FDA Moves On Endo’s Opana ER Unlikely To Sweep Up Other Opioids

Shift toward intravenous abuse with the reformulated long-acting opioid, coupled with reports of a serious bleeding disorder and HIV transmission, spurred US FDA advisory committee to recommend regulatory action, which could include new labeling, strict risk management measures or market withdrawal.

Endo Pharmaceuticals Inc. faces the prospect that the US FDA will request withdrawal of, or require new labeling and a restrictive Risk Evaluation and Mitigation Strategy (REMS) for, Opana ER (oxymorphone extended-release) due to issues with intravenous abuse.

However, given the unique circumstances surrounding the re-evaluation of Opana ER’s safety, there is no indication that other long-acting opioids on the market are necessarily headed for the same fate.

On March 14, 18 of 27 members of the Drug Safety and Risk Management and the Anesthetic and Analgesic Drug Products advisory committees voted that the benefits of the currently marketed version of Opana ER do not outweigh the drug’s risks.

Some panelists believed the drug should be removed from the market due to a lack of unique benefit and data suggesting an increased incidence of intravenous abuse since it was reformulated in 2011 with physicochemical properties that make it more difficult to crush, thereby discouraging intranasal abuse.

However, other committee members, including some who voted that the drug still had a positive risk/benefit profile, called for less drastic regulatory action. Their recommendations included new labeling limiting prescribing to second-line use, warnings about the serious risks of intravenous abuse, and a restrictive REMS limiting who could prescribe the drug.

Despite the potentially dire circumstances for Opana ER from a regulatory standpoint, analysts do not think FDA’s action will have any broad sweeping implications for opioids in general even though the agency still faces intense political pressure to stem the epidemic of opioid-related overdoses and deaths in the US.

“We don’t see widespread recalls or withdrawal of opioid products following the committees’ discussion this week,” Canaccord Genuity analyst Dewey Steadman said in a March 14 note. However, products that use formulations similar to Opana ER may face additional scrutiny, he cautioned.

Analysts also do not think FDA’s ultimate regulatory action will have much of a financial impact on Endo, which has increasingly de-emphasized its branded pain portfolio in favor of other therapeutic areas.

Endo “will evaluate the range of available options for maintaining access for legitimate use.”

In a March 15 note, JMP Securities analysts Donald Ellis and Nazibur Rahman said Opana ER accounted for only 4% of their 2017 revenue estimate for Endo and is not a growth driver. “We do not view this advisory committee as a meaningful event for Endo,” the analysts said.

In a press release issued after the two-day meeting, Endo said it believes that Opana ER remains an important clinical choice for appropriate patients, and the company “will evaluate the range of available options for maintaining access for legitimate use.”

"Endo remains confident that the body of evidence established through clinical research demonstrates that Opana ER has a favorable risk/benefit profile when used as intended in appropriate patients," said Matthew Davis, senior vice president of R&D for Endo’s Branded Pharmaceuticals division. “We plan to work collaboratively with the FDA as the agency completes its evaluation of Opana ER, while advocating to preserve the important benefits of the medicine for patients."

Unsuccessful Bids For Abuse-Deterrent Labeling

FDA’s safety concerns over Opana ER stem from abuse patterns that have evolved since the product was reformulated several years ago.

The currently marketed formulation includes a polyethylene oxide (PEO) matrix that is intended to make tablets more difficult to crush and abuse by the intranasal or injection routes. However, FDA’s December 2011 approval of the new formulation did not include labeling language on abuse deterrence. (Also see "US approval for Endo's 'crush-proof' Opana " - Scrip, 13 Dec, 2011.)

In February 2012, Endo began replacing distribution of original Opana ER with the new formulation. In 2013, FDA issued a complete response letter to the company’s supplemental new drug application (sNDA) requesting labeling that describes the product’s abuse-deterrent properties. The agency also denied Endo’s citizen petition requesting a determination that original Opana ER had been removed from the market for safety reasons. Had FDA granted the petition, it would have blocked generics of the older formulation.

FDA concluded there was insufficient evidence to establish that the original formulation had a higher abuse potential than the reformulated product. The agency noted certain data suggested the reformulation is more easily prepared for injection and the “troubling possibility” that more intravenous use was occurring compared to the original version.

Endo resubmitted the sNDA in January 2016 with results from an intranasal abuse study requested by FDA and interim epidemiologic study data on the abuse patterns. However, the company withdrew the supplement in August in anticipation of more complete epidemiological data becoming available in late 2016.

Although Endo said it is not currently seeking abuse-deterrent labeling claims, FDA nevertheless brought the product to its advisory committee due to concerns that epidemiological data suggest the reformulation has led to a shift in the preferred pattern of abuse from intranasal to intravenous.

Data On Patterns Of Abuse

At the advisory committee meeting, Endo and its experts defended Opana ER’s safety.

Harris Rotman, vice president of US regulatory affairs, asserted that two key events confound the interpretation of epidemiology data on Opana ER abuse patterns: the introduction of an abuse-deterrent formulation of Purdue Pharma LP’s OxyContin (oxycodone extended-release) in 2010, which led to an increase in Opana ER abuse, and the launch of generic oxymorphone extended-release products immediately before and after the introduction of reformulated Opana ER.

Endo pointed to evidence of decreased intranasal abuse with the reformulation and asserted that epidemiologic data suggesting a sharp jump in intravenous abuse of the drug in Tennessee was an anomaly.

“Endo believes the totality of the evidence demonstrates a favorable benefit/risk profile in the intended population,” Rotman said. “Coincident with the introduction of reformulated Opana ER, intranasal abuse was lower. I.V. abuse initially increased in Tennessee but has stabilized, and was stable or decreasing in other states.”

However, Jana McAninch, an FDA medical officer and epidemiologist, said the data are compelling that the reformulation has caused a shift from intranasal to injection route of abuse, although it’s unclear if the increase is greater than if the product had not been reformulated. In addition, limited geographic areas, including Tennessee and other Appalachian states, appeared to be driving the increases.

In addition to high incidence of injection abuse reported in Tennessee, FDA presented data showing that the state accounts for the highest number of dispensed prescriptions for branded and generic oxymorphone extended-release per 1,000 residents (18.5), followed by North Carolina (9.9).

Puzzled by the high amount of oxymorphone use and Opana ER intravenous abuse reported in Tennessee, advisory committee member Raeford Brown, a pediatric anesthesiologist at the University of Kentucky, asked Endo whether there is any difference in the way it markets drugs in different areas of the country.

“There is not, and actually at the current time we’re not prospectively marketing with sales representatives,” Rotman said. “But there’s no state-by-state difference.”

Intravenous Use Brings Other Serious Risks

The advisory committee also was presented with FDA research implicating high molecular weight PEO as a potential cause of the cases of thrombotic thrombocytopenic purpura (TTP), a potentially fatal bleeding disorder, associated with Opana ER intravenous abuse.

PEO is found in other long-acting opioid formulations, including OxyContin, Egalet Corp.’s Arymo ER (morphine sulfate extended-release) and Purdue’s Hysingla ER (hydrocodone extended-release). However, there have been more than 60 cases of TTP reported with Opana ER, compared to just a few with OxyContin.

Advisory committee members generally concluded that the epidemiologic data show a shift in abuse patterns from intranasal to intravenous and saw a biologically plausible pathway between Opana ER’s PEO component and TTP. When injected, Opana ER has a short duration of action. It needs to be dosed repeatedly and frequently, in a large injection volume, which could allow for PEO to accumulate in a person’s body, panelists said.

A 2015 HIV outbreak in rural Indiana likely resulted from the high injection volume and the drug’s high price, which make sharing Opana ER for injection more efficient, thereby increasing the risk of bloodborne disease transmission, panelists said.

Advisory committee members acknowledged that removing Opana ER from the market likely would shift misuse to other more readily abusable drugs, including the generic extended-release and immediate-release forms of oxymorphone. However, some panelists said that intranasal abuse of such products would be less worrisome than intravenous use with Opana ER.

Refocusing On Other Assets

Canaccord’s Steadman called the advisory committee outcome a “modest setback” for Endo and was generally not concerned about the financial impacts on the company.

“While Opana ER previously was a large contributor to Endo’s top and bottom lines, since generics launched against the original formulation annual revenue has declined to around $150m annually out of a $3.4bn consolidated top-line for the company,” Steadman said. “While no final decision has been made to pull Opana ER from the market (yet), we see little impact to Endo should Opana ER ultimately be pulled.”

Opana ER sales in the US totaled $159m in 2016, an almost 10% decline from the previous year.

Endo has been stepping away from the opioid area in favor of other assets. In December, the company announced it was returning rights to Belbuca, a buccal form of buprenorphine, to BioDelivery Sciences International Inc.

“As a result of this announcement, Endo restructured its US Branded Pharmaceuticals segment sales organization, which will allow the company to focus efforts and resources more fully on its core US Branded assets,” including the collagenase therapy Xiaflex (collagenase clostridium histolyticum), the company’s 10-K filing for 2016 states. Endo acquired Xiaflex through the 2014 acquisition of Auxilium Pharmaceuticals Inc. (Also see "Endo wins over Auxilium, QLT dropped" - Scrip, 9 Oct, 2014.)

The filing states that Endo’s legacy pain portfolio products, including Opana ER and Percocet (acetaminophen/oxycodone), will be managed as mature brands. The restructuring involved the elimination of the approximately 375-member US Branded pain field sales force.

“We forecast Opana ER sales declining 13% [year over year],” JMP analysts Ellis and Rahman said. “Endo’s new management team is focused on divesting noncore assets and focusing on Xiaflex, the Sterile Injectable business, and the Alternative Dosage/New Launches business segment, which we view as the primary growth drivers.”