Are there any reports concerning hepatic injury as a result of treatment with terbinafine (Lamisil)

Fråga: Are there any reports concerning hepatic injury as a result of treatment with terbinafine (Lamisil)? A 42-year-old man, a teetotaller and non-smoker, who was previously quite healthy, now has a nail dermatomycosis infection which has been treated with Lamisil (tablet 250 mg once daily) for six weeks. His father died of liver cancer. Now he has developed lassitude, headache, nausea, loss of appetite and mild abdominal pain. No fever. Dark urine and cement-coloured faeces. He was admitted to the hospital with jaundice. Bilirubin >200 umol/L, ASAT 1.9 ukat/L, ALAT 3.9 ukat/L and alkaline phosphatases 10.5 ukat/L. Ultrasound showed normal liver, gallbladder with some stones, but no stones in the bile ducts. Could this be a toxic effect of terbinafine?

Sammanfattning: A man with a nail dermatomycosis infection was treated with Lamisil (tablet 250 mg once daily) for six weeks. He was admitted to hospital with acute hepatitis. A similar picture as was recently published in a case report from Scotland. Both cases gradually improved upon cessation of the drug. Symptoms disappeared within one month and liver function values were normal within four months. The similarities in these two cases suggests a causal toxic liver reaction.

Svar: Terbinafine (Lamisil) is a new fungicidal medication for systemic and local treatment of skin and nail infections, first marketed in Sweden in September 1992 (1). It constitutes a modern alternative to griseofulvin. Terbinafine is completely metabolised (1). After oral administration of radioactively labelled drug, 72 per cent of the dose was found in the urine, all of which were metabolites. In all, 13 metabolites have been identified in the urine and seven in plasma. The plasma half-life in healthy volunteers is 17.2 hours. The plasma protein binding of terbinafine is 99.7 +/- 0.1 per cent (1).

Comparatively few patients (about 600) were treated in the premarketing clinical trials. The first review of adverse experiences with terbinafine by SADRAC mainly confirmed the ADR profile from the clinical trials (2). Gastrointestinal skin reactions, reversible modifications of taste and increases of transaminases were all known reactions which were also confirmed in the first year on the market. New reports of suspicious side-effects included erythema multiforme, mucocutaneous syndrome and photosensitisation. In a previous Drugline document concerning neutropenia associated with terbinafine (no support in the literature or by ADR reporting), the transaminases (s-ALAT 1.7 ukat/L and s-ALAT 1.3 ukat/L) were slightly elevated (3).

A literature search revealed one case report with a similar history (4). A 52-year-old man took terbinafine 250 mg daily for a Trichophyton rubrum skin infection. After eight days he ran out of pills; treatment was restarted after six days. Four days later he developed lassitude, upper abdominal pain, biliary regurgitation, nausea, and dark urine. He immediately stopped treatment but did not seek medical advice until eight days later, at which time there was mild hepatic tenderness and raised concentrations of alanine transaminase (470 U/l), gamma-glutamyltransferase (143 U/l), alkaline phosphatase (193 U/l), and bilirubin (29 umol/l). Routine haematology and an autoantibody screen gave negative results. Serial investigations for hepatitis A, B and C viruses, cytomegalovirus, and Epstein-Barr virus showed no evidence of current infection. Abdominal ultrasound showed normal liver, gallbladder, and bile duct with no gallstones. He had no history of liver disease, of recent vaccination, or of blood transfusion or anaesthesia, alcohol intake was minimal, and he was taking no other medication. Alanine transaminase values peaked 10 days later (35 days after starting and 18 days after discontinuing treatment) at 930 U/l but his symptoms resolved within one month and his liver function values returned to normal within two months. Up to September 1992 seven cases of hepatobiliary disorders of varying pattern and severity associated with terbinafine had been reported to the Committee on Safety of Medicines in the United Kingdom (4).

The resemblance between the history and development in these two case reports suggests a causal association between terbinafine and the liver reaction. Furthermore, the Swedish case supports a toxic rather than a hypersensitivity reaction, as was suggested in the British case report, where interruption in the treatment was noticed.

This case should be reported to SADRAC. Furthermore, it has been followed up and, in this patient as well, all symptoms and liver function values returned to normal, in this case within four months (5).