Posaconazole is a potent triazole antifungal agent used in the prevention of invasive fungal infections due to aspergillosis and candida in high risk patients. Posaconazole therapy is associated with transient, asymptomatic serum aminotransferase elevations and is a suspected but rare cause of clinically apparent acute drug induced liver injury.
Posaconazole (poe" sa kon' a zole) is a synthetic triazole that is believed to act through inhibition of the fungal 14α-ergosterol demethylase, which is responsible for converting lanosterol to ergosterol and which blocks cell membrane synthesis. Posaconazole is active against a broad spectrum of fungal agents including Candida albicans and Aspergillus fumigatus. Posaconazole was approved for use in the United States in 2006. Current indications are oropharyngeal candidiasis and prophylaxis against invasive fungal infections in neutropenic or immunosuppressed patients. Posaconazole is available as a 100 mg delayed-release tablet and as an oral suspension of 40 mg/mL under the brand name Noxafil. A loading dose is recommended followed by maintenance doses of 100 to 300 mg daily; however, the dosage varies depending upon indications and the formulation used. Common side effects include nausea, vomiting, diarrhea, abdominal pain, headache, dizziness and rash.
Transient elevations in serum aminotransferase levels occur in 2% to 12% of patients on posaconazole. These elevations are usually mild, asymptomatic and self-limited and rarely require discontinuation of the medication. Clinically apparent hepatotoxicity is very rare. Instances of jaundice and hepatitis during posaconazole therapy are mentioned in the product label, but little information was provided on clinical details.
Likelihood score: E* (unproved but suspected cause of clinically apparent liver injury).
Mechanism of Injury
The cause of the liver injury from posaconazole is unknown; however, it may have some correlation to the ability of voriconazole to alter human sterol synthesis. Because posaconazole inhibits CYP 3A4 activity, it can cause significant drug-drug interactions and including elevations in plasma levels of other medications that are metabolized by this P450 enzyme, sometimes resulting in toxicity.
Outcome and Management
The severity of the liver injury from posaconazole ranges from mild and transient enzyme elevations to hepatitis with jaundice. Fatal instances have not been described, but the drug has not been extensively used or studied. A single case report describes a patient with hepatotoxicity from voriconazole who was able to tolerate posaconazole without difficulty. Nevertheless, caution should be used in starting other azole antifungal agents in patients with clinically apparent liver injury due to ketoconazole, itraconazole, fluconazole or voriconazole.
REPRESENTATIVE TRADE NAMES
Posaconazole – Noxafil®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 17 May 2017
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(Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, two cases were attributed to fluconazole, and one to ketoconazole, one to itraconazole, none to voriconazole or posaconazole).
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Illmer T, Babatz J, Pursche S, Stölzel F, Schuler U, Schaich M, Ehninger G. Posaconazole prophylaxis during induction therapy of patients with acute lymphoblastic leukaemia. Mycoses 2011; 54: e143-7. PubMed Citation (In a pilot study using posaconazole as prophylaxis against fungal infections in 8 patients on an intensified chemotherapy regimen, 5 developed ALT elevations [3 were above 5 times ULN], but the toxicity was transient in all and none developed hepatitis).
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amphotericin B , itraconazole , ketaconazole , and posaconazole
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terbinafine , voriconazole , ketoconazole , posaconazole , and itraconazole ).
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persons treated with oral ketoconazole analyzed from a Kaiser Permanente
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associated with antifungal agents. Expert Opin Drug Saf 2017; 16: 149-165. PubMed Citation. (Review of the
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hepatic toxicity and discusses fluconazole, itraconazole, voriconazole,
posaconazole and isavuconazole but not ketoconazole).
Pettit NN, Miceli MH, Rivera CG, Narayanan PP, Perissinotti AJ, Hsu M,
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Multicentre study of posaconazole delayed-release tablet serum level and
association with hepatotoxicity and QTc prolongation. J Antimicrob Chemother
2017 May 5. [Epub ahead of print] PubMed Citation . (Among 166 patients with cancer who received posaconazole at 4 major medical centers, mean serum ALT, AST and Alk P levels increased but elevations were not associated with higher posaconazole drug levels and specific instances of liver injury were not described).
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analysis of 343 courses. Antimicrob Agents Chemother 2017 May 15. [Epub ahead of print] PubMed Citation . (Among 172 patients treated with prophylactic posaconazole who had no prev-existing liver abnormalities, 25 [15%] developed de novo liver test abnormalities [bilirubin elevations in 23 and ALT in 3] and the abnormalities were more common with higher plasma levels of posaconazole).
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