While the panel recommended approval of the new product, it did not find sufficient evidence for abuse-deterrent labeling.
By a vote of 16 to 4, an FDA panel has recommended approval of a new immediate-release (IR) pain formulation that includes benzhydrocodone hydrochloride (HCl) and 325 mg of acetaminophen. However, the panel rejected the abuse-deterrent labeling for the new drug by a vote of 18 to 2.
On May 5, 2016, the FDA Center for Drug Evaluation and Research (CDER) held a joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC), and Drug Safety and Risk Management Advisory Committee (DSaRM) to review KemPharm's new drug application for the product KP201/APAP ( proposed name: Apadaz). The manufacturer was seeking a recommendation for approval of the IR opioid analgesic, and requesting abuse-deterrent labeling based on company studies.
The committee members were asked to consider three draft points when voting on the applicantâs drug approval and labeling determinations.
â¢ Did the data show "that the nasal route of abuse is relevant for combination products such as theirs that contain hydrocodone and acetaminophen"?
â¢ Did KP201 demonstrate properties "that would be expected to deter abuse through both IV and nasal administration"?
â¢ Did the data support inclusion of "abuse-deterrent language on the label for both IV and nasal administration"?
During the meeting, KemPharm President and CEO Travis Mickle, PhD, described Apadaz as âa new molecular entity.â He described benzhydrocodone HCl as âa prodrug that is inert when taken orally ... and is rapidly metabolized in the gastrointestinal (GI) tract as an immediate-release drug.â Enzymes in the GI tract allow it to bind to receptors, which the company says allows the drug to offer âabuse-deterrent features but does not pose risk for being a treatment for pain.â
The immediate-release and abuse-deterrent properties of KP201 as intended by the manufacturer are of special interest to FDA. A year ago the agency issued final guidance to assist industry in the âdevelopment of opioid drug products with potentially abuse-deterrent properties,â citing the market absence of any âexisting single-entity or combination immediate-release opioid analgesics labelled with abuse-deterrent properties."
At present, five extended-release/long-acting opioid analgesic products have labeling that includes language and studies covering abuse-deterrent properties; no IR products currently have such labeling.
According to Mickle, abusers seek to alter opioid analgesics by crushing tablets to use through snorting, intravenous injection, or other routes of administration. Since the KemPharm candidate is uniquely converted in the GI tract, he said, this âmodifies the pharmacokinetic profileâ and therefore decreases user exposure to the active drug.
âThe abuse-deterrent properties occur at a molecular level, as crushing or grinding it has no affect in bioavailability, â Mickle said. He added that KP201 cannot be used by IV âas it converts very slowly in blood,â and âsmoking does not release any hydrocodoneâ without the GI enzymes.
The company said that âTampering with Apadaz to optimize its effect actually improves its abuse-deterrent capacity since there would be lower hydrocodone from snorting than by just taking it orally without tampering.â
While the panel recommended approval of the product for its proposed indication of short-term management of acute pain, the panel was concerned about the evidence for abuse-deterrent labeling.
Despite a market need for new abuse-deterrent opioid analgesics, committee panelist Tobias Gerhard, RPh, PhD, said, âWe have to remain critical. We havenât seen the kind of evidence that this product makes a difference [in terms of abuse deterrence].â Gerhard is associate professor, Department of Pharmacy Practice and Administration, at Rutgers University Ernest Mario School of Pharmacy Practice.
In a company response, Mickle stated, âWe continue to believe in the value of our prodrug technology as a platform for developing prescription opioids with abuse-deterrent properties. While it is inevitable that there will be different points of view when evaluating new molecular entities with abuse-deterrent properties, we will continue to work collaboratively with the FDA to complete the review process of Apadaz.â
Barbara Hesselgraveis a freelance journalist based in Baltimore.