FDA Panel Recommends Against First IR Antiabuse Oxycodone

Alicia Ault

September 11, 2015

A panel of US Food and Drug Administration (FDA) advisers voted against approval of what would have been the first immediate-release (IR) oxycodone tablet to come with abuse-deterrent properties.

The members of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 23 to 1 against allowing Purdue Pharma's Avridi to come to market.

Most said that Purdue had proven that those intending misuse through snorting or injecting the drug would not be able to successfully get a high.

But Purdue's studies also showed that participants who took Avridi orally after a meal had a much lower serum concentration of oxycodone and that there was a delayed—in some cases, a substantially delayed—analgesic effect.

That led to concerns that patients might overdose in an attempt to get relief.

"I see the risks outweighing the benefits," said panelist Nananda Col, MD, MPP, MPH, a principal at Shared Decision Making Resources in Georgetown, Maine. "There are circumstances in which it could be very good, but also circumstances in which it could be quite dangerous," she said.

Committee members said that clinicians would likely end up prescribing Avridi to only a small number of patients: those who had a history of misuse or who might be in a situation where their drugs could be diverted. They noted the large number of cheaper generic forms of oxycodone that could be prescribed without having to explain abuse deterrence or the need to take it on an empty stomach.

"The problem here is they have demonstrated they've developed something with deterrent properties but the product is inferior to the product that is marketed," said panelist Sharon Walsh, PhD, professor of behavioral science, psychiatry, pharmacology and pharmaceutical sciences at the University of Kentucky, Lexington.

Only Arthur Kibbe, RPh, PhD, thought that Avridi should be available. The retired professor of pharmaceutical sciences at the Nesbitt School of Pharmacy at Wilkes University in Wilkes-Barre, Pennsylvania, said that labeling could probably ensure safe use. He agreed, however, that most patients wouldn't want the new product because it would cost more.

FDA Encouraging Antiabuse Opioids

The FDA issued guidelines in April designed to speed development of opioids that could curb abuse. "We're aware of the immense public health problem today regarding abuse of opioid drug products," said Sharon Hertz, MD, director of the FDA's Division of Anesthesia, Analgesia, and Addiction Products.

IR single-entity oxycodone is the most-abused of the opioids, according to Purdue and the FDA. The oral route is the most common pathway for opioid abuse, although Purdue cited data showing that inhalation is slightly more common for single-entity oxycodone.

The single-entity IR form is also the most prescribed, accounting for some 15 million prescriptions in 2014. Prescribing of that form spiked from 2010 to 2014.

According to data from IMS Health cited by the FDA, the number of single-entity IR oxycodone prescriptions dispensed by outpatient retail pharmacies increased 52%, from 10.4 million in 2010 to 15.8 million in 2014. Only 0.1% of those were for Purdue's branded product, Oxecta. Most were for generic oxycodone formulations.

Meanwhile, prescriptions for extended-release oxycodone declined by about a third over the same period, from 7.3 million in 2010 to 4.7 million in 2014. Most of those were for Purdue's reformulated abuse-deterrent OxyContin, which was approved in 2010. The old version was withdrawn, and, in 2013, the FDA approved new labeling for the abuse-deterrent form.

After OxyContin, the FDA approved three other long-acting opioids with abuse-deterrent properties: Targiniq (oxycodone and naloxone extended-release tablets), Embeda (morphine sulfate and naltrexone extended-release capsules), and Hysingla ER (hydrocodone extended-release tablets).

Neither Purdue nor the FDA could say exactly why prescribing seemed to be shifting from long-acting to short-acting opioids.

Full Stomach a Problem

Avridi was designed to thwart misuse by incorporating properties that would make inhalation or injection difficult and unenjoyable. Purdue showed in a randomized trial with recreational users who had no dependence that the addition of sodium lauryl sulfate worked by causing an intense burning sensation for those who snorted a crushed tablet.

Pharmacokinetic studies demonstrated that attempts to crush and then liquefy the tablet for injection were derailed by the transformation into a gel.

But the FDA said that pharmacokinetic studies also showed that over the duration of the typical every-4-to-6-hour dosing interval, there was a consistently lower systemic exposure to Avridi when patients had eaten compared with those who had taken the same 15-mg dose of Roxicodone.

"This clearly indicates that oxycodone release and absorption is delayed significantly following administration of OCI tablet with food," said the agency in its briefing documents.

Purdue proposed to warn patients that "Avridi should be taken on an empty stomach, at least one hour prior to or two hours after eating."

But many panelists said that those instructions could be perplexing, especially to patients who already had a lot of confusion about opioids and who could be compromised by pain or other health conditions.

"What exactly does it mean to 'take on an empty stomach' – what's the definition?'" asked committee member Ruth Parker, MD, professor of medicine, pediatrics and public health, Emory University School of Medicine, Atlanta, Georgia.

"The educational plan you have for these patients in my mind is not adequate," said Anita Gupta, vice chair division of pain medicine and regional anesthesiology, Drexel University College of Medicine, Philadelphia, Pennsylvania. "They're not going to get it."

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