FDA pressed to rescind approval of Zohydro painkiller

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An Allegheny Health Network physician has joined the outcry over U.S. Food and Drug Administration approval of a potent new opioid painkiller, which shows potential for abuse, diversion for illegal use and accidental overdose.

The extended-release painkiller, Zohydro ER, consists solely of hydrocodone, a synthetic opioid that is released over a 12-hour period. In October, the FDA approved the drug manufactured by Zogenix Inc., despite an 11-2 vote by its advisory committee against its release.

Continuing controversy over FDA approval crescendoed in recent weeks with its pending release to the market. Zogenix announced March 5 that its sales force had begun educating prescribers and pharmacists about Zohydro ER, including providing patient education toolkits.

The company also announced that Zohydro ER is available in select pharmacies nationwide.

"I would have liked to see the FDA follow its advisory panel recommendation and not approve Zohydro ER for release," said Jack Kabazie, director of Allegheny Health Network's division of pain medicine. "There is no need for it. There are other extended-release drugs at our disposal to treat malignant and nonmalignant pain.

"If you are opioid-naive, and not taking narcotics on a regular basis, mistakenly chewing or crushing this medication could potentially be lethal," he said. "Even if one is tolerant to opioids, a 50-milligram capsule if chewed or crushed releases the equivalent of 10 Vicodin at one time, minus the Tylenol, and could result in overdose."

Synthetic opioids, including hydrocodone in Zohydro, resemble morphine or other natural opiates in how they control pain but with much greater potency. Adding to concerns are the 22 deaths and an unknown number of nonfatal overdoses that occurred since summer, due to abuse of a drug combination of heroin laced with another synthetic opioid painkiller, fentanyl.

About 40 consumer watchdog groups and addiction-treatment organizations petitioned the FDA to reconsider approval on grounds that Zohydro is too dangerous without a compelling need for another opioid painkiller. Opposition also comes from attorneys general in 28 states, including Kathleen Kane of Pennsylvania.

"We believe your approval of Zohydro ER has the potential to exacerbate our nation's prescription-drug abuse epidemic because this drug will be the first hydrocodone-only opioid narcotic that is reportedly five to 10 times more potent than traditional hydrocodone products, and it has no abuse-deterrent properties," states the attorneys general's letter to the FDA.

They also are seeking tighter restrictions on marketing and prescribing the drug, with Ms. Kane's office saying the new drug will serve only to worsen the public-health epidemic of addiction.

"We also know that those addicted to opioid pharmaceutical products often turn to street drugs, such as heroin, to further support their addiction," said Adrian R. King Jr., Ms. Kane's first deputy attorney general. "Given these facts, the FDA's approval of an even more powerful and addictive opioid pharmaceutical product is clearly regrettable and ill-advised."

In approving Zohydro, the FDA said its goal "is to balance the important public health concerns around the misuse and abuse of extended-release opioids with the need for continued patient access to effective pain medications."

Its response to the attorneys-general's concerns echo its previously stated reasons for approval. The FDA notes that Zohydro has been designated as a Schedule II controlled substance to be dispensed only through a physician's written prescription for which no refills will be allowed.

"There are stringent record-keeping, reporting, and physical security requirements for Schedule II controlled substances," said Sally Howard, FDA deputy commissioner for policy, planning, and legislation, in her reply to the attorneys general.

The FDA says the drug meets its regulatory requirements and is important for people requiring 24-hour-a-day relief for moderate to severe pain. The product's "benefits outweigh its risks when used as intended."

"Zohydro ER is not approved for as-needed pain relief and should be reserved for severe pain requiring daily, round-the-clock, long-term treatment and for which alternative treatment options are inadequate," the FDA says. "This type of debilitating pain often negatively impacts patients' ability to live normal daily lives."

Key to the controversy is Zohydro's lack of abuse-resistance properties. Oxycontin, the synthetic opioid that became a favorite street drug, now contains properties to render it impotent if tampered with. Without such properties, damage to Zohydro capsules, purposefully or accidentally, could lead to immediate release of the 12-hour dose, heightening the risk of a lethal overdose.

But the FDA says the need for Zohydro is compelling. It recently recommended restrictions against overuse of painkillers containing acetaminophen -- the over-the-counter analgesic pain reliever in Tylenol that, like aspirin, also reduces fever. In recent action, the FDA recommended limiting acetaminophen dosage to 325 milligrams, based on research that shows higher doses potentially can cause severe liver injury, liver failure and death.

Hydrocodone, the sole ingredient in Zohydro, long has been available in Vicodin, Lorco and Lorcotabs, that combine it with acetaminophen. Percocet combines acetaminophen with oxycodone, the same painkilling opioid agent in Oxycontin.

Growing concern about acetaminophen toxicity has increased the need for alternatives like Zohydro, Zogenix says.

Still, Dr. Kabazie said the FDA should have put Zohydro on hold until Zogenix develops a formulation that deters abuse or reduces overdose risks that could occur from a damaged capsule. FDA documents said development of abuse-resistant properties for Zohydro will take three years to complete.

"History repeats itself," Dr. Kabazie said. "Drugs like Zohydro will reach the street. It is inevitable. It will lead to abuse, diversion, addiction and possibly accidental overdoses.

"The illegal use of Zohydro aside, the well-meaning patient could be harmed by accidentally crushing or chewing the capsule and overdosing. Providing patients with education toolkits is all well and good, until someone makes a mistake and does chew the capsule. If it can happen, it will happen. It's called human error."

David Templeton: dtempleton@post-gazette.com or 412-263-1578.

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