SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel voted against approval of an extended-release, single-ingredient capsule formulation of hydrocodone for the treatment of chronic pain, citing the need for a tamper-proof formulation and a stronger risk mitigation strategy to address the high potential for abuse and misuse of the product.
At a Dec. 7 meeting of the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee, the panelists voted 11 to 2, with 1 abstention, against approval of the product, although they agreed that the manufacturer had met the current standards for approval for the proposed indication, the management of moderate to severe chronic pain when a continuous around-the-clock opioid analgesic is needed for an extended period. However, concerns about the potential public health impact of the availability of an extended-release formulation of hydrocodone that does not contain acetaminophen – which would make it more attractive as a drug of abuse, particularly for intravenous drug abusers – or a tamper-resistant design, swayed their votes.
Panelists voting against approval also said that the Risk Evaluation and Mitigation Strategy (REMS) for extended-release and long-acting opioids, which was approved by the FDA in July 2012 to minimize abuse and misuse of these drugs, was not stringent enough to assure the drug would be used safely, citing the need to make prescriber education mandatory and limit distribution of the drug.
Currently, the FDA cannot require that opioids be made tamper resistant, although this is something that the agency is considering making a condition of approval for opioid products. Since 2010, OxyContin (controlled-release oxycodone) has been available in a formulation designed to prevent it from being chewed, crushed, or dissolved.
The manufacturer of the extended-release, single-ingredient hydrocodone formulation, Zogenix, has proposed that it be approved at doses of 10 to 50 mg administered twice a day, with a proposed risk management strategy that goes beyond the REMS now required by the FDA for all extended-release and long-acting opioids, including features such as a locked bottle cap.
If approved, this product would be the first product that contains hydrocodone alone, and the first extended-release form of hydrocodone, according to the FDA. It would be regulated as a schedule II narcotic. Currently, marketed hydrocodone products contain limited amounts of hydrocodone and are regulated as schedule III narcotics.
The panel voted 8 to 5 with 1 abstention that the manufacturer had shown that the product was effective for the chronic pain indication, based on the pivotal phase III, randomized, double-blind, 12-week study comparing hydrocodone ER against placebo in patients with chronic low back pain. They voted 9 to 5 that it had not been shown to be safe, however.
Panelist Dr. James Ramsay, director of critical care services in the department of anesthesiology at Emory University Hospital, Duluth, Ga., said that hydrocodone is the most widely used and abused opioid, and if marketed, the extended-release product "will be the choice drug for diversion and extraction."
Making this available without an abuse deterrent would be like "opening up Pandora’s box," added another panelist, Dr. Alan Kaye, professor and chairman of the department of anesthesia at Louisiana State University, New Orleans.
In 2008, based on U.S. emergency department (ED) visits from the Drug Abuse Warning Network and retail pharmacy sales data, the FDA estimated that for hydrocodone combination products, the abuse ratio was 14 ED visits per million tablets dispensed. For oxycodone combination products, the ratio was 24 ED visits per million tablets dispensed, but for single-entity oxycodone extended-release products, the ratio increased to 85 ED visits per million tablets dispensed. This is a "substantial" difference, and "it is likely that similar patterns will be observed" between hydrocodone products and the extended-release, single-ingredient hydrocodone product, according to the FDA’s briefing documents.
During the open public hearing portion of the meeting, parents whose children died because they became addicted to prescription pain relievers, including hydrocodone, pleaded with the FDA not to approve the product.
The FDA usually follows the recommendations of its advisory panels, which are not binding. A decision is expected by March 1, 2013, according to Zogenix, which plans to market the product as Zohydro ER if approved. A statement released by Zogenix after the meeting said that the company remained confident in its plans to support safe use of the drug, and was committed to continue working with the FDA to make the product available for the proposed patient population.
Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may occasionally be given a waiver, but not at this meeting.