FDA Advisory Committee Expected to Meet Today to Review Zohydro Application

The FDA’s Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) is expected to meet today to review the New Drug Application (NDA) for Zohydro ER (hydrocodone bitartrate extended-release capsules), a hydrocodone-only opioid product developed by Zogenix, Inc.

According to the FDA, the Committee “will discuss the risks and benefits of new drug application (NDA) 202880, by Zogenix Inc., for hydrocodone bitartrate extended-release capsules (proposed trade name Zohydro ER)... This formulation of hydrocodone bitartrate extended-release capsules represents the first single-entity (ie, containing no other active pharmaceutical ingredients, such as acetaminophen or ibuprofen) hydrocodone-containing drug product. It will be formulated in dose strengths up to 50 mg, and administered twice daily (ie, every 12 hours). The committee will be asked to determine whether the benefit-risk assessment of this product favors its approval for marketing.”

Zogenix is seeking an indication of management of moderate to severe chronic pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time for Zohydro.

The briefing materials prepared for committee members by FDA staff note that the committee will be asked to consider the following questions at the advisory meeting:

• Has the Applicant demonstrated that Zohydro ER is effective for the management of moderate to severe chronic pain when a continuous around-the-clock opioid analgesic is needed for an extended period of time?
• Has the applicant demonstrated that Zohydro ER is safe in the intended population?
• Do any of the data presented or discussed suggest that the postmarketing experience concerning abuse with Zohydro ER would be expected to be different from the postmarketing experience associated with other approved Schedule II extended-release opioids?
• Are there data that support the need for additional postmarketing risk mitigation requirements beyond the ER/LA REMS?
• Based on the data presented and discussed today, do the efficacy, safety and risk-benefit profile of Zohydro ER support the approval of this application?

The summary of clinical trial results in the briefing notes that Zohydro met its efficacy targets (the primary efficacy endpoint was “the mean change from baseline to end of treatment in the average-24-hour pain intensity ratings as measured by an 11-point Numerical Rating Scale).

During the trial, the most frequently reported adverse events “were consistent with the known opioid adverse event profile and included constipation, nausea, somnolence, fatigue, headache and dizziness.”

Five subjects died during the trial period -- four were from non-Zohydro-related causes, the fifth was due to overdose related to misuse of Zohydro ER following completion of the study (the briefing materials state that the subject “hoarded Zohydro ER capsules and then opened and ingested all the medication").

Proponents of Zohydro approval note that the drug would provide pain management clinicians with a new, badly needed acetaminophen-free option for treating moderate to severe pain, enabling their patients to avoid exposure to liver toxicity issues associated with current combination products (Vicodin, etc).

In briefing materials prepared by Zogenix and submitted to the FDA, the company contends that “despite the availability of other ER opioid analgesic products, there remains a significant need for additional safe and effective ER opioid analgesic products for patients with chronic pain. Responsiveness to opioids varies greatly between individual pain patients. Comparative effectiveness, tolerance and cross-tolerance between opioids also vary greatly within individual patients. Over the course of chronic pain therapy, the prescriber needs the flexibility to use the same opioid when converting their patient from an IR treatment to their first ER regimen. Prescribers also need more choices when it is necessary to rotate to another ER opioid when issues of effectiveness, tolerance or tolerability develop on a current ER opioid analgesic regimen.”

Opponents of approval note that a single-entity hydrocodone product poses serious potential for widespread misuse and abuse. Ed Pullen, MD, a board certified family physician practicing in Washington state, recently wrote in his popular blog that he is concerned that “Zohydro is poised to become the next Oxycontin… It is difficult enough to keep drugs like Vicodin out of the hands of ‘patients’ who divert the drug for profit and develop addiction issues. Once the issue of acetaminophen excess is removed I predict that Zohydro would follow in the footsteps of Oxycontin.”

In related news, Zogenix announced today that NASDAQ has halted trading of the company's common stock prior to the advisory committee meeting. The company plans to host a conference call this evening to discuss the outcome of the AADPAC meeting.