The recent advisory committee review of the safety and efficacy of propoxyphene products left FDA with a quandary: the panel voted to remove propoxyphene-containing products from the market, citing little to no efficacy data, but also said their removal would be problematic.

The Anesthetic and Life Support Drugs and Drug Safety and Risk Management advisory committees met Jan. 30 to discuss the fate of propoxyphene-containing products at the urging of Public Citizen, which sued FDA after the agency failed to rule on its petition to remove the drug from the market.

Propoxyphene was first approved in 1957 as Darvon and to this day propoxyphene-containing products are the second most frequently prescribed opioid analgesic in the U.S., with more than 2 million prescriptions dispensed each year.

Despite its rampant use, the drug has marginal efficacy data and, as would be expected from a Schedule IV drug, propoxyphene comes with some hefty safety risks, including toxicity, and it is often used in suicides.

The joint committee voted 14-12 that the balance of risk and benefit do not support continued marketing of propoxyphene-containing products for the management of mild to moderate pain.

"The data demonstrate that the drug has no efficacy in and of itself and adds nothing to Tylenol when given in combination," said voting member Jeffrey Kirsch, Oregon Health and Science University, citing the drug's most common form, a propoxyphene-acetaminophen combination ( Darvocet ).

The overall risk of taking the drug off the market, members said, was small. NSAIDs, tramadol, butorphanol, codeine/acetaminophen combination products, and hydrocodone/acetaminophen combination products could all easily replace propoxyphene, and with better efficacy to boot.

Removal From Market Could Lead To "Chaos"

Despite their nearly unanimous decision that propoxyphene has at best marginal efficacy, and their majority vote that the drug should be taken off the market, the committee discussion revealed a great deal of inner conflict over the implications of taking propoxyphene products off the market, primarily because of the "psychological risk" of taking away a drug from a chronic use population.

"I think you will have a huge nightmare on your hands," temporary voting member Domenic Ciraulo, Boston University, said. "The psychological reliance on the product will be difficult for the patients and providers to handle. ... The risks from removing it from the market outweigh the risks it poses to patients."

That was a sentiment echoed by several panelists, with comments about creating an uncomfortable situation for pain providers and the unintended potential to do more harm by taking propoxyphene off the market.

"If the safety is uncertain and the benefit is not well known, then in removing an ineffective drug there would not be a lot of downside," countered temporary voting member William Hiatt, University of Colorado. "But I do think there would be a lot of psychological risk with taking this off the market."

Still, for some it came back to the lack of efficacy and the availability of other, efficacious products. "I don't really see a large patient population that would go unserved if the drug was removed from the marketplace. There are any number of opioid-combination products that could be substituted," said temporary voting member Patrick Beardsley, Virginia Commonwealth University.

Although there are possible replacements, panelists noted that the risks of those drugs are high and raised the possibility that due to the serious adverse effects of the alternatives, there could be more harm for patients who switch - including addiction issues.

But the committee members couldn't envision a way to handle the risks of propoxyphene if it were to stay on the market. "I'm not understanding how we should keep it on the market because it would be difficult to re-educate providers," said temporary voting member Julie Zito, University of Maryland. "I think we can adjust ... to adapt to other things."

In the end, the concerns about the difficult situation created by taking propoxyphene off the market probably will not matter much because they come down to issues of medical practice, which FDA traditionally considers outside its purview. The agency focuses on the pure arithmetic of the risk/benefit ratio, and that quantitative assessment was clear.

FDA Trying To Sway Members To Vote No?

Even so, Public Citizen's Health Research Group Director Sidney Wolfe, who presented the case against propoxyphene, said he felt the agency led the discussion and that the vote to remove the drug from the market should have been more decisive.

Wolfe is also a permanent member of the Drug Safety and Risk Management Advisory Committee, but recused himself of his committee assignment in order to present on behalf of Public Citizen (see ¹ Also see "Collaring Wolfe: Propoxyphene Moves Activist Back To Public Supplicant Role" - Pink Sheet, 9 February, 2009. ).

"There were some comments made by FDA at the end which were, to me, intended to try and get people not to vote for the ban," Wolfe said in an interview. "The vote was to ban the drug, but I think it would have been more in favor of banning the drug than just 14 to 12," he said. "There was a change in the tenor there once the FDA and the company started throwing out these things that are questionably untrue or questionably true or likely untrue."

His example was a comment from FDA that "there would be chaos if this would be taken off the market." Wolfe pointed to propoxyphene's successful transition off the market in the U.K. over a two-year period, which Public Citizen has been lobbying FDA to do now for over 30 years.

At the meeting, Director of the Division of Anesthesia, Analgesia and Rheumatology Products Bob Rappaport, in describing how a drug is taken off the market, said that there would be no phasing-out period. If the agency decided to take the drug off the market, it would be gone the next day, he said.

Public Citizen's 30-Year Quest For Removal

For Wolfe, the advisory committee review was the culmination of a 30-year crusade to remove propoxyphene-containing products from the market. In November 1978, the Health Research Group petitioned the then-Department of Health, Education and Welfare to either immediately ban propoxyphene's marketing or reschedule it as a Schedule II narcotic. The petition was denied a year later after the agency found the drug did not present an "imminent hazard" to public health.

A subsequent FDA hearing also determined that the drug was safe and effective and recommended it remain on the market with additional safety and education labels. HRG's most recent petition, filed Feb. 28, 2006, includes additional data from the U.K.'s experience with the phased removal of propoxyphene, showing a reduction in propoxyphene-acetaminophen combination drug deaths after the phase-out was announced, as well as data collected from the Drug Abuse Warning Network and an analysis of medical examiner reports from Florida in 2007.

That evidence stood out from the other data presented at the meeting because it was up-to-date and reflects modern reporting, which distinguished it from the historical aggregation of information collected over 50 years (most of which was deemed inconclusive).

Xanodyne A Victim Of Inherited Drug

Xanodyne is not the only company that markets propoxyphene-containing products, but since it markets the first approval, it took the brunt of the hits from Public Citizen's petition, and was the only sponsor to present at the meeting.

Xanodyne acquired Darvon and Darvocet from AAIPharma, which acquired the drug from Lilly, propoxyphene's original developer. In doing so, Xanodyne inherited the product and its problems, the biggest of which is lack of efficacy data.

That's because Darvon's approval predates the requirement for efficacy studies. Retrospective efficacy assessments were done for the drug in the 1960s - and those studies were what Xanodyne had to present.

That put Xanodyne in an unfavorable position. Not only did the studies not come close to the rigor of contemporary trials, the actual findings undermine the company's case. Five of the seven trials showed that propoxyphene alone had no statistically significant difference from placebo. Acetaminophen alone, which was used as a comparator, was statistically superior to placebo in all seven trials; the combination of acetaminophen and propoxyphene was superior to placebo in six of the seven trials, though the combination was comparable to acetaminophen alone.

Without being able to cite more favorable and recent trials (of which there are none), Xanodyne mounted its defense by trying to refute Public Citizen's claims and pulling out its own data from the National Poison Data System showing that propoxyphene rates lower than hydrocodone and oxycodone in terms of adverse drug reactions among opioids.

The sponsor claimed that propoxyphene-containing products in the U.K. cannot be compared to those on the market in the U.S. due to different fixed combination ratios and, most importantly, because the drug was not subject to the same controls and warning requirements in the U.K. as it is in the U.S., chiefly scheduling as a controlled substance.

Xanodyne also rebutted the DAWN data by saying it is not intended to scientifically assess a product's safety and that its data on drug abuse do not provide an accurate reflection of actual deaths "caused" by a specific drug, but rather only show whether a particular drug was reported or "mentioned" by a medical examiner.

FDA Weighs In, But Light On Conclusive Data

FDA's presentation also highlighted the paucity of data available. The agency did a literature review that showed propoxyphene exhibits weak analgesic effects and that the drug's contribution in acetaminophen combinations is variable across trials (i.e., the efficacy is driven by acetaminophen, not propoxyphene). In the agency's assessment of the drug's effect on renal and hepatic failure, and its use in elderly patients, it had only enough data to say that it alters PK.

The agency also weighed in with assessments on pharmacology/toxicology and summary reviews of the Adverse Event Reporting System, but the theme of FDA's data really could be that data were largely unavailable, and where there were data, it was not significant, but trended against propoxyphene. The challenge for the panel was that the level of evidence either for or against propoxyphene really fell short of the standards usually used for such evaluations.

Rappaport admitted that the situation is complicated by the antiquated nature of the product. "If you look back at a lot of drugs," he noted, "you will see similarly poor data. Keep that in mind as well when thinking about whether this is something we should be considering."

Committee Leaves A Door Open For Xanodyne

While the committee voted that propoxyphene-containing products should be taken off the market, members may have been cutting the company a little slack for the integrity of available data by suggesting multiple studies they deemed necessary for the drug to stay on the market.

When asked whether additional information about safety or efficacy could change their answers, panelists generally thought more thorough efficacy and systemic exposure trials should be conducted, particularly examining elderly populations.

Based on the data presented about non-clinical cardiac effects of propoxyphene and post-marketing reports of deaths in which propoxyphene was identified, members generally agreed that the drug is not cardiotoxic, but that additional data are needed to adequately assess the potential for cardiac effects as well as hepatic and renal impairment.

It is unclear whether Xanodyne would be willing, or financially able, to conduct any sort of studies on the drug. FDA's Rappaport acknowledged it is unlikely that such studies will get done. "To get the studies you think are appropriate requires us to ... get the sponsors to do the studies. They are enormously expensive and difficult to do," he said. And for a mature product with a PR problem and a real possibility that the studies will not provide the desired outcome, there's little incentive for Xanodyne or other sponsors to bother.

At the very least, if the drug is to stay on the market, members said there should be label changes and the drug should possibly be scheduled under Schedule III.

According to the Orange Book, there are 28 drugs approved that have propoxyphene listed as an active ingredient. But each drug could be approved in various formulations and it's easy to see how far-reaching the repercussions could be if FDA indeed decides to take it off the market.

After the meeting, FDA officials said they would be taking some sort of action, and brought up the possibility of imposing a Risk Evaluation and Mitigation Strategy. When asked whether this incidence will open the flood gates to questions about other drugs approved at a time when efficacy trials were not rigorous, FDA said no, that it was not in the business of "going back and revisiting" old drugs.

- Lauren Smith (lauren.smith@elsevier.com)

Public Citizen Takes On Propoxyphene Again, This Time Comes Out On Top

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