Fluconazole/posaconazole/tretinoin interaction

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Gastrointestinal and hepatic toxicity: case report A 33-year-old woman developed GI and hepatic toxicity during treatment with tretinoin, possibly due to interactions with posaconazole and fluconazole [routes and dosages not stated]. The woman was diagnosed with acute promyelocytic leukaemia (APL). She commenced induction treatment according to the PETHEMA/HOVON protocol APL2005, which included oral tretinoin 45 mg/m2/day in two divided doses. Posaconazole was also started for antifungal prophylaxis. She developed diarrhoea 3 days later. Diarrhoea was attributed to posaconazole, which was switched to fluconazole after 13 days of treatment. Two days later, her diarrhoea worsened and her total bilirubin level increased. The following day, she experienced about 18 bouts of diarrhoea and developed abdominal pain and distention. Tretinoin was subsequently stopped due to GI and hepatic toxicity. On day 18, the woman developed severe abdominal distention, respiratory difficulty, metabolic acidosis and had only two bowel movements; her bilirubin levels continued to rise. She was admitted to the ICU, where fluconazole was switched to amphotericin B liposomal, but her clinical condition worsened. On day 24, total and direct bilirubin levels peaked at 17.4 mg/dL and 16.4 mg/dL, respectively. Enterobacter cloacae was isolated in a bronchoaspirate sample. On day 25, she died after developing multiple organ failure with suspected refractory septic shock. Author comment: As tretinoin is metabolised by CYP3A4 and CYP2C9 and considering that fluconazole inhibits both cytochromes and posaconazole inhibits CYP3A4, we feel that this interaction might increase tretinoin’s toxicity by reducing its metabolism. Mas Morey P, et al. Possible fulminant toxicity by all-trans-retinoic acid in a patient with acute promyelocytic leukemia. Farmacia Hospitalaria 35: 44-5, No. 1, 803066546 2011 [Spanish; summarised from a translation] - Spain

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Reactions 4 Feb 2012 No. 1387