whether these generics can be properly marketed in view of the discontinuation of Opana ER for safety reasons,” Endo’s petition states. “The presence of both Opana ER CRF and generic, non-crush-resistant oxymorphone formulations on the market simultaneously would allow abuse or diversion to continue, limiting the potential benefits that can be provided by Opana ER CRF.”

Purdue Files Third OxyContin Citizen Petition

Endo may have a tough time convincing FDA, however. In announcing the approval of the new Opana ER, the agency said the labeling does not contain language about crush resistance or abuse deterrence Also see "No Abuse-Resistance Claim For Endo’s Opana ER Reformulation" - Pink Sheet, 12 December, 2011..

It is an important battle for Endo since Opana ER is its second largest product, generating revenues of $174.5 million in the first six months of 2012. Its top selling product, Lidoderm (lidocaine), faces generic competition in September 2013. FDA recently denied Endo’s citizen petition asking the agency to require clinical trials to demonstrate the bioequivalence of generic lidocaine patches Also see "Clinical Trials Not Required For Lidoderm Generics, FDA Tells Endo" - Pink Sheet, 3 September, 2012..

Endo is not alone in arguing against approval of generic versions of older opioid formulations. Purdue Pharma LP has filed three citizen petitions requesting that ANDAs citing its OxyContin (oxycodone) include data from in vitro and in vivo tests. The company submitted its first citizen petition in 2008 and a second in January 2011 seeking to block approval of King Pharmaceuticals Inc.’s NDA for Remoxy (oxycodone extended-release) Also see "Purdue Moves To Stave Off Branded, Generic Competitors To New OxyContin" - Pink Sheet, 14 February, 2011..

In July 2011 FDA denied Purdue’s second petition without comment on whether it agreed with the actions Purdue requested. Purdue had asked that King (now a subsidiary of Pfizer Inc.) be required to reference reformulated OxyContin as the listed drug since it is the “most similar” to Remoxy.

“Because King is precluded by statute from amending or supplementing its application to identify reliance on a different drug than that contained in the original Remoxy application, you request that FDA require King to withdraw its Remoxy application, confirm that a resubmitted application references reformulated OxyContin as the listed drug, and confirm that application contains appropriate certifications to reformulated OxyContin’s patents,” FDA stated in a letter to Purdue.

But the agency said that taking final action on the approvability of specific aspects of a specific NDA would interfere with both the statutory and regulatory scheme governing the review and approval of NDAs. FDA noted that it has not determined the approvability of the NDA as a whole. Remoxy has faced hurdles getting through FDA. The agency issued a second “complete response” letter in June 2011 Also see "Remoxy's "Complete Response" Letter Has No Clear Culprit But Many Suspects" - Pink Sheet, 24 June, 2011..

Purdue renewed its arguments in a third citizen petition, submitted to FDA two months ago. The company said it had discontinued the original formulation of OxyContin, noting that it was “subject to significant abuse and diversion” and had been “inadvertently misused by patients or their caregivers.”

Endo, Purdue Cite Safety Studies Of Reformulated OxyContin

FDA approved Purdue’s abuse-resistant formulation, designed to make breaking, crushing or chewing the drug more difficult, in April 2010. In August 2010 the company stopped shipping the original formulation and began distributing the reformulated product. FDA required the company to conduct postmarketing studies and implement a Risk Evaluation and Mitigation Strategy.

In July, the agency issued a class-wide REMS for long-acting extended-release opioid products. Thirty-five products from 19 sponsors are subject to the REMS, including Opana ER and OxyContin Also see "Long-Acting Opioid REMS Tally: FDA Lists 12 Brand, 23 Generic" - Pink Sheet, 16 July, 2012..

In its most recent petition, Purdue asserts that reformulated OxyContin has been extensively tested under a variety of in vitro conditions designed to simulate attempts to abuse or misuse the product, and was also tested in pharmacokinetic and abuse potential studies.

“Based on these data, Purdue believes that reformulated product offers substantial safety advantages over the original,” the petition states. The company requests that “all purported generic copies of reformulated OxyContin” also be subject to a rigorous in vitro test program and appropriate confirmatory in vivo study or studies.

Endo also cited studies done on reformulated OxyContin in its petition to FDA. It references a study that found the abuse of extended-release oxymorphone has risen by approximately 139% since the introduction of abuse-deterrent OxyContin.

A New England Journal of Medicine report also found that the abuse deterrent formulation of OxyContin had helped reduce abuse of the opioid. But the researchers said the reformulation had led addicts to turn to other drugs, particularly heroin Also see "OxyContin Abuse-Deterrent Formulation Has Addicts Switching To Heroin" - Pink Sheet, 16 July, 2012..

Endo Seeks To Block Generics Of Opana ER That Are Not Crush-Resistant

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