FDA Okays Abuse-Deterrent Zohydro ER

Susan Jeffrey


February 02, 2015

The US Food and Drug Administration (FDA) has approved a new formulation of hydrocodone (Zohydro Extended Release Capsules, CII, Zogenix Inc) with abuse-deterrent properties.

The single-entity hydrocodone product will be formulated with BeadTek, a technology "designed to provide abuse-deterrent properties without changing the release properties of hydrocodone when Zohydro ER is used as intended," a statement from Zogenix said.

The company is conducting ongoing human abuse liability studies, "which will further characterize the abuse-deterrent properties of the new formulation," the statement notes. "Zogenix intends to submit these data in the second half of 2015 to the FDA to support an amended product label, including abuse-deterrent claims consistent with the FDA's current draft Guidance for Industry, Abuse-Deterrent Opioids – Evaluation and Labeling."

The FDA approved Zohydro ER in October 2013, indicated 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. It was the first hydrocodone formulation that did not contain acetaminophen, unlike many immediate-release hydrocodone products, with the aim of reducing the risk for potential liver toxicity due to overexposure of acetaminophen.

However, the FDA approval of Zohydro ER came against the advice of its own advisory committee, which expressed concerns about the potential for abuse.

Since then, the drug has been at the center of ongoing controversy, with consumer groups and attorneys general of numerous states asking the FDA to reverse its approval of the drug, and bills introduced in the House and Senate to keep it off the market.

A major criticism of Zohydro ER has been that it was not available in abuse-resistant formulation. In September 2014, a coalition of more than 15 consumer groups and medical experts fighting the opioid epidemic called for new leadership at the FDA, charging that the agency's opioid policies are exacerbating the nation's epidemic of opioid addiction and overdose deaths.

In October 2014, Zogenix announced submission of this supplemental New Drug Application for a modified formulation of Zohydro ER designed to have abuse-deterrent properties. The new formulation uses BeadTek, which, the company notes, "incorporates well-known pharmaceutical excipients that immediately form a viscous gel when crushed and dissolved in liquids or solvents."

"Zohydro ER is the only long-acting hydrocodone product administered every 12 hours, and the new formulation maintains the same efficacy and pharmacokinetic profile of the original formulation," the new Zogenix release notes.

Transition from the current to the new formulation is expected to occur in the second quarter of 2015 for all prescribed strengths ranging from 10 mg to 50 mg, without disruption to patients currently receiving therapy, the company said.

"Because of the risks of addiction, abuse and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve Zohydro ER for use in patients for whom alternative treatment options (eg, nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated or would be otherwise inadequate to provide sufficient management of pain," the new release notes.

The product already carries a boxed warning outlining risks associated with use; these are noted by the company in their announcement:

  • Use of Zohydro ER exposes users to risks for addiction, abuse, and misuse, which can lead to overdose and death. "Assess each patient's risk before prescribing, and monitor regularly for development of these behaviors or conditions," the statement notes.

  • Serious, life-threatening, or fatal respiratory depression may occur. "Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow Zohydro ER whole to avoid exposure to a potentially fatal dose of hydrocodone."

  • Accidental ingestion of this product, especially in children, can result in a fatal overdose of hydrocodone.

  • Prolonged use during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. "If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available."

  • Patients should be instructed not to consume alcohol or any products containing alcohol while taking Zohydro ER because co-ingestion can result in fatal plasma hydrocodone levels.

  • Initiation of CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of hydrocodone with the product.

See Zohydro ER full prescribing information for the complete boxed warning and safety information.

Zohydro ER is contraindicated in patients with significant respiratory depression, acute or severe bronchial asthma, known or suspected paralytic ileus, and hypersensitivity to hydrocodone bitartrate.

Zohydro ER has warnings for: interactions with central nervous system (CNS) depressants; elderly, cachectic, debilitated patients; those with chronic pulmonary disease; hypotensive effects; patients with head injury or increased intracranial pressure; and concomitant use of CYP3A4.

Potential serious adverse events caused by opioids include addiction, abuse, and misuse; life-threatening respiratory depression; neonatal opioid withdrawal syndrome; interactions with other CNS depressants; hypotensive effects; gastrointestinal conditions, and seizures. The most common adverse reactions associated with Zohydro ER (2% or greater) include constipation, nausea, somnolence, fatigue, headache, dizziness, dry mouth, vomiting, pruritus, abdominal pain, peripheral edema, upper respiratory tract infection, muscle spasms, urinary tract infection, back pain, and tremor.

With intravenous abuse, the inactive ingredients in Zohydro ER can result in death, local tissue necrosis, infection, pulmonary granulomas, and increased risk for endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious organisms, such as hepatitis viruses and HIV, the statement adds.

"While we are very pleased with the outcomes from our safe use initiatives, implemented with the introduction of Zohydro ER last year, we believe moving forward with this formulation change at the earliest possible time is a responsible action for us to take," said Stephen Farr, PhD, president of Zogenix. "We are also committed to completing the ongoing studies to seek additional changes in the product label relating to abuse-deterrent properties by the end of the year." 

In November 2014, the FDA approved the extended-release single-entity opioid analgesic hydrocodone bitartrate (Hysingla ER, Purdue Pharma) with abuse-deterrent properties.

In July 2014, the agency approved an abuse-deterrent extended-release formulation of oxycodone (Targiniq ER, Purdue Pharma LP), a combination of oxycodone hydrochloride and naloxone hydrochloride.


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