ASK DIS: Effect of Fluconazole and Phenytoin on Liver

Fluconazole and Liver

associated with rare cases of serious hepatic toxicity, including fatalities primarily in patients with serious underlying medical conditions
no obvious relationship to total daily dose, duration of therapy, sex, or age o
Patients who develop abnormal liver function tests during fluconazole therapy should be monitored for the development of more severe hepatic injury
spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities.
occur primarily in patients with serious underlying medical conditions (predominantly AIDS or malignancy)
incidence of abnormally elevated serum transaminases was greater in patients taking fluconazole concomitantly with one or more of the following medications: rifampin, phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents.
ALT elevations above 8 times the upper limit of normal are reported to occur in 1% of patients taking fluconazole and to represent the most common adverse event leading to early discontinuation of treatment
liver function returned to baseline on discontinuation of fluconazole. recovery may be delayed for several weeks after stopping fluconazole and may be slow requiring 2 to 3 months

Phenytoin and liver

Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported
Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, and eosinophilia
In these patients with acute hepatotoxicity, phenytoin should be immediately discontinued and not re-administered.

Interaction

Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor
There was a significant increase in phenytoin AUC in a study carried out.
The mean ± SD increase in phenytoin AUC was 88% ± 68% (range: 16 to 247%).
The absolute magnitude of this interaction is unknown because of the intrinsically nonlinear disposition of phenytoin.

Recommendations

To do TDM to assess level of phenytoin
Monitor liver function for worsening or further deterioration
No hepatic dose adjustment suggestions.
For cryptococcal meningitis, based on paediatric dosing, doses of 6mg/kg to 12mg/kg per day can be used. Similarly, for adults, doses of 200mg-400mg/ day can be used. Thus, may consider lowering to lower end of dose range

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ASK DIS