Shortly after Purdue Pharma announced in July that it was taking its 24-hour opioid Palladone off the market because of a potentially fatal interaction with alcohol, the Food and Drug Administration said it was looking into the possibility that other sustained-release narcotics could pose the same danger.
The Palladone withdrawal (hydromorphone HCL extended release) came at the same time the FDA announced it was investigating whether the transdermal fentanyl patch marketed as Duragesic might be linked to a number of deaths.
“We are investigating 120 deaths that seemingly are related to overdose,” Robert Meyer, M.D., director of the Office of Drug Evaluation II at the Center for Drug Evaluation and Research (CDER), said in a statement.
The FDA actions throw yet another category of painkillers into an uncertain light.
Stamford, Conn.-based Purdue withdrew Palladone just 5 months after it was introduced to a limited number of prescribers. The FDA and the company agreed that testing showed that concomitant use of alcohol could cause a “dosage dump” of the hydromorphone. But there's a difference of opinion on what was known when.
Purdue, which also makes the oft-diverted and abused oxycodone (OxyContin) had conducted several tests to assess Palladone's susceptibility to tampering, spokesman James Heins said in an interview. In the lab, Purdue researchers used various means to cause an instantaneous release of Palladone's contents to produce euphoria. Dissolving capsules in alcohol did just that, Mr. Heins said.
A similar effect was observed when healthy volunteers were given 8 ounces of various proofs of alcohol (all the subjects were given naltrexone as a block).
Data from these studies were given to FDA in November, several months after the drug's approval in September 2004, but before it had been formally launched, he said.
The FDA, however, said those were “preliminary” data, and that a full report was not received until February 2005. With those full data in hand, CDER officials met with Purdue again in May to discuss strengthening Palladone's warnings. But the agency decided that the risk of death from inadvertent concomitant alcohol use was significant enough that even Palladone's strict risk management plan could not prevent potentially serious adverse events or deaths, according to an FDA spokesperson.
“CDER concluded that had it been aware of the alcohol interaction prior to approval, Palladone would not have been approved,” the spokesperson said in an interview.
The Purdue tests on Palladone led the agency to consider whether other sustained-release opioids might pose the same risk. Both FDA and the company conducted in vitro testing of currently marketed products. The agency won't say what those tests revealed, but the spokesperson said that based on the results, the FDA has asked “sponsors of certain products” to perform human studies to determine if there is any interaction with alcohol, and when it might occur.
Extended-release product labels already warn against using alcohol simultaneously.
The removal of Palladone does not leave a huge treatment gap, although the new drug was widely anticipated because of its ease of use, said B. Eliot Cole, M.D., executive director of the American Society of Pain Educators. “There are still plenty of other medications, not just opioids, that are useful for pain control, including antidepressants, anticonvulsants, anti-inflammatory agents, and more,” he told this newspaper.
Dr. Cole said warnings already contained in Palladone's label made it clear “that using alcohol with Palladone was a very bad idea.” But he did not disagree with the decision to remove the drug from the market. Dr. Cole participated on an advisory board for Palladone last fall and has been a speaker for Purdue.
Neither Purdue nor the FDA received any reports of serious adverse events or deaths related to Palladone and alcohol use, and Dr. Cole said that he had not heard of any anecdotally, either.
With Duragesic, however, there have been multiple reports of potential overdoses. In June, Janssen, the Johnson & Johnson division that makes and sells Duragesic, notified health professionals that concomitant use with cytochrome P450 3A4 inhibitors could lead to potentially fatal reactions. The company also issued stronger warnings against using Duragesic with alcohol or using patches that were torn.
The FDA issued a public health advisory in July stating that it was investigating deaths related to Duragesic. It urged physicians to educate patients about signs of overdose, proper patch application, and use of other medications while using the patch, as well as proper storage and disposal of the patch. The agency said that initial reviews indicated that unintentional overdoses might be related to use of multiple patches, application of heat to a patch (which might increase fentanyl absorption), injection or ingestion of the patch contents, leaking patches, and accidental exposure to the drug by coming into contact with a discarded patch.