FDA Determines Original OPANA ER Not Discontinued for Safety Reasons; Decision Affirms Case-by-Case Review

By Kurt R. Karst –       

Late last Friday, FDA announced that the Agency denied an August 13, 2012 Citizen Petition (Docket No. FDA-2012-P-0895) submitted by Endo Pharmaceuticals Inc. (“Endo”) requesting that the Agency determine that OPANA ER (oxymorphone HCl) Extended-release Tablets approved under NDA No. 021610 were discontinued for safety reasons in light of the availability of a reformulated version of OPANA ER approved under NDA No. 201655, and that FDA refuse to approve any pending ANDAs and suspend and withdraw the approval of any ANDAs citing original OPANA ER as its Reference Listed Drug.  The decision, which is apparently the first under the new 270-day timeframe at FDC Act § 505(w) covering discontinuation petitions submitted pursuant to 21 C.F.R. § 314.161, comes less than a month after FDA determined that OXYCONTIN (oxycodone HCl) Controlled-release Tablets approved under NDA No. 020553 were discontinued for safety reasons in light of the availability of a reformulated version of OXYCONTIN approved under NDA No. 022272 (see our previous post here).  On the same day FDA announced its decision concerning reformulated OXYCONTIN, the Agency approved abuse-deterrent labeling for the drug.  A decision on abuse-deterrent labeling for reformulated OPANA ER did not surface last week, perhaps presaging FDA’s petition decision.

Endo argued in its petition that the reformulated version of OPANA ER approved under NDA No. 201655 (referred to as “OPR”) offers safety advantages over original OPANA ER (referred to as “OP”) because, among other things, the reformulated version “is resistant to crushing by common methods and tools employed by abusers of prescription opioids . . . [and] is less likely to be chewed or crushed even in situations where there is no intent for abuse, such as where patients inadvertently chew the tablets, or where caregivers attempt to crush the tablets for easier administration with food or by gastric tubes, or where children accidentally gain access to the tablets.”  According to FDA, however, “[w]hile there is an increased ability of OPR to resist crushing relative to OP, data from in vitro and pharmacokinetic studies show that OPR’s extended-release features can be compromised, causing the product to ‘dose dump,’ when subjected to other forms of manipulation such as cutting, grinding, or chewing, followed by swallowing.”  Moreover, commented FDA, it “appears that OPR can be prepared for insufflation (snorting) using commonly available tools and methods, [and] certain data suggest that OPR can more easily be prepared for injection than OP.”  In addition, the data from the postmarketing investigations Endo relies to support the advantages of OPR over OP “are inconclusive,” determined FDA.

Citing drug product and data differences in the cases of OPANA ER and OXYCONTIN, FDA says that it is reasonable for the Agency draw different conclusions:

Based on in vitro, pharmacokinetic, clinical abuse potential, and post-marketing data, we were able to conclude that [original OXYCONTIN] posed an increased potential for intranasal abuse compared to [reformulated OXYCONTIN]. . . .  While the available data show that there is an increased ability of OPR to resist crushing relative to OP, OPR still can be prepared for insufflation (snorting) using commonly available tools and methods. . . . .  [T]he preliminary data from the Opana ER post-marketing investigations have significant limitations and are not as mature as the OxyContin postmarketing investigations . . . .

Perhaps the most important takeaway from FDA’ petition decision is this message: “Our decisions take into account the totality of the evidence for the particular drug at issue, and must be made on a case-by-case basis.”  The OPANA ER and OXYCONTIN decisions can thus perhaps be viewed as bookends (or at least two opposing points on a continuum) for how FDA will address similar issues in the future.  And it seems highly likely that the issue will arise again.  It may arise when a non-abuse-deterrent version of a drug is replaced with a reformulated version alleged to be abuse-deterrent, or perhaps where an abuse-deterrent version of a drug is replaced with a new and improved abuse-deterrent version.