FDA decided May 10 that the crush resistance of Endo Pharmaceuticals Inc.’s reformulated Opana ER provides insufficient abuse deterrence to keep generics of the original version of the drug off the market.

There is not enough evidence that original Opana (OP) has a higher abuse potential than the reformulated version (OPR), FDA said in response to a citizens petition from Endo, so the agency concluded that the product was not removed from the market for safety and efficacy reasons. The petition requested the agency to determine that the original product was withdrawn due to safety and efficacy and to not approve any generic versions of OP and suspend any approved ANDAs referencing OP ([A#14121203008]).

That decision allows the original product to remain on the Discontinued Drug Product List in the Orange Book as a reference product for generics. Two companies already have launched competing products – Allergan PLC in July 2011 and Impax Laboratories Inc. in January 2013.

FDA rests its decision on findings that while the reformulated version has an increased ability to resist crushing, it does not deter other forms of abuse.

In vitro and pharmacokinetic studies show the extended-release features of the OPR reformulation can be overcome by cutting, grinding or chewing to “dose dump” the narcotic, FDA says. It also appears that snorting is possible using commonly available tools and methods and the drug “can be readily prepared for injection, despite Endo’s claim that OPR tablets have ‘resistance to aqueous extraction.’”

Purdue Pharma LP held off generics for OxyContin (oxycodone HCl controlled-release) in April by obtaining labeling claims that the product reduces abuse by snorting and injecting ([A#14130416009]).

This led to FDA’s decision to remove original OxyContin (OC) from the Orange Book because it has an increased potential for abuse by some routes of administration compared to the OxyContin reformulation (OCR) Also see "OxyContin’s Abuse-Deterrent Claims Strong, But Stronger Claims Possible" - Pink Sheet, 22 April, 2013..

Endo asked FDA for a similar ruling in an April supplement to its petition, but agency’s response explained that “any attempt by Endo to draw parallels between OCR and OPR and thereby make assumptions regarding the regulatory implications for OP is misplaced.”

Each opioid must be judged on its own merits, FDA said. “Abuse-deterrent properties must be supported by sound science taking into consideration the totality of the data for the particular drug at issue.”

Opana, OxyContin Not The Same

Nevertheless, FDA went on to cite differences between the two products that support the different decisions.

In vitro, pharmacokinetic, clinical abuse potential and post-marketing data support a conclusion that “OC posed an increased potential for intranasal abuse compared to OCR,” while the in vitro data shows that abusers must spend more effort and time and have more experience and use tools to create a fine powder to produce a product for intranasal abuse, FDA said. In addition, PK and post-marketing data supported the potential to deter snorting, the agency noted, and a clinical abuse potential study showed less liking for the finely ground OCR than for finely ground OC after attempted snorting.

Endo did not provide a clinical abuse potential study to evaluate abusers’ ability to snort the reformulation or their preferences, FDA said.

As to post-marketing data submitted by Endo, FDA said they “have significant limitations and are not as mature as the OxyContin post-marketing investigations, which themselves were only supportive, and not conclusive, of reduced intranasal abuse.”

Purdue submitted findings from a suite of epidemiological studies indicating a decline in abuse and misuse of OxyContin following introduction of the reformulated drug, but continues to monitor whether the positive trend is continuing Also see "Opioid Abuse-Deterrent Labeling Claim Decision By FDA Could Come Soon" - Pink Sheet, 15 April, 2013..

Data from Endo’s post-marketing investigations are inconclusive and, “as the company repeatedly acknowledges, ‘preliminary,’” FDA said. The data include only two to three quarter-years of data in the post-the reformulated version timeframe and “suffer from significant additional deficiencies (including small sample sizes, likely misclassification of drug exposure, and possibly artificially elevated OP baseline abuse rates), such that it is not possible to draw meaningful conclusions based on them.”

Endo Has Difficult Path Forward

FDA guidance on abuse-deterrence lays out four possible claims and four types of studies necessary to support them ([A#00130114010]).

Three of the claims – the presence of physicochemical barriers, expectations that manipulation can be blocked and expectations of a meaningful reduction in abuse – would be based on one or all of three types of pre-marketing studies – laboratory manipulation and extraction studies, PK studies or clinical abuse studies. The FDA decision indicates these studies for OPR did not support a claim.

The fourth claim is that the product has “demonstrated reduced abuse in the community.” Even if Endo collects more robust epidemiological data, the guidance notes that FDA “anticipates” that data from all four types of studies, both formal studies and supporting data, would be necessary to support a claim of reduced abuse in the community.

The company said its epidemiological data indicate that on a per 100,000 prescriptions dispensed basis, the past 30-day abuse rate of OPR was 79% lower than the abuse rate of generic oxymorphone ER drugs on the market in 2012.

It is a “little bit early to be definitive” about the company’s path going forward, the company said. CEO Rajiv De Silva noted that in anticipation of additional generics coming on the market, the company “will carefully assess Endo’s position in the competitive landscape and explore all options, including those intended to mitigate the effect of this decision.”

The firm estimates that the additional competition could lower 2013 net sales of Opana by up to $120 million and reduce adjusted diluted earnings per share by up to approximately $0.55.

FDA also issued a “complete response” to Endo’s supplemental NDA requesting labeling language describing reformulated Opana’s abuse-deterrent properties.

FDA Crushes Endo’s Hopes, Allows Original Opana Generics To Remain On Market

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