Massachusetts’ ban on Zohydro ER prescriptions signals a new kind of activism by states: challenging FDA’s authority to approve drugs. But it is far from the only challenge the agency faces regarding its approval of Zogenix Inc.’s single-entity hydrocodone product, with concerns now coming from within the Obama administration itself.

While Massachusetts is the first to override an approval, Vermont has issued an emergency rule to restrict prescribing of the product. And Ohio legislators have introduced a bill to bar prescriptions by making Zohydro ER a Schedule I controlled substance.

FDA is also facing continued pressure from members of Congress who oppose the drug’s approval. The pressure has become so intense that Attorney General Eric Holder said he plans to evaluate FDA’s action. At an April 4 hearing of the House Appropriations Subcommittee on Commerce, Justice, Science and Related Agencies Holder said he was “a little baffled” by the approval and would be checking with FDA about the basis for the decision.

Appropriations Committee Chairman Hal Rogers, R-Ky., stated that the drug is 10 times the strength of OxyContin (oxycodone) and is being released with no abuse deterrent technology. “Why did the FDA do this and what can we do about it?” he asked.

“Efforts by Congress and at the state level to legislate the approval or marketing withdrawal of medications is extremely troubling,” FDA said.

Holder replied that he would be talking with FDA to get a better understanding of what was behind the decision. “If it is inconsistent with the efforts we have painstakingly put in place [to prevent opioid misuse] that is something that would give me great concern,” he stated.

FDA approved Zohydro ER, the first single-ingredient, long-acting hydrocodone product, in October against the recommendations of its Anesthetic and Analgesic Drug Products Advisory Committee, which voted 11-2 against approval, with one abstention. The opioid is indicated for the management of pain severe enough to require daily, around-the-clock, long-term treatment and limited to patients for whom non-opioid analgesics or immediate-release opioids are ineffective or not tolerated ([A#14131025007]).

The agency’s approval also came amid opposition from 29 state attorneys general and several consumer organizations. They have continued to speak out against the drug, as have several members of Congress.

Three Republican senators sent a letter to FDA in February asking the agency for information on safeguards for Zohydro’s distribution and questioning the drug’s lack of abuse deterrent features ([A#14140213002]).

Senator Charles Schumer, D-NY, issued a March 3 release calling on HHS Secretary Kathleen Sebelius to overturn the approval. Six state AGs also sent a March 25 letter to Sebelius making the same request. And at the federal level Sen. Joe Manchin, D-W.Va., introduced the “Ban Zohydro Act,” which would require FDA to withdraw approval of the drug and prevent the agency from approving any application for pure hydrocodone bitartrate that lacked abuse deterrent properties.

Patient Groups Stand With FDA

Despite the widespread opposition, FDA has stood by its decision. In response to questions about the Massachusetts ban, FDA said “efforts by Congress and at the state level to legislate the approval or marketing withdrawal of medications is extremely troubling.”

The agency also used the approval of a naxolone auto-injector to indirectly defend its approval of Zohydro.

On April 3 FDA held two briefings, one for stakeholders and one with the media, with top government officials to discuss the approval of Kaléo Inc.’s Evzio, the first auto-injector for naxolone, with FDA touting the device as potentially useful tool a layperson could use to help a victim of an opioid overdose.

The agency also issued a statement by FDA Commissioner Margaret Hamburg in which she asserted that the agency has been working to prevent opioid abuse while ensuring access to pain medications. She said these goals are not incompatible and that “actions to address one should not be at the expense of the other” ([A#14140403005]).

FDA does have support among patient groups, as the briefing with stakeholders conveyed. A representative from the U.S. Pain Foundation said she appreciated FDA’s balance. She said millions of people living with pain are helped by medicines, and the vast majority of patients use them safely. She noted that many have had their prescriptions discontinued as doctors have stopped providing treatment.

Zogenix Going Beyond The REMS

Zogenix Chief Medical Officer Bradley Galer said in an interview that the voice of the patient is being lost in the discussions about Zohydro.

“Approximately 2.5 million Americans are taking Vicodin [a combination of hydrocodone and acetaminophen] or generics on a chronic basis, putting them at risk for severe liver toxicity,” he stated. “We’ve made medicine safer by removing acetaminophen. It’s a better and more effective medicine” that is taken two times a day instead of four to six times a day.

The company also emphasized that it has taken steps beyond the FDA-mandated Risk Evaluation and Mitigation Strategy to prevent Zohydro ER’s abuse.

The REMS for the class of long acting/extended-release opioids requires prescribing training courses. Zogenix is also providing educational tools to pharmacists and patients, assuring that sales representatives are not compensated on sales volume of Zohydro ER but rather on provision of educational material, and providing patients with free locking pill bottle caps and discounted lock boxes.

Galer called Massachusetts’ ban “shocking and unprecedented.” As to whether Zogenix might challenge the action, he said the company is continuing to evaluate all its options.

Zogenix issued a statement in response to Vermont’s rule saying, “While we appreciate the fact that Vermont authorities have not completely shut the door on chronic pain patients in their state with regard to access to Zohydro ER, we have serious concerns that they have added additional restrictions to only one specific product.”

“Because there are risks of misuse and abuse to all opioid medications, we believe that any restrictions should be applied to all Schedule II opioids, including both extended-release and immediate-release opioid medications,” the company stated.

“These actions in Vermont and other states that have voiced opposition to Zohydro ER fly in the face of sound regulatory and legislative guidance at the federal level and represent an arbitrary and short-sighted view of this complex issue.”

Market And Regulatory Impact Uncertain

Zogenix began shipping the drug in March, and Galer said it was too early to comment on the level of sales. The company is developing two abuse-deterrent formulations of Zohydro ER but does not expect one could reach the market before 2016.

Purdue Pharma LP announced in March that it is planning to file an NDA for an abuse-deterrent extended-release hydrocodone product later in 2014. Purdue’s product – which, if approved, might force Zohydro ER off the market for safety reasons – is using the same abuse-deterrent technology as its reformulated OxyContin, which is the only drug to include abuse-deterrent claims in labeling ([A#14140312002]).

Hydrocodone products are the most commonly prescribed opioid analgesic in the U.S., with nearly 143 million prescriptions for hydrocodone-containing products dispensed in 2012, according to the Drug Enforcement Administration Also see "Opioid Market Snapshot: No Pain, No Gain For Abuse-Deterrence Claims" - Pink Sheet, 24 March, 2014..

Domino Effect In The States

Massachusetts’ move may have a domino effect. On March 27, Gov. Deval Patrick declared a public health emergency in response to the growing epidemic of opioid addiction. As part of his plan to combat the problem he directed the state’s Department of Public Health to immediately prohibit the prescribing and dispensing of Zohydro ER “until determined that adequate measures are in place to safeguard against the potential for diversion, overdose and misuse.”

A spokesperson for the governor’s administration said the office had received positive feedback about the action from other states, one of which is planning to follow Patrick’s lead and implement its own ban.

Vermont, meanwhile, has enacted a less drastic measure. At an April 3 press conference Vermont Gov. Peter Shumlin announced that the state Health Commission was issuing an emergency rule to tighten how health care providers prescribe Zohyodro. The rule requires physicians to document that other alternatives are not available or are ineffective; receive signed consent forms from patients; conduct urine screening at least every 120 days; and evaluate in follow-up visits whether to switch to an alternative treatment.

Shumlin said the problem of opioid addiction was mostly driven by FDA’s approval of OxyContin. “What puzzles all of us is the recent FDA action to approve a new opioid that is stronger and likely to be more addictive because of its strength – Zohydro,” he stated. He said the new rule is intended to prevent the mistakes that were made with OxyContin.

The governor was joined by several Vermont mayors and Health Department Commissioner Harry Chen. Chen said the rule, which went into effect April 4, is a requirement and that prescribers who ignore it will be subject to censure, conditions on their licenses or suspension or revocation of their licenses. He also criticized FDA’s approval of the drug. “One might wonder if they are on the same planet,” he said.

Legislatures in other states are also considering possible bills to limit or block Zohydro use. Ohio introduced a bill on March 20, H.B. 501, which would move Zohydro ER from Schedule II to Schedule I of the Controlled Substances Act. Schedule I substances, which include heroin and LSD, are deemed to have no accepted medical use and a high potential for abuse.

FDA’s Zohydro ER Headache Worsening: States, DOJ Question Approval

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