FDA, on Tuesday, announced that new data showed an increased chance of overdose in patients who use medications containing propoxyphene (used since the 1950s in products such as Darvon and Darvocet, among others) to treat mild to moderate pain.

In January, an FDA advisory board voted 14 to 12 to ban use of the drugs altogether, but FDA declared them an acceptable option, though with increased warnings.  To reduce the likelihood of overdose, FDA is now asking manufacturers to strengthen the language in labels, add a boxed warning, and include a medication guide with each prescription or refill.

Additionally, drug firms must conduct a safety study to determine how propoxyphene affects patients’ hearts when taken at higher-than-recommended doses. Xanodyne, manufacturer of Darvon and Darvocet, was issued a letter indicating the need for a required study. 

Both the Centers for Medicare & Medicaid Services and the Veterans Health Administration will also contribute data and help study why the drug is leading to overdose. 

CDER Director Janet Woodcock cited a study in Scotland that found that the rate of fatality from overdose was high, and data from a Florida medical examiner that showed a correlation between propoxyphene overdose and death. 

“Many of the overdoses were intentional ingestions, of which there are slightly different patterns in Europe than in the United States,” Woodcock said at a press conference. “In the US, we typically see multi-drug overdoses, which makes it very difficult to sort out what’s doing what.”

From 1969 through 2005, there have been 91 deaths reported in the AIRS database from persons taking propoxyphene, the majority of which have been overdoses and suicide attempts. Most overdoses, however, involved multiple drugs. 

In related news, FDA denied a petition from the public interest group Public Citizen requesting a phased withdrawal of propoxyphene, according to Woodcock. “The reason for the denial is that FDA determined that propoxyphene is an acceptable option for pain relief at recommended doses, given the alternatives,” she said. 

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News Analysis

Pain medications containing propoxyphene could lead to overdose and death, according to new labeling mandated by FDA. However, public requests to take these drugs (including Darvon and Darvocet) off the market have been denied.

FDA Boosts Warnings on Propoxyphene Pain Meds

A potential blockbuster took a big step closer to market last week as FDA approved Sanofi-Aventis’ atrial fibrillation treatment Multaq (dronedarone).

The approval represented a comeback for the drug, which was rejected by FDA three years ago over safety concerns. In one of its clinical trials, called Andromeda, Multaq not only failed to benefit patients suffering from severe heart failure, but also increased overall mortality. 

That may sound like a good reason to shelve a drug, but Sanofi instead set scientists to work figuring out what had gone wrong. 

“Based on the Andromeda study, we were able to examine the data and see what sort of patients should not get Multaq, and that was the basis of starting the Athena trial,” said Paul Chew, chief science officer and chief medical officer for Sanofi-Aventis US. 

Rather than focus on patients suffering from severe heart failure, Sanofi decided to examine atrial fibrillation (AF)-an irregular rhythm in the upper chamber of the heart found in adults and the elderly, which leads to blood clots and possibly strokes. Patients with the disease have an increased risk of hypertension, high blood pressure, and an associated risk of heart attack. 

Until now, the most commonly used therapy for AF has been amiodarone-a drug that is not approved for the indication, and only reluctantly approved at all by FDA because of its potentially significant side effects: pulmonary fibrosis, hyperthyroidism, tremors, and severe skin rash. Amiodarone also has a two-month half-life, an undesirable quality in a drug with a high side-effect profile. Multaq, by comparison, has a half-life of 24 hours. 

In the subsequent Athena study, Sanofi eschewed patients with severe heart failure and focused on patients with AF and few or no instances of heart failure. Multaq was found to have a 24 percent combined endpoint reduction in mortality and cardiovascular hospitalization, when compared to placebo. The drug was also found to have a very good safety profile, with only a few GI side effects. 

“This data should help Multaq gain share,” stated an analyst for Zacks Equity Research, in a report. “We expect the product to contribute significantly to revenues and believe it could eventually achieve blockbuster status. Multaq should reach the €500 million mark in 2012.”

The company resubmitted the NDA in 2008, and was approved by an FDA advisory panel earlier this year. Sanofi is now gearing up for a summer launch and is developing additional clinical trials for the drug. No word yet on marketing strategy. 

Sanofi-Aventis is banking that its highly anticipated atrial fibrillation/flutter treatment Multaq will be a huge success. The path to approval has been ridden with a failed trial and a very long review process, but for Sanofi, the wait has been worth it.

Pharmaceutical Executive-07-09-2009

FDA Boosts Warnings on Propoxyphene Pain Meds

Sanofi Gets Green Light on Blockbuster Heart Treatment