A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs

Aims The aim of this cohort study was to estimate the risk of clinical acut e liver injury among users of oral antifungals identified in the general po pulation of the General Practice Research Database in UK. Methods The cohort included 69 830 patients, 20-79 years old, free of liver and systemic disease, who had received at least one prescription for eithe r oral fluconazole, griseofulvin, itraconazole, ketoconazole, or terbinafin e between 1991 and 1996. Results Sixteen cases of acute liver injury were identified and validated. Ten cases occurred during nonuse of oral antifungals with a background rate of 0.6 per 100 000 person-months (95% confidence interval 0.3,1.1). Five c ases occurred during current use of oral antifungals. Two were using ketoco nazole, another two itraconazole, and one terbinafine. Incidence rates of a cute liver injury were 134.1 per 100 000 person-months (36.8,488.0) for ket oconazole, 10.4 (2.9-38.1) for itraconazole, and 2.5 (0.4,13.9) for terbina fine. The remaining case was associated with past use of fluconazole. Ketoc onazole was the antifungal associated with the highest relative risk, 228.0 (95% confidence interval 33.9,933.0), when compared with the risk among no nusers, followed by itraconazole and terbinafine with relative risks of 17. 7 (2.6,72.6) and 4.2 (0.2,24.9), respectively. Conclusions Ketoconazole and itraconazole were the two oral antifungal asso ciated with a marked increase of clinical acute liver injury. The risk asso ciated with ketoconazole should be taken into account when prescribing it a s initial treatment for uncomplicated fungal infections.