Pfizer Inc.’s extended-release opioid Troxyca ER (oxycodone/naltrexone) received positive advisory committee recommendations June 8, but they came with a call for FDA to make decisions about abuse-deterrent claims that are informed by post-marketing data.

One member of the joint Anesthetic and Analgesic Drug Products and Drug Safety and Risk Management advisory committees even suggested the agency should not consider abuse-deterrent claims for a particular product until it has some post-marketing experience.

Troxyca ER is intended for management of pain severe enough to require daily, around-the-clock, long-term opioid treatment where alternative treatment options are inadequate. It is intended to be administered orally twice daily with or without food.

Committee members recommended approval and two of three abuse-deterrent claims for Troxyca, but they were far from enthusiastic.

After voting 9-6 in favor of approving the product, the committee endorsed a nasal abuse-deterrent claim 11-4 and intravenous abuse-deterrent claim 9-6. Committee members voted 9-6 against recommending an oral abuse-deterrent claim.

Making Decisions In A Data Vacuum

But many panelists appeared conflicted and said FDA should enhance its regulatory approach to abuse-deterrent formulations.

FDA has required post-marketing epidemiologic studies for abuse-deterrent formulations to determine whether the products are resulting in meaningful reductions in abuse, misuse and adverse clinical outcomes, such as addiction, overdose and death. However, the data for the six products approved with abuse-deterrent labeling are not yet available.

Committee Acting Chairman Raeford Brown, professor of anesthesiology and pediatrics at the University of Kentucky, said following a vote in favor of the intravenous claim that he was worried decisions were being made without enough information.

“I really fear that this committee and perhaps the agency are making decisions about drugs such as this in a vacuum of no data, and I worry constantly about our [ability] to do the right thing … without being able to see post-marketing data,” Brown said.

“Once again, I’m going to ask that the agency make some concerted effort to get those data out so that we can begin to evaluate them so we can know the decisions we’re making are the right decisions,” Brown said.

Technology Similar To Embeda

Troxyca is designed so that oral administration of intact capsules or sprinkling of the pellets contained within on food will allow pain relief as intended. If physical or chemical manipulation is attempted, the naltrexone in the product, a mu-opioid receptor agonist, would block the effects of the oxycodone.

The technology is similar to that employed by Pfizer’s Embeda (morphine sulfate/naltrexone extended-release capsules), which is one of only two long-acting opioid products approved with both oral and intravenous abuse-deterrent claims ([A#14160606001]).

Post-marketing data on Embeda were not available to draw any conclusions about the technology and whether it curbs abuse, much to the panel's dismay.

Almut Winterstein, professor of pharmaceutical outcomes and policy at the University of Florida, suggested that FDA consider not approving any abuse-deterrent labeling claims without first having post-marketing data on the product.

“I think ideally, the determination of abuse deterrence would maybe be made post-marketing and not upon approval because we really don’t know what people will do with those medications,” she said. “In general, we have said that there should not be a discussion that should happen in the approval phase at all unless there really is the magic bullet that shows up that we would all agree that there is no way to abuse a particular medication.”

Extraction Too Easy To Deter Some Abuse

Much of the concern throughout the meeting centered on whether Troxyca capsules could be dissolved in a solvent and the oxycodone extracted and completely separated from the naltrexone.

Data indicated that with some of the solvents tested, it appeared possible to pull most of the oxycodone out of the formulation, although some naltrexone may still remained attached. Such a process might take several hours.

The time required was expected to be one of the deterrents for abusers, along with the potential of ingesting some naltrexone along with the oxycodone.

“I believe as a clinician [that] naltrexone, even at a very, very low dose, even in the most extreme extraction version, the data is compelling enough to vote yes,” Alan Kaye, anesthesia professor at Louisiana State University, said after voting in favor of the oral abuse claim.

But Tobias Gerhard, associate professor in the Rutgers University Department of Pharmacy Practice and Administration, said that the extraction method is easy and there are not enough data to show otherwise.

“If the perception is that these drugs may be perceived by prescribers as more safe and less likely to lead to addiction, all things that have not been shown with any data, then we have to be very careful with granting that status,” he said after voting against the oral abuse claim.

The extraction concerns even permeated the committee's discussion about a nasal abuse-deterrent claim, which a majority of committee members supported.

Elaine Morrato, dean for public health practice at the University of Colorado, said the extra step of having to dry the oxycodone after extracting it with a solvent so that it could be snorted may be too much effort for an opioid abuser.

Notably, the committee recommended the IV abuse-deterrent claim despite FDA’s concerns about the potential for easily extracting the oxycodone from the product for that route of administration ([A#14160606002]).

Review Goal Already Missed

Troxyca would be the first approved extended-release product combining oxycodone and naltrexone.

Its review goal was Jan. 19. Pfizer said FDA has not provided a new date.

The joint committee’s consideration of Troxyca culminated two days of sessions on proposed abuse-deterrent opioids.

Committee members voted overwhelmingly for approval, as well as oral, nasal and intravenous abuse-deterrence labeling claims, for Teva Pharmaceutical Industries Ltd.’s long-acting opioid Vantrela ER (hydrocodone extended-release) on June 7, calling it an incremental improvement in the product class ([A#14160607005]).

Opioids Need Post-Marketing Data To Inform Abuse-Deterrent Claims, FDA Panel Says

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