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

References:

1. http://reference.medscape.com/drug/diflucan-fluconazole-342587
2. www.drugs.com
3. http://livertox.nih.gov/Fluconazole.htm