Published: Oct 28, 2013 | Updated: Oct 29, 2013
By John Fauber, Reporter, Milwaukee Journal Sentinel/MedPage Today; Kristina Fiore , Staff Writer, MedPage Today
Against the recommendation of its own advisors, the U.S. Food and Drug Administration approved a new high-dose narcotic painkiller, a drug that the FDA concedes has a high risk for abuse and one which was using a method that critics say may give the drug the appearance of greater efficacy.
Zohydro ER will be the first hydrocodone-only opioid, and it will come in doses packing five to 10 times more heroin-like narcotic than traditional hydrocodone products such as Vicodin that combine hydrocodone with over-the-counter pain relievers such as acetaminophen or ibuprofen.
Abuse Potential
Though the narcotic in Zohydro ER is designed to be released slowly over 12 hours, pleasure seekers will be able to crush it, chew it or mix it with alcohol to unleash its full punch at once. That abuse potential would have been blunted if the FDA required that the drug be formulated with abuse-prevention technology -- a process the FDA has publicly backed, but did not require in this case.
A November 2012 memo from the FDA's own staff warns that the drug will be abused more than traditional hydrocodone products. The memo compares what likely will occur with Zohydro to what happened with extended release oxycodone-containing opioids.
The most famous oxycodone product, OxyContin, for years was one of the most abused narcotics in America. In 2010, its maker, Purdue Pharma, reformulated its recipe to make it abuse resistant, a protection that Zohydro won't have.
In an email, FDA spokesperson Morgan Liscinsky said that while the agency supports a transition to abuse-deterrent opioids, "we do not believe it is appropriate or feasible at this time to require all products in the class to be abuse-deterrent.
"Rather, FDA will continue to take a product-by-product approach to regulatory decisions concerning the abuse-deterrent properties (or lack thereof) of opioid products."
Zohydro drugmaker Zogenix, based in San Diego, said in a statement to the Journal Sentinel/MedPage Today that it plans to develop an abuse-deterrent formulation of the drug and is "committed to advancing the program as rapidly as possible."
Liscinsky added that the FDA concluded that the benefits of Zohydro outweighed its risks and that data show it is safe and effective for round-the-clock use. Its label will have prominent warnings about abuse, she said. The label will urge prescribers to monitor patients for addiction or misuse.
"Prescribers now have a hydrocodone option for patients who require an extended-release opioid, which is important for several reasons," she said. "First, individual patients can respond differently to different opioids. Second, the benefits of opioids can wane as the patient becomes opioid-tolerant."
"While the current formulation of Zohydro ER does not have abuse-deterrent or tamper-proof features, we have started the development of an abuse-deterrent formulation and are committed to advancing the program as rapidly as possible," said a statement from Zogenix, the company that makes Zohydro.
But during the FDA advisory committee hearing last December, a company official said an abuse-deterrent formulation of the drug was only in early development and was "several years away from the market."
Friday's approval of Zohydro is the latest action by the agency, which recently has been the target of claims that it is too friendly toward the opioid industry. And it comes follows closely complaints that the FDA had not done enough over the years to curtail the booming overuse of opioids.
The U.S. already consumes 99% of the hydrocodone used in the world.
In 2010, Vicodin was the most prescribed medication in the U.S. with 131 million filled prescriptions. That same year, more than 16,000 people died of overdoses from narcotic painkillers, up from about 4,000 in 1999.
Vicodin comes in doses of 5, 7.5 and 10 mg of hydrocodone along with 300 mg of acetaminophen. Zohydro will come in six doses: 10, 15, 20, 30, 40 and 50 mg without any acetaminophen, which can cause liver damage in high amounts.
"If the FDA was really interested in protecting the public, they would have said, 'No thanks.... we have too many people dying of opioids in this country to justify approving Zohydro,'" said David Juurlink, MD, PhD, director of pharmacology and toxicology at the University of Toronto. "Minus the pesky acetaminophen, plus the crushability, it's a disaster in the making."
An FDA "Flip-Flop?"
On Thursday, after years of resisting the measure, the FDA finally moved to tighten restrictions on hydrocodone products. When the change occurs next year, hydrocodone products will have the same Schedule II restrictions as oxycodone products such as OxyContin.
However the day after the move, the agency reversed course, and approved Zohydro, despite the fact that its own advisory panel voted 11-2 in December not to approve the drug.
The Zohydro decision is "worrisome," U.S. Rep. Harold "Hal" Rogers (R-Ky.), said in a statement provided to the Journal Sentinel/MedPage Today. Kentucky has experienced substantial opioid abuse over the years.
"I am counting on the FDA to perform rigorous post-marketing studies and analysis to ensure this drug doesn't create another new wave of addiction," he said.
Rogers is chairman of the House Appropriations Committee and has co-hosted the National Rx Drug Abuse Summit.
"I am surprised," said Jeanmarie Perrone, MD, an associate professor of emergency medicine at the University of Pennsylvania and member of the FDA advisory panel who not to approve Zohydro.
Perrone said she was concerned about the safety of the drug and its lack of abuse resistance. At the advisory panel meeting, she also questioned its effectiveness.
The approval also suggests that the FDA is trying to help drug makers show that that opioids are safe and effective for treating long-term non cancer pain, said Lewis Nelson, MD, a New York emergency medicine specialist who has served as an FDA advisory panel member on opioid issues.
"I don't see any reason why the FDA should be helping pharma," said Nelson, also a medical toxicologist at NYU School of Medicine.
Enriched Data
The main research on Zohydro took place over a 12-week period. Experts say there is little rigorous research showing the drugs are beneficial when used for many months or years.
A Journal Sentinel/MedPage Today investigative report earlier this month documented how, for years, FDA officials and executives of companies that make pain drugs held annual private meetings at expensive hotels through an organization funded by the drug companies. The story was based on emails obtained through public records requests and provided to the Journal Sentinel/MedPage Today.
A topic at those meetings was a research approached called enriched enrollment, a technique that allows drug companies to weed out people who don't respond well to a drug or who can tolerate it before the actual clinical trial begins.
Zohydro clinical trials used the enriched enrollment methodology.
Experts say that approach makes it much more likely a drug will prove effective and possibly win FDA approval. It's also cheaper for drug companies to conduct such trials.
However, the approach has been described by critics as cheating because drugs tested that way are not likely to reflect what will happen when the drug gets on the market and is prescribed for large numbers of people.
Indeed, when the panel of FDA advisors voted against approving Zohydro last December, several of them expressed concerns about what would happen once the drug moved from the rarefied realm of clinical trials to the real world of everyday medicine, according to a transcript of the hearing.
"The question of what's effective is much greater than (the pain score of the test subjects) at the end of 12 weeks in a very limited, controlled experiment that somehow was a little bit better than a placebo group," panel member Judith Kramer, MD, a professor of medicine at Duke University, said at the meeting.
"...With treatment of chronic pain, are we really, in the long run, helping people, or are we creating an epidemic? This drug will almost certainly cause dependence in the people that are intended to take it," Kramer said.
Liscinsky, the FDA spokesperson said enriched enrollment follows the concept of personalized medicine in that it attempts to find those who a drug will be most effective in.
"Enrichment will not save a drug that is not safe of effective, but it will help find one that is," she said.
However, advisory panel members had a different view, according to a transcript of the meeting.
"I happen to live in the real world, and I would think that the (Zohydro) study population is very different than the real world population," said Alan Kaye, MD, PhD, a professor of anesthesia at Louisiana State University School of Medicine. "And as such, I certainly feel there would be quite a bit of morbidity and mortality that would result."
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