A joint US Food and Drug Administration (FDA) advisory committee has recommended that a new immediate-release (IR) opioid analgesic be approved and that labeling describe the product as deterring abuse via intranasal (IN) and intravenous (IV) routes.
The product — oxycodone hydrochloride tablets with the proposed trade name RoxyBond (Inspirion Delivery Sciences LLC) — would be indicated for the management of moderate to severe pain where use of an opioid analgesic is appropriate.
If the FDA acts on these recommendations, the product would be the first approved IR opioid with abuse-deterrent properties.
"This medication represents a really important advance," said Brian T. Bateman, MD, associate professor of anesthesia, Department of Medicine, Brigham and Women's Hospital, and Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston.
"While it's not perfect, it does provide at least some barrier to abuse by IV and IN routes and therefore meets an important public health need."
Dr Bateman made his comments during a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee, convened April 4 to discuss the new drug application.
Most committee members voted to approve the drug, and the abuse-deterrent labeling, but some were concerned about the safety of people attempting to abuse the drug intravenously and the potential costs of this abuse-deterrent medication.
The new product has been formulated to deter abuse using technology that imparts multiple physical and chemical barriers. The multilayer coated tablet comes in three strengths: 5 mg, 15 mg, and 30 mg.
As a component of its strategy to address the opioid abuse epidemic, the FDA has encouraged pharmaceutical companies to create abuse-deterrent formulations. There are now nine approved extended-release (ER)/long-acting abuse-deterrent formulations (ADFs) of opioids.
However, there are currently no approved IR opioid analgesics with abuse-deterrent labeling.
Abuse Potential
During the meeting, Richard C. Dart, MD, director, Rocky Mountain Poison and Drug Center, Denver, and professor of emergency medicine, University of Colorado School of Medicine, Aurora, outlined how prevalent IR products are across the United States. For example, in 2016, 93% of all prescriptions for oral opioid analgesics were for IR products.
Abuse potential for IR products is relatively high. Population-adjusted rates of intentional abuse are 4.6 times greater, and rates of drug diversion are 6.1 times greater, for IR products than ER products, said Dr Dart.
For IR oxycodone specifically, the population-adjusted rates of intentional abuse are 2.9 times higher than those for ER oxycodone and 6.8 times higher than those for ER morphine.
Snorting and injection are common routes of IR oxycodone abuse. IN and IV routes of abuse are particularly concerning because this is associated with significantly higher risks for death or overdose than the oral route, said Dr Dart.
As well, he added, IV opioid abuse carries additional health risks, including the potential transmission of HIV and hepatitis C virus and blood clots.
The company carried out many studies to test the abuse-deterrent potential of the product. These included attempts to extract the drug by crushing, cutting, grating, and grinding it using various household tools, with different solvents, and at different temperatures, and testing the drug's "syringeability." These studies compared RoxyBond with Roxicodone (Mallinckrodt), a non–abuse-deterrent IR opioid that comes in the same strengths and has the same dosing schedule.
The studies showed that converting the drug into an "abusable" form for IN or IV abuse was difficult and that reducing particle size didn't defeat the abuse-deterrent properties, said Robert Bianchi, president and chief of scientific and technical affairs, Prescription Drug Research Center, Fairfax, Virginia.
"All extraction experiments produced considerably lower and slower oxycodone release compared to Roxicodone," he reported.
As well, he added, when manipulated and subjected to a liquid environment, the tablet creates a viscous material that is difficult to use in a syringe.
Human Abuse Potential
During the meeting, Lynn Webster, MD, vice president, scientific affairs, PRA Health Sciences, Raleigh, North Carolina, discussed the results of a randomized, double-blind, double-dummy, crossover IN human abuse potential study in 31 recreational nondependent opioid users, 29 of whom completed it. The four arms were Roxicodone manipulated, RoxyBond manipulated, RoxyBond intact, and placebo.
The results showed a statistically significant lower "maximum drug liking" rating for manipulated RoxyBond vs manipulated Roxicodone, and vs RoxyBond oral intact (both P < .001) among study participants.
As well, said Dr Webster, the analyses found that study participants were less likely to take the manipulated drug again, and they gave the drug a lower rating for getting "high" and a lower "overall drug liking" rating.
Research shows that reductions in overall drug liking for abuse-deterrent formulations of ER oxycodone translate into less nonmedical use, he noted.
For the most part, the joint committee agreed. They voted 19 to 1 (no abstentions) that the drug should be labeled as an abuse-deterrent product by the nasal route of abuse.
Only Ronald S. Litman, DO, professor of anesthesiology & pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, and medical director, Institute for Safe Medication Practices, Horsham, Pennsylvania, voted against this labelling.
"I'm just not convinced that we could label something as abuse deterrent when we don't know if it really is or not; I certainly haven't seen the evidence," said Dr Litman.
He noted that many of the speakers during the meeting's open public hearing were supported by drug companies.
Red Herring
Dr Litman added that he's also concerned about the costs associated with state laws that could force physicians to prescribe an abuse-deterrent product if and when available.
"I think ADFs are a red herring, a distraction from the real problem," he said.
Other committee members noted that approving this drug would not by itself address the troubling opioid abuse epidemic.
The committee as a whole had more reservations about the product being able to deter the IV route of abuse. Here, 16 members voted that the product should have such labeling, but 4 voted against it (no abstentions).
One of "no" votes came from Mary Ellen McCann, MD, senior associate in anesthesia, and associate professor, Department of Anesthesiology, Perioperative and Pain Medicine, Children's Hospital Boston, Massachusetts.
"If you really wanted to abuse this drug, it's relatively easy to do it in an IV fashion," said Dr McCann.
Terri L Warholak, PhD, assistant professor, Division of Health Promotion Sciences, College of Public Health, College of Pharmacy, University of Arizona, Tucson, also expressed concerns about IV abuse-deterrent labeling.
While the company demonstrated that getting the drug into an injectable form requires a multistep process, "I was able to find information online on how to step through the process for IV drug abuse right now, and it's not even on the market," said Dr Warholak.
She and others expressed concern about possible consequences of injecting excipients from the drug.
If abusers try to find a way to defeat this product and to inject it, they could suffer serious side effects, said Arthur H. Kibbe, RPh, PhD, retired professor of pharmaceutical sciences, Nesbitt School of Pharmacy, Wilkes University, Wilkes-Barre, Pennsylvania.
"One of the best deterrents to abusing this product intravenously is to let members of the opioid-using community know that they're not just getting a high; they're getting kidney damage and liver damage and lung embolisms."
Many members wanted some kind of black box or other warning about possible negative outcomes of trying to inject this drug.
Approval Vote
For the vote on whether to approve the drug for the management of pain, again, 19 members voted in favor of this. Many mentioned the impressive presentations made by experts on behalf of Inspirion.
They presented enough evidence to indicate that this product may offer some advantage and another option for patients who have pain, said Anita Gupta, DO, PharmD, vice chair and associate professor, Division of Pain Medicine & Regional Anesthesiology, Drexel University College of Medicine, Philadelphia.
"There are certainly unanswered questions regarding excipients, and there is still risk of abuse, but I am excited to know that there is some innovation occurring, that there is some type of promise with this technology."
The FDA had no questions on the study methods or results presented by the company, said Sharon Hertz, MD, director, Division of Anesthesia, Analgesia and Addiction, Office of Drug Evaluation, FDA.
No member voted against the drug approval, and only one — Dr Litman — abstained.
But this vote wasn't because the drug isn't effective. Dr Litman said it "clearly will work just fine as an opioid to treat severe pain." However, he said he was philosophically opposed to voting for another abuse-deterrent product.
Individual members expressed other concerns. Meeting chair, Raeford E. Brown Jr, MD, professor of anesthesiology and pediatrics, College of Medicine, University of Kentucky, Lexington, questioned the use of this drug in children. "My guess is this product will become the 'go to' product for treatment of pain in children."
Kevin L. Zacharoff, MD, faculty and clinical instructor, pain and medical ethics, State University of New York Stony Brook School of Medicine, thought prescribers should get direction on deciding which patients are appropriate candidates for an abuse-deterrent formulation vs a non–abuse-deterrent formulation, "assuming that non–abuse-deterrent formulations are still available on the market."
"I think there is a lack of clarity at the general prescriber level," said Dr Zacharoff.
Costs of the product and inclusion on drug formularies are additional issues to consider, he said.
Other members underlined the importance of postmarketing studies to determine whether IR abuse-deterrent products actually prevent abuse in the real world.
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Cite this: FDA Panel Recommends Approval for Abuse-Deterrent IR Opioid - Medscape - Apr 06, 2017.
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