An FDA advisory committee voted 11-2 on Friday against recommending approval of a single-entity hydrocodone product, raising questions about its abuse potential as a member of a drug class with a history of problems.
The manufacturer, San Diego, Calif.-based Zogenix, is seeking approval for hydrocodone bitartrate extended-release capsules (Zohydro ER) for the management of moderate-to-severe chronic pain when an around-the-clock opioid analgesic is needed for an extended period of time.
It would be the first single-entity hydrocodone analgesic approved, as all others include non-opioid analgesics such as acetaminophen or ibuprofen.
But members of the FDA's Anesthetic and Analgesic Drug Products Advisory Committee expressed concern with addiction and long-term safety even when used safely.
"The consequences of taking this kind of medication long-term, longer than 12 weeks, [are] not well studied," said panelist Judith Kramer, MD, professor of internal medicine at the Duke University Medical Center.
When studied in a randomized, placebo-controlled, 12-week trial of patients with moderate-to-severe low back pain, hydrocodone showed superiority over placebo. Patients taking the drug candidate showed an average change in pain intensity score of 0.48 +/- 1.56 from baseline to day 85 compared with 0.96 +/- 1.55 (P=0.008) for placebo, the FDA said in briefing documents released ahead of Friday's meeting.
Zohydro also was found to be generally safe and well-tolerated with no new or unexpected safety concerns when studied in nearly 1,500 patients, some as long as a year.
However, panelists raised questions about the narcotic falling into the wrong hands or being misused and abused, even if already tight distribution channels only give the drug to the intended patients.
"The sponsor didn't offer any remedy on how it would limit unintended use," said consumer representative Rodney Mullins, of Duluth, Ga.
Members voted 5-9 against the safety of the stand-alone hydrocodone in the intended population, and 7-6, with one abstention, that it is effective for its intended use.
Kramer noted that the study was only in lower-back pain patients and not those with other common pain aliments such as cancer and arthritis.
Zohydro also contains no tamper deterrent. It comes in coated carrier beads and hard-gelatin capsules and is administered twice daily.
"I would feel very uncomfortable approving a non-abuse-deterrent product," Kramer said.
Zogenix noted a new narcotic on the market would provide some benefit for clinicians and added it has reasons to believe their candidate would be better controlled.
Having a free-standing, extended-release hydrocodone product for chronic pain would eliminate the risk of liver toxicity in long-term users, Zogenix said.
Zohydro also would allow providers to convert patients using immediate-release hydrocodone to an extended-release alternative. It would also provide an alternative to other long-acting opioids such as methadone, oxycodone, and morphine.
Zogenix said it sees the use of Zohydro in a very small set of patients - roughly 90,000 at its peak - when roughly 4 million patients receive an extended-release opioid.
The drug would be a Schedule II controlled substance, while combination products are a less restrictive Schedule III.
Schedule II drugs must be handwritten and pharmacies must have the original prescription in hand before dispensing. Also, in many states, mid-level practitioners are not authorized to prescribe Schedule II drugs.
Zohydro would also fall under the class-wide risk management and mitigation strategy (REMS) for extended-release opioids. The REMS was issued in July and the FDA could provide no evidence of how or whether it has affected abuse.
Among the many requirements, the REMS creates a patient-education brochure, education program for prescribers, and a tool kit for providers before dispensing.
"These requirements alone would make Zohydro the most stringently prescribed hydrocodone product," Zogenix President Stephen Farr, PhD, told the committee.
But even the REMS didn't seem strong enough to limit abuse for committee members. "I'm concerned that REMS is not enough," said Jeanmarie Perrone, MD, director of medical toxicology in the department of emergency medicine at the University of Pennsylvania, in Philadelphia.
Zogenix also noted its candidate's highest dose - 50 mg - is lower than the highest doses of other currently marketed extended-release hydrocodone products in terms of morphine equivalents.
"We will not encourage the use of the medication by any physician or provider who demonstrates inappropriate prescribing," Farr said, adding the company would report such a person to the correct authorities.
The FDA is expected to make a determination on the drug by March 1. The agency isn't required to follow to recommendation of its advisory committees but usually does.