FDA Panels Recommend Approval of Abuse-Deterrent IR Oxycodone

Deborah Brauser

November 15, 2018

Two US Food and Drug Administration (FDA) panels have given the thumbs up to recommending approval of a new abuse-deterrent formulation (ADF) of immediate-release (IR) oxycodone hydrochloride tablets known as MNK-812 (Mallinckrodt Pharmaceuticals) for the treatment of adult patients with severe pain.

The manufacturer's application notes that the product has properties "intended to deter abuse by the nasal and intravenous [IV] routes utilizing both physical/chemical barriers to manipulation and incorporation of aversive agents into the formulation."

The company adds that it plans to replace its currently marketed branded and generic IR single-entity oxycodone tablets that have no abuse-deterrent properties with MNK-812.

With several of the members noting that it is at least "a step in the right direction," the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee together voted 10-7 that the abuse-deterrent product should be approved "for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate."

"I voted yes. There's a clear need for an abuse-deterrent formulation of immediate-release oxycodone," said acting chairperson of the joint meeting Brian T. Bateman, MD, associate professor at Harvard Medical School and chief of the Division of Obstetric Anesthesia at Brigham and Women's Hospital, Boston, Massachusetts.

"While the abuse-deterrent properties of this medication are perhaps not as robust as we might like, it is an important advance over the existing formulations," Bateman said. However, "there will be a real need for close surveillance of this product during the postmarketing period to detect any unintended consequences."

Progression of Frustrations

This IR drug is a "hard, non-brittle tablet that resists particle size reduction, making it difficult to turn into a form that can be used via intranasal or IV routes of abuse," the manufacturer reports. MNK-812 also contains "aversive agents" that cause nasal irritation when administered intranasally, and it produces a thick, sticky hydrogel when dissolved in solvents, making it difficult to syringe.

"We have created a progression of frustrations" for would-be abusers regarding the product's deterrent properties, Martha Schlicher, PhD, vice-president of research and development at Mallinckrodt Pharmaceuticals, said during the official applicant presentation.

Still, several committee members mentioned concerns that there could be problems reminiscent of those that occurred with Opana ER (Endo Pharmaceuticals), an ADF of oxymorphone. As reported by Medscape Medical News, Endo Pharmaceuticals agreed to remove the product from the US market last year following a withdrawal request from the FDA.

Postmarketing data for that drug showed a significant shift in the route of abuse from nasal administration to injection after the drug's reformulation.

A representative from Public Citizen noted during the open public hearing portion of the meeting that approving the new drug formulation would create the same problem as was seen with the Opana product, meaning increased injection abuse.

On the other hand, other members of the public and some committee members noted that abuse deterrence does not mean that a product is 100% abuse proof.

"Everyone wants these absolute standards, and that's very hard for us to do," Sharon Hertz, MD, director of the FDA's Division of Anesthesia, Analgesia, and Addiction Products, said during a discussion period.

"Is good 'good enough'? How much do we need to worry about the unintended consequences that we saw with Opana, and are we going to be driving that behavior here? That's why we need your help" with panel discussions, Hertz said.

Pharmakinetic, Abuse-Potential Studies

The applicant provided data in its briefing materials from two phase 1 pharmacokinetic studies and a human abuse–potential study that included recreational opioid users who did not already have a dependence on this type of drug.

The safety and efficacy of MNK-812 were determined on the basis of a demonstration of bioequivalence to Roxicodone (Roxane), an approved IR single-entity oxycodone hydrochloride product without abuse-deterrent properties. The data included "some abuse deterrence shown by the intranasal route," Jennifer Nadal, MD, medical officer at the FDA, reported during the agency's presentation of its briefing information.

However, "results of category-1 studies demonstrate that oxycodone suitable for IV use can be extracted under certain conditions. Large volumes can be extracted that could potentially result in solution sharing," Nadal said.

"There is potential for improved product safety through reduced abuse by patients or others who may access the drug, but the benefits to society are theoretical at this point and are not supported by data," she added. "Currently there are no data to show that ADFs slow progression of opioid use disorder or reduce the risk for addiction."

Still, "I voted yes [on recommending approval] because I think it's a step in the right direction," said Jennifer Higgins, PhD, director of research and policy at the Association of Developmental Disabilities Providers, Framingham, Massachusetts, and the panel's acting consumer representative.

"I was also persuaded by several points that were made today, specifically that there are fewer IR single-entity products being prescribed. This means to me there are less readily available products for diversion," Higgins noted.

Traci C. Green, PhD, Boston University School of Medicine and Public Health, Massachusetts, disagreed and voted no on recommending approval.

"We are continuing to see that the trends for oxycodone IR are reducing over time, and we're starting to see a change in our national epidemic to indicate that. I see the effect of this introduction of an approval for this vote as too incremental," Green said.

"The insignificant advances that it would put onto the marketplace do not counterbalance the risks that it may introduce on public health," she said.

Split Votes

Two other votes from earlier in the day were split. When asked whether, if approved, MNK-812 should be labeled as an abuse-deterrent product by the nasal route of abuse, 12 members of the panel voted yes and five voted no.

However, asked about labeling as an abuse-deterrent product via the IV route, 10 members voted no and seven voted yes. The data presented by the FDA suggested that it took about an hour to treat the medication and dissolve it in solvent in order to extract 60% to 80% of the opioid for IV use, whereas particles from Roxicodone can be extracted within 10 to 15 minutes.

"I think it's pretty clear that it is harder than Roxicodone to turn this into a syringeable form, but how much harder does it need to be to truly be abuse deterrent?" Bateman asked.

"While I agree that there may be a barrier here, I think that barrier is pretty flimsy," said Steven B. Meisel, PharmD, system director of patient safety at Fairview Health Services, Minneapolis, Minnesota.

"I'm very concerned about the long-term safety, and I wasn't as convinced of the abuse deterrence" of this route compared with the nasal route, added Cynthia Arfken, PhD, Department of Psychiatry and Behavioral Neurosciences at Wayne State University, Detroit, Michigan.

Jon E. Zibbell, PhD, Behavioral Health Research Division at RTI International, who is also from Emory University, Atlanta, Georgia, voted no on both of these questions, as well as on recommending overall approval for the newly formulated drug.

"For the majority [of abusers], initiation to opioids is oral, and this medication wouldn't prevent that at all," he said.

After taking opioids orally, some users develop tolerance and a physical dependence on the drug, "so there's an incentive to switch the route of administration," Zibbell added. "If they're physically dependent, I do not think that nasal irritation is going to prevent that use, which is my concern."

"Not Impressed" vs "Important Drug"

The panel's consumer representative, Suzanne Robotti, executive director of DES Action USA, New York City, agreed that deterrence should also be created for the oral route of abuse.

"I'm not impressed that it may or may not decrease abuse via nasal or IV routes. We need to manage it by adding an aversive agent that accumulates if you take too many pills. This is my seventh meeting on abuse deterrence, and never have I heard anything significant about stopping abuse at the oral level," Robotti said. "Also, I thought the testing [for this drug] was very thin and unconvincing."

On the other hand, "I find the data convincing and sufficient," Higgins countered. "I feel like the drug is demonstrated to be too difficult to physically and chemically abuse" via the nasal route, she said. Higgins also voted yes as to whether it deters via the IV route.

The evidence "gives me confidence that this is probably a stronger nasal deterrent than [other abuse-deterrent products] that have been previously approved," noted Abigail B. Shoben, PhD, College of Public Health, the Ohio State University, Columbus. She also voted yes on all three questions.

Overall, "I think this is an important drug, it's an important step, and it's important for patients," said Joseph O'Brien, president and chief executive officer of the National Scoliosis Foundation in Stoughton, Massachusetts, and the dedicated patient representative for the meeting.

"I voted yes because IR oxycodone is out there and it's abused. If this provides abuse deterrence to even a small percent of patients, then it's worth it," Lonnie Zeltzer, MD, director of the University of California–Los Angeles Pediatric Pain and Palliative Care Program, concluded.

There are currently 10 opioid analgesics labeled as having abuse-deterrent properties, all of which were approved after guidance was issued by the FDA in 2015. If approved by the FDA, MNK-812 will be required to be included in the opioid analgesic risk evaluation and mitigation strategy.

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