FDA issues advisory about Ketek and hepatotoxicity

Pre-marketing data from a 25,000-patient safety study indicated that liver problems were infrequent.

The FDA has issued a public health advisory after three reports of a possible risk of serious hepatotoxicity in patients who use telithromycin.

FDA officials based their advisory on a review that documented three hepatotoxicity events, which were reported to both MedWatch and the Annals of Internal Medicine.

“While it is difficult to determine the actual frequency of adverse events from voluntary reporting systems, such as the MedWatch program, the FDA is continuing to evaluate the issue of liver problems in association with use of telithromycin (Ketek, Aventis) in order to determine if labeling changes or other actions are warranted,” FDA officials noted on the FDA Web site.

In their study, Kimberly D. Clay, MD, MPH, and colleagues from the Carolinas Medical Center in Charlotte, N.C., noted that within a few days of receiving telithromycin, patients presented with acute hepatitis. All of the patients had jaundice and markedly abnormal results on liver function tests.

One patient spontaneously recovered, one required orthotopic liver transplantation and one died, Clay and colleagues noted. A histologic examination of the last two patients showed massive hepatic necrosis. All three patients were previously healthy, according to FDA officials, and had not been using other prescription medications.

“Phase-3 data provided by Sanofi-Aventis described seven cases of hepatitis or hepatocellular damage in patients taking telithromycin,” Clay and colleagues wrote. “Alcohol use, baseline elevations in aminotransferase levels and hepatitis B virus infection were confounders in four of the cases.”

Sanofi-Aventis previously reported that three cases in a large study that compared telithromycin with amoxicillin-clavulanate met safety endpoints for possible substantial drug-related hepatic injury. “Two of these cases were determined to have a compatible temporal relationship between the hepatic adverse event and telithromycin exposure, and the third was determined to involve medical complications, but an effect of the drug could not be discounted,” researchers wrote in their study.

“The FDA’s Adverse Event Reporting System describes 10 postmarketing cases of hepatic adverse events associated with telithromycin use, but eight of these cases involve a wide range of additional agents taken concomitantly with telithromycin. ... Only two cases were described with telithromycin in the absence of other agents; both involved increased aminotransferase levels and required hospitalization, but neither resulted in death,” Clay and colleagues wrote.

Pre-marketing data from a 25,000-patient safety study indicated that liver problems were infrequent.

FDA officials urged health care professionals to monitor patients taking telithromycin for signs or symptoms of liver toxicity, and to discontinue treatment if these occur. The FDA urged patients who are currently using telithromycin to contact their health care providers immediately if they develop jaundice or other symptoms such as yellow eyes or blurry vision.

Health care professionals are encouraged to report adverse events related to the use of telithromycin to the FDA’s MedWatch reporting system by phone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at www.fda.gov/medwatch.

Telithromycin is the first ketolide antibacterial approved by the FDA.

For more information:
Clay KD, Hanson JS, Pope SD, et al. Brief communication: severe hepatotoxicity of telithromycin: three case reports and literature review. Ann Intern Med [serial online]. 2006;144. Available at: www.acponline.org/journals/annuals/hepatotoxicity. Accessed Jan. 26, 2006.