Friday, November 19, 2010

Propoxyphene Products Withdrawn in USA. Why?

FDA LogoAfter more than 5 decades of use in many millions of patients the opioid analgesic propoxyphene is being withdrawn from the United States market at the FDA’s request due to concerns about potential cardiac arrhythmias. Was this prudently cautious or a delayed overreaction? And, it raises a further question: Could a ban on methadone lie ahead?

Earlier today (November 19, 2010), Xanodyne Pharmaceuticals agreed to withdraw the DEA-Schedule IV opioid analgesic propoxyphene — eg, Darvon® and Darvocet® brands — from the U.S. market at the request of the United States Food and Drug Administration (FDA). New data showed that the drug could cause serious cardiotoxicity, even when used at therapeutic doses, so the FDA concluded that the safety risks of propoxyphene outweigh its benefits for pain relief. The agency requested that generic manufacturers of propoxyphene-containing products remove their products as well.

The new data came from a “Multiple Ascending Dose” or MAD study — a randomized, double-blind, placebo-controlled, sequential multiple-ascending dose, parallel trial — in which 18 healthy subjects were enrolled. A first cohort of study subjects received 600 mg/day of propoxyphene (the maximum labeled daily dose) and a second cohort received 900 mg/day (to approximate what might occur in patients unable to effectively metabolize a normal dose). Participants were monitored via telemetry and intermittent ECG recordings.

Statistically significant QTc-interval prolongations were observed with both doses at steady state on treatment day 11. At 600 mg/d the largest mean increase in QTc was 29.8 milliseconds (ms) (90% CI: 11.7, 47.9), and at 900 mg/d the largest mean increase was 38.2 ms (90% CI: 19.0, 57.4). Drugs that prolong the QTc interval by >20 ms are believed to substantially increase the likelihood of potentially harmful arrhythmia. Additionally, a dose-dependent prolongation of PR and QRS cardiac-conduction intervals was observed in the study. Because the elderly and patients with renal insufficiency have a reduction in the clearance of propoxyphene and its cardioactive metabolite, norpropoxyphene, through the kidneys, these populations can be especially susceptible to proarrhythmic effects of the drug, according to the FDA. A copy of the MAD study report, redacted by the FDA, is available [here].

The FDA recommends that healthcare professionals stop prescribing and dispensing propoxyphene-containing products to patients, and they should contact patients currently taking such products to discuss alternative pain management strategies. Patients should not stop suddenly on their own, because withdrawal symptoms such as diarrhea can occur. Leftover propoxyphene should be properly discarded; however, for unknown reasons, this is one of the few opioid agents not on the FDA’s list of drugs that should be disposed of by flushing. So, patients should discard unused propoxyphene in household trash by following the recommendations outlined in Federal Drug Disposal Guidelines [here].

For further details, read the FDA MedWatch safety alert, including links to the Drug Safety Communication, News Release, and supporting documents [here].

COMMENTARY: In early July 2009, the FDA had considered removing propoxyphene-containing products from the market and, at that time, we applauded their reserve and circumspection in deciding not to do so [see “FDA Right in Not Banning Propoxyphene Analgesics” here]. First approved by the FDA in 1957, propoxyphene is used to treat mild to moderate pain. It is a fairly weak, synthetic opioid — half as potent as codeine and comparable in analgesic effect with high-dose NSAIDs — yet some patients find that propoxyphene works well in relieving their pain. So, it could be of consequence in certain patients to lose this analgesic option.

Through the years, largely due to concerns about persons overdosing on propoxyphene, there have been petitions submitted to the FDA for its removal. In England, a phased discontinuation of propoxyphene was mandated in 2005 due to rising rates of its use in suicides. In June 2009, the European Medicines Agency (EMEA) recommended that the marketing authorization for propoxyphene be withdrawn across the European Union.

The FDA had collected 1,400 reports of propoxyphene-related deaths since 1957, although the sole contributory role and cardiac effects of the drug were uncertain; furthermore, taking into account the extremely large numbers of prescriptions for the drug through the years, we estimated the propoxyphene-associated mortality rate was only about 0.0001%. In 2009, following an advisory committee meeting to address the efficacy and safety of propoxyphene, the FDA decided to strengthen overdose warnings on labeling and gather additional information about the drug’s cardiac effects.

However, the MAD study to assess propoxyphene’s cardiotoxicity (noted above) enrolled very few subjects; therefore, it could be important that QTc-interval prolongations of concern were largest average point estimates and the confidence intervals (CIs) were quite broad. At both doses, 600 and 900 mg/d, the lower end of the CIs were at acceptable QTc-change limits. So, while the data may be statistically significant and of importance, the quality of evidence is less than robust and the clinical significance might still be questioned. Perhaps, the FDA has additional data that were not revealed in the publicly disclosed documents. Gerald Dal Pan, MD, director of the FDA’s Office of Surveillance and Epidemiology, stated in a news release, “With the new study results, for the first time we now have data showing that the standard therapeutic dose of propoxyphene can be harmful to the heart.”

It is understandable that once the FDA has such data at hand they are obligated to act in some fashion; else they might be accused at a future time of having neglected the public welfare. And, they apparently concluded that implementing a risk evaluation and mitigation strategy (REMS) to restrict propoxyphene prescribing would be insufficient and/or not worth the effort for a relatively weak opioid analgesic. Possibly of greatest importance, this latest action may be indicative of increasingly “risk aversive” policies at the FDA that will carry over to other analgesics, as may become more evident when the FDA’s opioid-REMS initiative is released in the months ahead.

All of this also might raise questions about the future of a synthetic, Schedule II opioid medication that is a chemical cousin of propoxyphene — methadone. The two drugs share several parallel areas of concern: for example, both are generic products and manufacturers have invested few resources, if any, on education regarding safe prescribing and use. As with propoxyphene, methadone is an older drug, having been used therapeutically since the 1940s, yet there have been increasing rates of methadone-associated deaths in recent years. These have been due largely to high incidences of abuse and overdose, but there also have been published, controversial allegations of lethal methadone-induced cardiotoxicity at typical therapeutic doses [see article here and blogpost here]. Finally, in the past, highly vocal anti-methadone citizens groups have petitioned for severely restricting or banning the “killer drug” in the interest of public safety [eg, see].

Methadone is a more effective analgesic than propoxyphene and it also is used in opioid addiction treatment, so it might still be perceived as having benefits outweighing risks. However, for various reasons methadone has periodically raised the ire of politicians and community organizations, and when that is combined with an increasingly risk-aversive regulatory climate — plus a demonstrated willingness to remove well-established analgesics from the market — the days of methadone may be numbered and growing shorter. We shall see.