Itraconazole, Terbinafine Possibly Linked to Liver Failure
The agency took action after reviewing 24 cases of liver failure possibly associated with itraconazole therapy and 16 cases of liver failure possibly linked to oral terbinafine therapy. Some of these patients did not have liver disease before starting systemic antifungal therapy. Both reviews included 11 reported deaths. About half of the cases of liver failure associated with itraconazole therapy involved patients taking the drug for a fungal nail infection or other dermatological infection.
In addition to liver failure, itraconazole seems to be associated with the onset of congestive heart failure (CHF). FDA reported that 58 patients had CHF as a consequence of itraconazole therapy and 13 of them died. Forty-five percent of these patients had been taking the drug to treat a suspected fungal nail infection.
The black-box warning in the labeling for itraconazole products (PDF) now includes the instruction not to administer the drug for the treatment of onychomycosis in patients who, at any time, have had signs or symptoms of CHF or another condition involving ventricular dysfunction. Therapy with the drug should stop once signs or symptoms of CHF develop.
Also new to the black box is the contraindication to the simultaneous use of dofetilide and itraconazole because of the possibility of serious cardiovascular events. Itraconazole strongly inhibits the cytochrome P-450 3A4 isoenzyme and thus may increase the plasma concentration of dofetilide, an agent that can cause serious ventricular arrhythmias and whose use requires close monitoring.
A precaution about erythromycins ability to increase the plasma concentration of itraconazole has been added to the latters labeling on the basis of a single-dose pharmacokinetic study.
The new labeling for both products advises clinicians to ask their patients to report any symptom of hepatic dysfunction, such as nausea, anorexia, unusual fatigue, vomiting, jaundice, dark urine, or pale stools. Patients who will be taking itraconazole should be told to report any sign or symptom of CHF. The labeling for itraconazole does not provide examples of CHF signs and symptoms for clinicians to use in communicating with patients, but FDA offered the following patient-friendly list: shortness of breath; swelling of the feet, ankles, legs, or abdomen; weight gain; unusual tiredness; coughing up of white or pink mucous, and a sensation of unusually fast heartbeats.
Itraconazole is marketed as Sporanox by Janssen Pharmaceutica Products L.P. Terbinafine is sold as Lamisil (PDF) by Novartis Pharmaceuticals Corp.