FDA Makes Zohydro ER the First Approved Single-Entity Hydrocodone Analgesic, First ER/LA Opioid to Contain Hydrocodone, and First ER/LA Opioid With New Labeling

By Delia A. Stubbs –

The amount of government activity on issues involving controlled substances last week makes the furlough seem like a figment of our imagination.  Following issuance of a press release on hydrocodone rescheduling and a court ruling on DEA’s delay on the scheduling of FYCOMPA (see prior posts here and here) on Friday, FDA announced its approval of New Drug Application (“NDA”) No. 202880 for Zogenix, Inc.’s (“Zogenix’s”) single-entity, extended-release, hydrocodone pain-killer drug, Zohydro ER.  FDA’s approval renders Zohydro ER the first U.S. approved single-entity hydrocodone product, the first extended-release/long-acting (“ER/LA”) opioid analgesic to contain hydrocodone, and the first ER/LA opioid analgesic to display new labeling proposed for that class of drugs.

Although Congress placed single-entity hydrocodone in Schedule II, when it first passed the Controlled Substances Act in 1970, Zohydro ER is the first drug subject to that rule.  Fortunately for Zogenix, this pre-determined schedule means that Zogenix need not wait to market Zohydro ER while DEA determines whether and in which schedule to place the drug.  This is in sharp contrast to the experience of manufacturers of new chemical entities (“NCEs”) with abuse-potential, who customarily agree to refrain from marketing their products until DEA issues a final scheduling order, which can take over a year, and who may lose their exclusivity rights in the interim.  (See prior posts here and here, and a challenge to FDA’s position on the start of the exclusivity clock here.)

Other than rendering it the first U.S. approved single-entity hydrocodone product, FDA’s approval of Zohydro ER marks two other important firsts: it renders Zohydro ER the first FDA-approved ER/LA opioid to contain hydrocodone and, consequently, the first drug to exhibit new labeling that FDA has proposed apply to all drugs in that class.  As previously reported, on September 10, 2013, FDA requested that all holders of NDAs, biologic license applications (“BLAs”), or abbreviated new drug applications (“ANDAs”) for ER/LA opioid analgesics submit supplemental NDAs with revised labeling that would, among other things, indicate that those drugs are for “the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.”  The affected applicant holders had 30 days to submit supplements or provide reasons for not doing so in writing to FDA.  Zohydro ER is the first opioid to display the recommended labeling.

In addition to marking several firsts, Zohydro ER’s approval has received sharp criticism by lawmakers due to its apparent departure from a movement by FDA to potentially require abuse-deterrent technology for all opioids, like hydrocodone.  Earlier this year, FDA found that Purdue withdrew its drug, OxyContin (oxycodone), for reasons of safety or efficacy in the wake of the FDA’s approval and the Company’s marketing of the same drug with that technology.  FDA declined to reach the same result for Endo’s drug, Opana ER (oxymorphone).  See FDA, CDER, Response to Center for Lawful Access and Abuse Deterrence Citizen Petition, Docket No. FDA-2013-P-0703, at 5-6 (Oct. 25, 2013) [hereinafter, “CLAAD Petition Response”].

Within hours after FDA issued its press-release announcing Zohydro ER’s approval, Congressman William Keating (D-MA) issued a letter condemning FDA’s approval of the drug without abuse-deterrent technology.  He explained:

Last year, a FDA panel questioned the medical need to have such a strong drug on the market and today, FDA not only approves this dangerous drug, but does so without requiring any abuse-deterrent features.  This is outrageous.  Abuse-deterrent technologies should not be the anomaly – they must be the norm.

The Congressman is referring to an Advisory Committee meeting held on December 7, 2012.  Congressman Keating called for support of proposed legislation, the STOPP Act, which would, among other things, require FDA to refuse to approve an ANDA that references a listed drug that utilizes abuse-deterrent technology, absent a showing of comparable tamper-resistance (see our previous post here).  

On the same day that FDA approved Zohydro ER (we told you it was a busy week!) the Agency responded to a Citizen Petition filed by CLAAD.  In that response, which mentioned the agency’s approval of Zohydro ER, FDA stated that its policy is to consider whether abuse-deterrent technology is necessary to ensure adequate safety of a drug on a “product-by-product” basis.  See CLAAD Petition Response at 5.  To illustrate that point, FDA discussed how it came to different conclusions regarding the reformulations and subsequent withdrawal from the market of the original formulations of OxyContin and Opana ER. Id. at 5-6.  It reasoned that it would be ill-advised to require such technology for all opioids at this time, in part because the “science of abuse deterrence technology is in its early stages” and those technologies “have important limitations” such as that they are not “intended or believed to have any impact on the most common form of abuse of this and many other prescription opioids-swallowing intact tablets or capsules.”  Id.  at 5.  However, FDA also stated that it strongly encourages “the development of opioids that can be expected to significantly reduce abuse,” and incentivizes that behavior by allowing companies to label their drugs accordingly.  Id.

Zohydro ER, as an ER/LA prescription opioid analgesic, is also subject to a class-wide Risk Evaluation and Mitigation Strategy.  This and other measures recently adopted by FDA do not apply to immediate-release opioids.  It is unclear yet how FDA will apply its “product-by-product” review for that class of drugs in the future.