SILVER SPRING, MD. — The antibiotic Ketek (telithromycin) is neither safe nor effective for treating acute exacerbation of chronic bronchitis or acute sinusitis, according to a Food and Drug Administration advisory committee that recommended that the agency remove those indications from the drug's approved labeling.
The panel—a joint meeting of the FDA's Anti-Infective Drugs and Drug Safety and Risk Management Advisory committees—concluded that although Ketek has been marketed since 2004, safety concerns argue against using the drug in two conditions that generally resolve on their own.
The panel voted 16–3 that Ketek should retain its approval for treating mild to moderate community-acquired pneumonia, but as a second- or third-line therapy. Ketek's maker, Sanofi-Aventis, also presented data suggesting that the drug may be effective against multidrug resistant Streptococcus pneumoniae, which was persuasive to the committee.
Although the panel supported keeping Ketek on the market, a majority of panelists recommended that a black box warning be added to the labeling.
“This is a drug that we need, but this is not something I'd reach for, and this is something I'd discourage people from using,” said Dr. Margo Smith, a panelist from the Washington Hospital Center.
If the FDA follows the panel's advice, as it normally does, the agency would determine how to educate physicians on the revised uses. Sanofi-Aventis agreed that it would create a medication guide for consumers. The FDA and Sanofi-Aventis would work out the content of the black box warning, which is likely to touch on the potential for liver toxicity, visual disturbances, loss of consciousness, and exacerbations of myasthenia gravis.
Ketek was under scrutiny during most of 2006. Senator Chuck Grassley (R-Iowa) has alleged that the drug was approved on the basis of a fraudulent trial, known as study 3014. On the eve of the 2-day FDA panel meeting, Sen. Grassley released results—so far—of his Finance Committee's Ketek investigation. He alleged that FDA managers failed to notify the Anti-Infective Drugs Advisory Committee when it met in 2003 that the agency had concerns about study 3014's integrity.
The panel recommended approval at that time. The agency later held a closed-door meeting with the panel to discuss problems with study 3014, but Sen. Grassley alleges that the committee members still were not given a complete story.
In making the original approval decision, the agency determined that it could toss out tainted data from study 3014 and instead rely on postmarketing data collected on about 4 million patient exposures in Europe, said Dr. Janice Soreth, director of the FDA's division of anti-infective and ophthalmology products, at the December meeting.
Several speakers at the FDA meeting—including a recently departed reviewer from the Ketek team—expressed outrage over the agency's reliance on postmarketing data instead of a prospective safety study for approval.
The panel did not seem as concerned.
The older postmarketing safety information—combined with updated surveillance reports from Europe and postmarketing data collected in the United States since Ketek's introduction—was presented at length.
FDA staffers disagreed on the incidence and import of side effects, as did the FDA and Sanofi-Aventis. Sanofi estimated that to date, the reporting rate in Europe for serious hepatic reactions is 4–10 cases/million courses of therapy. According to the FDA, from 2004 to 2006 there were 12 cases of acute liver failure among 5 million U.S. prescriptions, for a reporting rate of 23 per 10 million prescriptions. By comparison, the antibiotic Trovan (trovafloxacin) had a rate of 58 per 10 million in its first year on the market. The drug was subsequently recalled.
The FDA asked several experts from the Drug-Induced Liver Injury Network to take a closer look at 53 reports of hepatic toxicity associated with Ketek use. The network is a cooperative funded by the National Institute of Diabetes, Digestive, and Kidney Disorders.
One of those experts, Dr. William Lee, director of the clinical center for liver diseases at the University of Texas at Dallas, said that of the 53 patients, 44 were hospitalized, 5 died, and 2 had liver transplants. The cases had similar clinical features, including rapid onset, prominent fever, joint aches, and right upper quadrant pain.
Dr. Lee said he believed that 28 of the 53 cases were very likely or probably caused by Ketek, 17 were possibly related, and 8 had insufficient data to make a ruling. He said the hospitalization rate was probably 1 in 20,000 or 1 in 30,000 for liver toxicity and 1 in 150,000 for acute liver failure. Ketek's profile would be worse if it was a chronic medication, he said.