Warning issued on Cephalon painkiller

The Food and Drug Administration warned doctors and patients yesterday of potentially fatal side effects linked to Cephalon Inc.'s Fentora after recent reports of several deaths.

Fentora, a potent narcotic pain medicine, is approved only to treat intense bouts of "breakthrough" pain in cancer patients who are taking opioid pain medicines on a round-the-clock basis, the FDA said in a public-health advisory on its Web site.

The alert comes more than two weeks after Cephalon sent letters to doctors and health-care professionals warning them of three deaths linked to Fentora, which is often prescribed "off label" to treat ailments such as migraine headaches, sports injuries and back pain.

"FDA is monitoring this issue very closely," said Steven Galson, director of the FDA's Center for Drug Evaluation and Research. "We are working with the manufacturer to ensure the safest use of this medicine. Health-care professionals and patients need to be aware of the potential for fatal overdose with the improper use of Fentora."

The agency said that it was critical to follow product labeling and dangerous to use Fentora to treat short-term pain such as migraines. Fentora should be used only by patients who take opioids regularly and have developed a tolerance to narcotic pain medicines.

FDA spokeswoman Susan Cruzan said the agency issued the advisory to reinforce proper dosing and prescribing. "We don't do it all the time, but we do it when there's a need," Cruzan said of the advisory. "We just wanted to make sure that the health-care community had the information and was aware of the issue."

The FDA said the deaths reported were the result of improper selection of patients, improper dosing, or improper product substitution.

Cephalon said Fentora has been linked to three deaths due to inappropriate prescribing. None of the people had cancer. Two patients had migraines and were not taking opioids on a daily basis. The third patient was taking another opioid, but it appeared Fentora was not appropriately dosed for the patient.

The Frazer company received a report of a fourth death, a person who committed suicide while taking the drug, but wasn't prescribed Fentora by a doctor.

While doctors are free to prescribe medicines for any condition they think appropriate, drug manufacturers can promote products in the United States only for uses approved by the FDA.

The FDA said it has asked Cephalon to strengthen warnings and improve the dosing instructions in Fentora's product labeling. The FDA also asked the company to improve its education plan for prescribers and pharmacists on the proper patient selection, dosing instructions, and restrictions on substituting Fentora for other pain products.

Life-threatening respiratory depression can occur at any dose in patients who cannot tolerate opioids, such as morphine or oxycodone.

The FDA stressed that Fentora, also known as fentanyl buccal, is not the same as other fentanyl products and cannot be substituted for Actiq, Cephalon's predecessor fentanyl product, used to treat breakthrough cancer pain.

Because Fentora delivers more fentanyl to the blood than Actiq, substituting Fentora for Actiq using the same dose can result in a fatal overdose, the FDA said.

Unprocessed fentanyl is a highly addictive substance 80 times more potent than morphine. Fentanyl is regulated as a Schedule II substance by the Drug Enforcement Agency and in the same category as cocaine and methamphetamine, with the highest potential for abuse and risk of fatal overdose. Fentora was approved by the FDA in September 2006, and sales were $68 million in the first half of this year.

Starting in 2004, federal and state investigators raised concerns about Cephalon's promotion of its narcotic drug Actiq.

The company has denied marketing Actiq and other drugs outside FDA-approved uses. However, its promotion practices have come under scrutiny by the U.S. attorney in Philadelphia, the Connecticut attorney general, and a House oversight committee looking into off-label marketing of drugs by several companies.

Cephalon recently said it had set aside $56 million in the second quarter to resolve investigations, and it indicated that amount would not likely cover the cost of fines and remedial measures. Company officials are in discussions with authorities to settle the allegations.

Cephalon spokeswoman Stacey Beckhardt said yesterday that the FDA simply wanted to emphasize to health-care professionals information that was in the company's Sept. 10 letters. "It's another communications vehicle," she said, "to reinforce the safety messages that were already communicated."

Cephalon shares closed down one cent to $72.45 yesterday on the Nasdaq.

Cephalon Inc. has come under scrutiny for its alleged promotion of several of its drugs for uses not approved by the FDA.

May 2004: Former Pennsylvania Attorney General Jerry Pappert says Actiq, a narcotic lollipop, is showing up in illegal sales in Philadelphia under the street nickname "perc-o-pops."

June 2004: Former Cephalon quality-assurance auditor David Brennan sues the company, asserting he was fired after he pressed superiors to comply with stringent regulatory requirements for monitoring Actiq.

Summer 2004: Connecticut's attorney general begins a probe about "off-label" use and "diversion" of Actiq after the 2003 death of a woman who overdosed after buying the drug from a dealer.

September 2004: U.S. attorney in Philadelphia subpoenas documents about Cephalon's sales and marketing of Actiq and two other products, Provigil for sleep disorders and Gabitril for epilepsy.

March 2007: U.S. Rep. Henry A. Waxman (D., Calif.) requests information from five companies, including Cephalon, about their marketing. The House oversight committee asks about safety and off-label use of Actiq and Fentora, a narcotic pain lozenge.

July 2007: Cephalon establishes a $56 million reserve as an "estimate of the minimum liability" to resolve federal and state investigations.

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