Analgesics Pose Regulatory Challenge to FDA

[August 15, 2009, AJHP News]

Cheryl A. Thompson

BETHESDA, MD 31 July 2009—Regulating analgesics—some of which became available before the regulations—is proving anything but routine for FDA.

Public outcry over the agency’s plan to stop the manufacture and distribution of concentrated morphine sulfate oral solution had officials in April giving a reprieve to companies for the benefit of hospice and palliative care patients (see June 1 AJHP News).

In June, advisers to the agency voted in favor of putting a boxed warning about liver toxicity in the labeling of all prescription products containing acetaminophen, which itself is a nonprescription drug.

And, most recently, FDA officials have decided not to ban the pain reliever propoxyphene.

An acceptable choice. Although FDA is often said to follow the recommendations of its advisory committees, the agency in July did not.

Janet Woodcock, director of the Center for Drug Evaluation and Research, announced on July 7 that FDA would let manufacturers continue marketing propoxyphene-containing products for the management of mild to moderate pain.

The agency’s decision was not what most voting members of two advisory groups had recommended (see March 15 AJHP News).

To the majority of advisers casting a vote, propoxyphene’s balance of risk and benefit did not support letting the drug remain on the U.S. market.

But all analgesics currently available "have significant liabilities," Woodcock told reporters during a briefing.

Evaluation of the data available to FDA led the agency to decide that "propoxyphene is an acceptable choice for the treatment of mild to moderate pain when it’s taken as directed," Woodcock said.

Some patients with mild to moderate pain do not obtain adequate relief from acetaminophen or a nonsteroidal antiinflammatory drug (NSAID) and should not use a pain-relieving dosage of aspirin, explained Sharon H. Hertz, from FDA’s division of anesthesia, analgesia, and rheumatology products.

Clinicians commonly have these patients proceed to an acetaminophen–opioid combination product, she said.

But the adverse effects of codeine, particularly constipation, can be dose-limiting in older patients. Hydrocodone can adversely affect cognition, resulting in confusion or sedation.

"Propoxyphene," Hertz said, "tends to be considerably less constipating than codeine, based on some analyses, including an analysis conducted by FDA, and tends to have fewer side effects, such as sedation and confusion," in the elderly.

She said that even though NSAIDs can relieve mild to moderate pain, therapeutic dosages can produce gastrointestinal bleeding, renal impairment, liver impairment, and fluid retention.

In addition, the American Geriatrics Society now recommends that clinicians prescribe NSAIDs "rarely, and with extreme caution," to older persons needing relief from persistent pain.

Potential for fatal overdosage. The nonprofit interest group Public Citizen had petitioned FDA to ban propoxyphene products because of the risk of fatal overdosages.

In its petition, Public Citizen had cited data from a nationwide database of autopsy results.

Medical examiners submitting results to the database implicated propoxyphene in 5.6% of all deaths in 1981–99 involving at least one prescription medication, nonprescription drug product, or illicit drug, the interest group stated.

To reduce the risk of overdosage in patients using propoxyphene under a prescriber’s direction, FDA said it has given the manufacturers of propoxyphene products 30 days in which to emphasize that risk in the products’ labeling.

FDA-approved labeling for propoxyphene-containing products already has a boxed warning that emphasizes appropriate patient selection, treatment not exceeding the recommended dosage, and limits on alcohol intake.

The boxed warning, FDA said, will be strengthened and a medication guide for patients will be created.

More research. Gerald Dal Pan, who oversees drug surveillance and epidemiology at FDA, said the agency’s adverse-event-report database had records on 91 deaths related to the use of acetaminophen–propoxyphene products in 1969 through 2005.

Most of those records, he said, described fatal overdosages and completed suicides, often involving multiple drugs.

"Because of the multiple drugs and other conditions, it’s hard to establish a direct causal role for propoxyphene," he said.

Woodcock said FDA will ask the Centers for Medicare and Medicaid Services to determine how often the elderly are prescribed propoxyphene instead of another pain reliever. Also, FDA will ask the Veterans Health Administration to use its patient database to evaluate any differences between the safety profiles of propoxyphene and other analgesic drugs.

As for the manufacturers, Woodcock said FDA is requiring them to conduct a "new safety study to assess unanswered questions about what propoxyphene does to a patient’s heart when taken at higher-than-recommended dosages."

Xanodyne Pharmaceuticals Inc., marketer of the Darvon and Darvocet lines of propoxyphene products, said in a press release that the safety study involves providing "additional clinical data." The company, at presstime, had not responded to a request for further information.

Reprieve for concentrated morphine solution. According to a July 10 query of the National Drug Code Directory, no morphine sulfate 20-mg/mL oral solution product is associated with an FDA-approved drug application.

FDA on March 30 sent letters informing seven firms that they were marketing the oral solution—an unapproved new drug—in violation of federal law. The agency gave the firms 90 days to stop shipping the product or face legal consequences.

But, on April 9, FDA announced that it would not start taking legal action until 180 days after any firm receives approval of its application to market a morphine sulfate 20-mg/mL oral solution product or until the agency decides that alternative medications are available to palliative care patients.

Queries to the firms about their intention to submit a drug application brought replies from two.

Covidien, parent company of Mallinckrodt Inc. Pharmaceuticals Group, is undecided.

"We will comply and are currently reviewing our options, which could include applying for approval of our product," Bruce Farmer, vice president of public relations, said in an e-mail.

Lannett Company Inc., founded in 1942, did not directly address the issue of a drug application.

Spokesman Robert Jaffe said Lannett is offering the agency evidence substantiating that the firm is "in compliance with FDA’s own policy guide" by virtue of a grandfather clause.

According to the 2006 compliance policy guide on marketing new drugs not having an approved new drug application, one of the grandfather clauses covers certain products that were sold commercially before 1962.

But FDA also states in the guide that the agency "believes that . . . very few drugs on the market" are entitled to grandfather status because they likely differ from the previous versions in some respect, such as formulation, dosage, strength, dosage form, route of administration, indications, or intended patient population.