Itraconazole hepatotoxicity

All azole antifungals carry the potential for rash, photosensitivity, and hepatotoxicity. In general, hepatotoxicity is mild and reversible, presenting as asymptomatic increases in liver transaminases. However, fulminant hepatic failure has been reported with itraconazole. Therefore, serial monitoring of liver function... 

Hepatotoxicity Itraconazole has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease, nor a serious underlying medical condition. If liver function tests are abnormal, discontinue treatment. In patients with raised liver enzymes or an active liver disease or who have experienced liver toxicity with other drugs, do not start treatment unless the expected benefit exceeds the risk of hepatic injury. In such cases, liver enzyme monitoring is necessary. 

Itraconazole is usually well tolerated but can be associated with nausea and epigastric distress. Dizziness and headache also have been reported. High doses may cause hypokalemia, hypertension, and edema. Itraconazole, unlike ketoconazole, is not associated with hormonal suppression. Hepatotoxicity occurs in fewer than 5% of cases and is usually manifested by reversible Uver enzyme elevations. 

Itraconazole Topical 1% suspension 1 drop qlh Oral 200 mg PO qd-bid Topical not effective for severe infections, penetrates cornea poorly not commercially available must be compounded Penetrates all eye tissues poorly with oral administration Side effects include hepatotoxicity, gastrointestinal problems, hypokalemia, elevated Uver enzymes, rash, vasculitis, headache, fever, HTN, hypertriglyceridemia Many drug interactions exist including CYP3A4 substrates. Coadministration of itraconazole is contraindicated with multiple antiretrovirals (refer to Table 11-12) Pregnancy category C lactation safety unknown... 

In most clinical reports, there were some cases of raised liver enzyme activities the changes were transient or disappeared after withdrawal of itraconazole (36). More serious hepatotoxicity was not reported. 

Saperconazole is an experimental, water-insoluble, lipophilic, fluorinated triazole. Its structure resembles that of itraconazole and it has a long half-life. It has a broad antifungal spectrum, including Cryptococcus Species and Aspergillus species. In early studies in cases of compassionate use, only a few adverse effects were described, including hepatotoxicity (1,2), and its adverse effects were expected to resemble those of itraconazole (3). However, the manufacturers stopped developing it because of concerns about toxicity. 

Second statement Itraconazole is less hepatotoxic than fluconazole. 

The serum levels of the active metabolite of leflunomide are reduced by activated charcoal, and colestyramine. The manufacturers advise against the concurrent use of alcohol because of the potential for hepatotoxicity. Methotrexate may also increase leflunomide hepatotoxicity, so in general the combination is not recommended. A case of fatal fulminant hepatic failure has been reported in a patient taking leflunomide and itraconazole. A case of peripheral neuropathy has been reported in a patient taking leflunomide and tegafiir/uraciL The manufacturers predict interactions between leflunomide and phenytoin or tolbutamide, and advise caution with rifampicin as it may increase leflunomide metabolite levels. No clinically relevant interaction occurs with cime-tidine, corticosteroids or NSAIDs. 

A 68-year-old woman who had been taking leflunomide 10 mg daily for about 4 months was started on itraconazole 300 mg daily for a fungal infection. About one month later her leflunomide dose was increased to 20 mg daily, and liver function tests were normal. The following month, she developed abdominal pain, vomiting, and weakness. Despite symptomatic treatment and washout with colestyramine, fatal fulminant hepatic failure occurred. The authors of the report attribute the reaction to additive hepatotoxicity between the leflunomide and itraconazole. This interaction serves to highlight the cautions about the use of other hepatotoxic drugs, see (a) and (h). 

A 63-year-old woman who had been taking Iovastatin 80 mg, nicotinic acid 3 g daily, timolol and aspirin for almost 10 years without problems, developed weakness and tenderness in her arms, back and legs within 2 weeks of starting to take itraconazole 100 mg twice daily. A few days later her urine became brown, and positive for haem. She was diagnosed as having acute rhabdomyolysis and hepatotoxicity. The Iovastatin, nicotinic acid and itraconazole were stopped, and she was treated with ubide-carenone. Over the next 18 days her elevated serum enzymes returned to normal, although her plasma cholesterol levels almost doubled. She was restarted on nicotinic acid 11 weeks later without problems. ... 

Cadena J, Levine DJ, Angel LF, Maxwell PR, Brady R, Sanchez JF, Michalek JE, Levine SM, Restrepo MI. Antifungal prophylaxis with voriconazole or itraconazole in lung transplant recipients hepatotoxicity and effectiveness. Am J Transplant 2009 9 2085-91. 

The toxicity of LEF is similar to MTX (133,134). The most commonly reported side effects are diarrhea, nausea, alopecia, rash, and headache (135). Anecdotally, alopecia seems more common with LEF than with MTX. However, diarrhea and nausea are more common with MTX. LEF has been successfully used in patients who have discontinued MTX due to GI toxicity (97). Although the rate of liver function abnormalities appears similar to that observed with MTX, the rate of severe liver toxicity is lower with LEF (135). Severe toxicity has been mostly reported when LEF is combined with other hepatotoxic agents such as MTX (136) or itraconazole (137). 

N. Somchit, A. R. Norshahida, A. H. Hasiah, A. Zuraini, M. R. Sulaiman and M. M. Noordin, Hepatotoxicity induced by antifungal drugs itraconazole and fluconazole in rats a comparative in vivo study. Hum. Exp. Toxicol, 2004, 23, 519-525. 

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