FDA Panel Votes for IR Opioid but Without Abuse Labeling

Pauline Anderson

May 09, 2016

A joint US Food and Drug Administration (FDA) advisory panel voted to approve an immediate-release (IR) benzhydrocodone and acetaminophen combination product (Apadaz, KemPharm Inc) for the short-term treatment of acute pain up to 14 days but decided that it should not be labeled as an abuse-deterrent product.

The product, which contains hydrocodone (the active opioid), benzoic acid (the ligand), and acetaminophen, is a "prodrug" intended to be converted into hydrocodone by enzymes in the gastrointestinal (GI) tract.

According to the company, this requirement for conversion in the GI tract can modify the pharmacokinetic profile and decrease the exposure to hydrocodone when taken by the nasal or intravenous (IV) route for the purpose of abuse.

The joint panel of the FDA's Anesthetic and Analgesic Drug Products and Drug Safety and Risk Management advisory committees voted 16 to 4 to approve the drug. Most felt it meets the indication for the treatment of acute pain and were convinced by the evidence of bioequivalence with the reference product.

Among those who did not agree was committee chair Raeford E. Brown Jr, MD, professor of anesthesiology and pediatrics, College of Medicine, University of Kentucky, Lexington. "It worries me to put another opioid on the market that does not have robust deterrence properties," said Dr Brown.

On the question of whether the product should carry abuse-deterrent labeling, only 2 voted for and 18 voted against.

"We would all like to see an abuse-deterrent product for IR that has an effect, but we have to remain critical when being presented with data for such products, and I think here we haven't seen the type of evidence that would suggest that this product really makes a difference compared to the available IR products," commented Tobias Gerhard, PhD, associate professor, Department of Pharmacy Practice and Administration, Rutgers University, Piscataway, New Jersey.

And Charles W. Emala Sr, MD, professor and vice-chair for research, Department of Anesthesiology, Columbia University College of Physicians & Surgeons, New York, New York, was concerned about giving "a false sense of security to prescribers that could actually accelerate the volume and number of these pills prescribed."

Abuse-Deterrent Labeling

There are currently 6 approved extended-release (ER) opioid products with abuse-deterrent properties, but to date, the FDA has not approved any such abuse-deterrent labeling for IR opioid analgesics.

Hydrocodone combination products are the most widely prescribed opioid analgesics. Although ER opioids are associated with more overdose risk, the IR versions are also subject to abuse.

In the wake of a rising opioid abuse epidemic in the United States, the FDA is encouraging pharmaceutical companies to develop novel interventions to reduce or even prevent misuse and abuse of these drugs. In April 2015, the agency issued guidance to the pharmaceutical industry on the evaluation and labeling of abuse-deterrent opioids.

And earlier this year, the FDA announced an opioid action plan with an aim to reduce the impact of opioid abuse on public health. As part of that plan, the agency is committed to working more closely with its advisory committees before making product and labeling decisions, according to Sharon Hertz, MD, Director of the Division of Anesthesia, Analgesia and Addiction Products, Center for Drug Evaluation and Research (CDER), FDA.

During the joint meeting, members heard that opioid abuse often starts with an oral prescription and then, to get a better or faster "high," progresses to nasal inhalation (snorting) and to intravenous (IV) injections, and possibly to other drugs, such as heroin.

According to Travis Mickle, PhD, chief executive officer, KemPharm, Inc, the new product has several advantages in the field. It's different from drugs that have other ingredients added to the formulation to make them abuse-deterrent — ingredients that aren't necessary for analgesia and can lead to adverse effects, he said.

"Apadaz is different; the abuse-deterrent properties are conferred at the molecular level by adding a naturally occurring substance to hydrocodone."

Crushing or grinding has no effect on the release profile of this formulation, said Dr Mickle.

At the meeting, the company provided results of several studies, including one demonstrating the bioequivalence of the product to a comparator (Norco [Actavis], another IR hydrocodone-acetaminophen combination product).

Evidence from these studies, said Dr Mickle, shows that with Apadaz, abusers don't achieve the rapid highs they seek with snorting and that, unlike Norco, the drug produced almost identical profiles for pharmacokinetics and reported "drug liking" compared with the oral drug.

The research, added Dr Mickle, showed that snorting the new product led to lower hydrocodone exposures and lower scores for "drug liking" at earlier time points compared with Norco.

"In fact, snorting Apadaz provides either similar or lower drug liking than simply taking Apadaz orally; this is important because abusers won't receive the reinforcement of faster or greater highs."

Another deterrent, he said, is that adverse nasal effects from snorting were more common and more severe with Apadaz than with Norco.

And, because the evidence shows that Apadaz can't effectively be extracted for injection and that the prodrug converts slowly to hydrocodone in blood, this will deter abuse by the IV route, he said.

Abusers who try smoking or vaporizing the drug will find that these methods don't release any hydrocodone, he noted.

The drug adds no additional risks to patients, said Dr Mickle. The studies showed a similar incidence of adverse events, which, as expected, included nausea, drowsiness, and constipation.

Significant Deficiencies

The FDA, however, took issue with some of the company's studies, outlining what it called "significant deficiencies." One such deficiency, said James Tolliver, PhD, Controlled Substance Staff, CDER, FDA, was the lack of placebo in the treatment phase of one of the studies.

"It is not known how subjects might have responded to the drug-liking VAS [visual analog scale] when administering placebo intranasally. It is also not possible to validate assessment of the drug-liking VAS."

Among other things, Dr Tolliver also pointed out that in the company's study of the potential for oral human abuse, similar low, medium, or high doses of Apadaz and Norco produced similar levels of drug liking, high, and "take drug again" scores. "This study failed the primary endpoint of maximum effect (Emax) for drug liking," he said.

FDA officials also questioned the evidence showing that it's difficult to overcome the abuse-deterrent properties of Apadaz.

There was some debate among committee members as to whether intranasal opioid abuse is even an issue when it comes to opioid misuse and abuse. They heard that the prevalence of snorting hydrocodone combination products varies widely but that there may be certain populations, such as adolescents, who are at higher risk.

It's unclear what the true incidence of adverse effects of snorting, such as nasal tissue damage, truly are. Committee members also heard that most hydrocodone-related deaths may involve oral ingestion, not snorting.

But many agreed that even if snorting is a relevant pathway of abuse, it's not known whether this new product would prevent progression to such abuse.

Some committee members questioned the time points in a study comparing drug liking of snorting Apadaz vs Norco. They felt that a time point before 15 or 30 minutes might have more clearly shown an advantage for abusers.

"We kind of missed the window, the really relevant window" in terms of "what we expect an IR drug to do and what we expect a substance abuser would want," commented Melinda Campopiano, MD, medical officer and branch chief, Regulatory Programs, Center for Substance Abuse Treatment, Substance Abuse and Mental Health Services Administration.

As for experiments on how easy it is to manipulate the drug, Dr Campopiano noted that "the type of creativity you'd expect from the average drug user is a little bit lacking to make it really compelling that we've captured accurately how extractable or not extractable the product is."

As well, she said, she was concerned about labeling the drug with abuse-deterrent qualities because this might "undermine our credibility."

"Are we going to use the entire population as research subjects without their permission; is that where we're setting the bar?" she concluded.

Jennifer Higgins, PhD, a consumer representative and director of strategic planning and business development, Center for Human Development, was concerned that the studies included only young people.

Lynn Webster, MD, vice president, scientific affairs, PRA Health Sciences, who presented results of some of the studies submitted, explained that most participants entering such studies are aged 20 to 30 years, and if it's an intranasal study, they have been using these kinds of drugs recreationally.

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