WASHINGTON -- Two FDA advisory committees will have their say Wednesday about yet another opioid manufacturer's attempt to design an immediate-release oxycodone product that significantly discourages abuse.
The product is MNK-812, from Mallinckrodt Pharmaceuticals' SpecGx unit, which aims to be "more difficult to crush and is designed to form a viscous hydrogel not suitable for injection," according to . "Additionally, two aversive agents were included in the formulation to cause potentially irritating effervescence when the tablet comes into contact with water."
The FDA's and committees will address the following questions:
- Whether MNK-812 tablets should be labeled a nasal abuse-deterrent product
- Whether the tablets should be labeled an intravenous abuse-deterrent product
- Whether the data support approval for managing pain severe enough to require an opioid analgesic when current alternative treatments are inadequate
- Whether there are substantial concerns about the product's impact on public health, including its potential effect on overall opioid abuse, as well as the possible consequences of unintended use of MNK-812
"While most abuse of oxycodone occurs via the oral route," the FDA noted, "intranasal and IV abuse of oxycodone is common in individuals entering treatment for substance use disorder." Citing a 2017 study, the agency added: "While oral abuse remains the most common route of administration for the majority of prescription opioid products, even for (abuse deterrent) formulations, alternative routes of administration such as snorting and injection are reported among 20%-30% of individuals endorsing."
Mallinckrodt submitted a New Drug Application in January following two Phase I pharmacokinetic studies conducted to demonstrate bioequivalence to the FDA-approved drug Roxicodone (at a 15-mg dose of the new drug), and a human abuse potential study.
In the briefing document, FDA staff offered no clear opinions on whether Mallinckrodt had conclusively demonstrated abuse deterrence for its product, leaving such judgments to committee members. At the same time, the document suggested that the sponsor had conducted its premarket research in line with the agency's guidelines.
Agency staff indicated Mallinckrodt would likely have to conduct postmarketing descriptive studies of the drug's utilization compared to selected similar medications, and of abuse of the drug and related clinical outcomes. It would also have to conduct formal observational studies to examine if the drug's properties "actually result in a meaningful decrease in misuse and abuse, and their consequences, addiction overdose, and death, in post- approval settings."
The new drug would also be covered by the FDA's Risk Evaluation and Mitigation Strategy (REMS) for opioids, "to ensure the benefits of the drug outweigh the risks of adverse outcomes (addiction, unintentional overdose, and death) resulting from inappropriate prescribing, abuse, and misuse."
The FDA has approved 10 opioid analgesics with labels touting abuse-deterrence, including one immediate-release version: RoxyBond (oxycodone HCl tablets), which was approved last year.
MNK-182 is one of a few new oxycodone medications suggesting the ability to deter abuse, although most are in extended-release forms. Blue Cross and Blue Shield of Alabama, for example, it is including the ER-form Xtampza and IR-form Roxybond in its commercial plans, while dropping coverage of the standard formulation of OxyContin.
Importantly, actual abuse deterrence has yet to be clearly proven for any of these agents. Manufacturers including Mallinckrodt have conducted clinical "liking" studies in lab settings, but real-world behaviors can't readily be tested in premarket research. Past experience with opioids has shown that abusers are ingenious in finding ways to defeat technologies intended to deter abuse. As an extended-release product, the original OxyContin was thought to be safer than immediate-release oxycodone when first introduced.
"It is important to keep in mind that the science of abuse deterrence is relatively new, and both the formulation technologies and the analytical, clinical, and statistical methods for evaluating those technologies are rapidly evolving," according to the FDA briefing. "Based on this, the Agency intends to take a flexible, adaptive approach to the evaluation and labeling of potentially abuse-deterrent products."
This drug marks the latest effort to address an opioid epidemic that shows few signs of abating. In 2016, 11.5 million Americans age 12 and up misused prescription opioids, while 1.8 million had a prescription opioid analgesic substance use disorder. (By comparison, 15 million abused alcohol.) Oxycodone was the second-most misused opioid (3.9 million), behind only hydrocodone (6.9 million); oxycodone use was also the second-most-reported cause (35%) cited by patients entering opioid use disorder treatment, behind only heroin (57%). Between 5,000-6,000 deaths involving oxycodone were reported annually between 2010-2015.
Immediate-release forms of oxycodone show signs of being more dangerous than extended-release. Calls to U.S. Poison Control Centers between 2012-2016 reporting intentional exposure to oxycodone were far more likely to involve IR products than ER ones. The number of prescriptions for single-ingredient oxycodone IR products increased from about 14.5 million in 2013 to about 17.3 million in 2017.