Tighter REMS For Zohydro ER Still Insufficient For FDA Advisory Panel

FDA’s Anesthetic and Analgesic Drug Products Advisory Committee wants Risk Evaluation and Mitigation Strategies enhanced for all extended-release/long-acting opioids as it recommends 11-2, one abstention, against approval of Zogenix’s single-entity hydrocodone product.

Zogenix Inc. offered a Risk Evaluation and Mitigation Strategy for its single-entity hydrocodone Zohydro ER that was more extensive than the class-wide REMS imposed on extended-release/long-acting opioid drugs, but FDA’s Anesthetic and Analgesic Drug Products Advisory Committee still found it wanting as it voted the product down at its Dec. 7 meeting. The panel’s focus on general risk management concerns, however, offers a ray of hope for the sponsor.

The 11-2 vote against approval, with one abstention, reflected the panel’s dissatisfaction with risk management of the ER/LA opioid class of drugs, and members urged FDA to tighten the class-wide REMS that was imposed on ER/LA opioid manufacturers in July (Also see "Opioid Training Syllabus Increases Emphasis On Patient Monitoring In Final REMS Blueprint" - Pink Sheet, 16 Jul, 2012.).

With regard to Zohydro ER (hydrocodone bitartrate) in particular, the committee also suggested that it not be approved until Zogenix returns with a tamper-proof formulation.

James Ramsey, Emory University Hospital, suggested the class-wide ER/LA REMS restrict prescribing, require patients to lock up the medications and enhance surveillance. Several members also called for mandatory education, a proposal made in previous reviews of the REMS by the committee.

To prevent abuse and misuse of Zohydro, Zogenix proposed to restrict its promotional activities and to undertake physician, patient and pharmacist education programs and surveillance activities beyond those contained in the ER/LA risk management program (Also see "Opioid Training Syllabus Increases Emphasis On Patient Monitoring In Final REMS Blueprint" - Pink Sheet, 16 Jul, 2012.).

Hate The Class, Not The Product

On the plus side for Zogenix, in his summary of the day’s discussions, chairman Randall Flick, Mayo Clinic, said the committee felt the sponsor met the current requirements for approval but the addition of Zohydro ER to this class of drugs would not serve the public health unless the REMS program is strengthened or an abuse-deterrent formulation is proposed.

This is important because Division of Anesthesia, Analgesia and Addiction Products Director Bob Rappaport spent time explaining to the panel that FDA could not review the Zohydro NDA using different standards than those applied to other drugs in the class.

To apply a different standard would require that there be something different with this drug, otherwise the sponsor and drug would be punished because of the sins of previous developers and products, he said. From a regulatory standpoint, that is not something the agency can do.

The panel also voted 7 to 6, with one abstention, that Zogenix had demonstrated the efficacy of Zohydro ER for managing moderate to severe chronic pain when an around-the-clock opioid analgesic is needed.

The Zohydro ER NDA is supported by a single Phase III study in patients with chronic back pain that demonstrated superiority of Zohydro ER over placebo for the primary efficacy endpoint of the mean change from baseline to the end of treatment (day 85) in the average 24-hour pain intensity ratings as measured by an 11-point numerical rating scale, according to the FDA briefing documents.

On a 9 to 5 vote, the panel said safety was not demonstrated for the intended population.

First-In-Class Benefits And Worries

Zohydro ER would be the first single-entity hydrocodone analgesic product to enter the U.S. market. Currently, hydrocodone is marketed as an immediate-release combination with acetaminophen. Zohydro ER would be a Schedule II controlled substance. The combination products are designated as Schedule III controlled substances if they contain no more than 15 mg of hydrocodone per dosage unit. The user fee date for Zohydro ER is March 1, 2013.

Using data from the Drug Abuse Warning Network on estimated emergency department visits in 2008 and drug utilization figures from IMS Health, FDA says the abuse ratio for hydrocodone combination products was 14 emergency visits per million tablets dispensed. For oxycodone combination products, the abuse ratio was 24 emergency visits per million tablets dispensed, compared to 85 for single-entity oxycodone ER products.

Zohydro ER, which is dosed every 12 hours, utilizes the Spheroidal Oral Drug Absorption System (SODAS) from Alkermes PLC to control release of the drug using a mixture of immediate-release and sustained-release beads of hydrocodone. The single-entity hydrocodone offers the option for patients to manage their pain without risking liver injury associated with combination products containing acetaminophen in high dosages or over long periods of time, the company says (Also see "Zogenix’s Stand-alone Hydrocodone To Stand Before Advisory Panel" - Pink Sheet, 12 Nov, 2012.).