December 4, 2012

Endo Sues FDA to Keep Non-Crush Resistant Generics Off the Market as Unsafe

Thumbnail image for Thumbnail image for FDA logo.jpgOn November 30, Endo Pharmaceuticals Inc. ("Endo") sued FDA, seeking declaratory and injunctive relief for FDA to determine that Endo's original Opana® ER (oxymorphone hydrochloride extended-release) was withdrawn from sale for safety reasons, because the product is inherently vulnerable to misuse and abuse. The current crush-resistant formulation of Opana® ER, which goes by the same name, was approved in December 2011, and Endo began marketing this formulation, which Endo called "Opana® ER CRF" in its Complaint to distinguish it from its earlier-marketed formulation. For consistency and clarity, this blog will use the same nomenclature. Endo's complaint states that Opana® ER CRF is bioequivalent to Opana® ER but embeds the active ingredient in a polyethylene oxide matrix to make the pill harder and less crushable, as well as more difficult to liquefy and inject.

According to the Complaint, Endo discontinued Opana® ER on May 31, 2012, because it believed Opana® ER CRF to be less susceptible to misuse and abuse. Endo believes that FDA was required to make a determination whether Opana® ER was withdrawn from the market "promptly" (emphasis in original), because, by this time, FDA had already approved two generic versions to be marketed by Impax Laboratories, Inc. ("Impax") and Actavis South Atlantic LLC ("Actavis"). Endo's Complaint further explains that when FDA failed to make a prompt determination. it filed a Citizen Petition, requesting that FDA make the determination that Opana® ER was discontinued for reasons of safety and cannot be a reference listed drug and that only Opana® ER CRF can have generic versions, which must be similarly crush resistant. Endo further filed a second Citizen Petition and supplemented its original Citizen Petition. The second Citizen Petition sought to classify Opana® ER CRF as a separate dosage form to Opana® ER and require generic versions of Opana® ER CRF to be similarly crush-resistant. The supplement to its original petition included data suggesting that Opana® ER CRF resulted in less reports of abuse and diversion, among other things, which is also described in the Complaint.

Endo's Complaint asserts that Opana® ER was safe and effective when used according to its FDA-approved labeling, but it became evident over time that it posed risks to humans. First, when crushed into a fine powder and inhaled or otherwise ingested, the active ingredient could be released very quickly, risking overdose. Opana® ER could also be chewed, either inadvertently or intentionally, also causing an accelerated release of its active ingredient. Approximately one year after introduction of Opana® ER into the market, Endo decided to develop a crush-resistant formulation with a German partner to reduce these potentials for abuse and misuse, the Complaint recounts..

Around the same time Endo submitted its new drug application ("NDA") for Opana® ER CRF under a new NDA number (not a supplement to its original NDA for Opana® ER), Purdue Pharma L.P. introduced a crush-resistant formulation of Oxycontin® (oxycodone hydrochloride controlled-release). Similar to Opana® ER CRF, the active ingredient in Oxycontin® was an opioid medication for the management of pain that had a potential for abuse and misuse when crushed. But once the older, crushable Oxycontin® formulation was no longer available, Endo's Complaint continues, abusers began switching to crushable opioid pain medications, such as Opana® ER, under its "'squeezing-the-balloon effect'" theory. After Opana® ER CRF was approved and introduced into the market, however, Endo states that abuse rates for Opana® ER CRF were much lower than for Opana® ER. Both sets of abuse and misuse data were provided in the supplement to Endo's original Citizen Petition. When Endo submitted its Opana® ER CRF NDA to FDA, in contrast, FDA apparently did not know whether crush resistance was important: "In standardized studies, oxymorphone HCl ER was shown to resist crushing forces in excess of [redacted] however the clinical significance of this property and the impact on abuse liability has not been established." (see DRISK REMS REVIEW(September 30, 2011 on page 2, Introduction)).

Endo's Complaint alleges harm by FDA's failure to make a determination as requested, in particular loss of its investment in the crush-resistant formulation, loss of sales once generic versions of Opana® ER are available as soon as January 2013 (based on a settlement agreement with Impax), and price erosion of Opana® CRF. In the interim while the Court decides on the merits of Endo's Complaint, Endo asks the Court to grant injunctive relief to suspend the approval of any ANDAs citing to Opana® ER.

We will continue to monitor this case, as it may impact the entire community of products regulated as controlled-drug substances, where manufacturers are always seeking ways to make their products less prone to abuse and diversion and protect their investments