Liver voriconazole

Many experts now consider voriconazole as the initial drug of choice for invasive aspergillosis in patients without significant contraindications (e.g., drug interactions or preexisting liver dysfunction) to azole therapy. 

Visual disturbances If treatment continues beyond 28 days, the effect of voriconazole on visual function is not known. If treatment continues beyond 28 days, monitor visual function including visual acuity, visual field, and color perception. Hepatic toxicity There have been uncommon cases of serious hepatic reactions during treatment with voriconazole (eg, clinical hepatitis, cholestasis, and fulminant hepatic failure, including fatalities). Liver dysfunction usually has been reversible on discontinuation of therapy. 

Evaluate liver function tests at the start of and during the course of voriconazole therapy. Monitor patients who develop abnormal liver function tests during voriconazole therapy for the development of more severe hepatic injury. Discontinuation of voriconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to voriconazole. Hepatic function impairment It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh class A and B) receiving voriconazole. 

The most frequently reported adverse events (all causalities) in the therapeutic trials were visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, sepsis, peripheral edema, abdominal pain, and respiratory disorder. The treatment-related adverse events that most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances. 

Adverse Effects. Skin rashes and vision disturbances (blurred vision, seeing bright spots) are common during voriconazole administration, but these side effects are usually transient and fairly uneventful. Serious problems, such as liver toxicity and cardiac arrhythmias, may occur in susceptible patients. 

IMATINIB 1. ANTIBIOTICS - clarithromycin, erythromycin 2. ANTIFUNGALS -fluconazole, itraconazole, ketoconazole voriconazole 3. ANTIVIRALS -efavirenz, ritonavir 4. GRAPEFRUIT JUICE 5. H2 RECEPTOR BLOCKERS - cimetidine t imatinib levels with t risk of toxicity (e.g. abdominal pain, constipation, dyspnoea) and of neurotoxicity (e.g. taste disturbances, dizziness, headache, paraesthesia, peripheral neuropathy) Due to inhibition of CYP3A4-mediated metabolism of imatinib Monitor for clinical efficacy and for the signs of toxicity listed, along with convulsions, confusion and signs of oedema (including pulmonary oedema). Monitor electrolytes and liver function, and for cardiotoxicity... 

RIFABUTIN VORICONAZOLE t plasma concentrations of rifabutin, with risk of toxic effects of rifabutin (nausea, vomiting). Dangerous toxic effects such as leukopenia and thrombocytopenia may occur Due to inhibition of metabolism of rifabutin by the CYP3A4 isoenzymes by voriconazole Avoid concomitant use. If absolutely necessaiy, close monitoring of FBC and liver enzymes and examination of eyes for uveitis and corneal opacities is necessary... 

FLUCONAZOLE, ITRACONAZOLE, KETOCONAZOLE, POSACONAZOLE, VORICONAZOLE CALCIUM CHANNEL BLOCKERS Plasma concentrations of dihydropyridine calcium channel blockers are t by fluconazole, itraconazole and ketoconazole. Risk of t verapamil levels with ketoconazole and itraconazole. Itraconazole and possibly posaconazole may t diltiazem levels The azoles are potent inhibitors of CYP3A4 isoenzymes, which metabolize calcium channel blockers. They also inhibit CYP2C9-mediated metabolism of verapamil. Ketoconazole and itraconazole both inhibit intestinal P-gp, which may t bioavailability of verapamil. Diltiazem is mainly a substrate of CYP3A5 and CYP3A5P1, which are inhibited by itraconazole. 75% of the metabolism of diltiazem occurs in the liver and the rest in the intestine. Diltiazem is a substrate of P-gp (also an inhibitor but unlikely to be significant at therapeutic doses), which is inhibited by itraconazole, resulting in t bioavailability of diltiazem Monitor PR, BP and ECG, and warn patents to watch for symptoms/signs of heart failure... 

Micafungin Topical 0.1% solution 1 drop ql h while awake Side effects include pulmonary edema, blood dyscrasias, hypercalcemia, hepatotoxicity (rare), gastrointestinal symptoms, headache, fever, chills, anemia, eosinophilia, hypokalemia, liver function test elevations, infusion site reactions. Drug interaction with cyclosporine and additional voriconazole. Pregnancy category C lactation safety unknown. Coadministration of caspofungin is contraindicated with multiple antiretrovirals (refer to Table 11-3) Topical not commercially available... 

In a patient who took tacrolimus after hver transplant, co-administration of voriconazole resulted in raised trough tacrolimus concentrations (nearly 10-fold) there were no changes in another patient, who took a placebo (123). Voriconazole inhibits the metabohsm of tacrolimus in liver microsomes by 50% in vitro. 

Venkataramanan R, Zang S, Gayowski T, Singh N. Voriconazole inhibition of the metabolism of tacrolimus in a liver transplant recipient and in human hver micro-somes. Antimicrob Agents Chemother 2002 46(9) 3091-3. 

In an open, non-comparative, multicenter study in immunocompromised patients with proven or probable invasive aspergillosis, 116 patients were treated with intravenous voriconazole 6 mg/kg bd twice and then 3 mg/kg bd for 6-27 days, followed by 200 mg bd orally for up to 24 weeks voriconazole was given as primary therapy in 60 (7). There were good responses in 56 16 had a complete response and 40 a partial response there was a stable response in 24 patients. There were adverse events in 91% of the patients who received at least one dose of voriconazole, but only 15% were attributed to the drug. The most common adverse events attributed to voriconazole were skin rash (8.7%), reversible visual disturbances (11%), and raised liver function tests (15%). There was evidence of a concentration-dependent incidence of adverse events six of seven patients with voriconazole plasma concentrations over 10 pg/ml developed adverse events requiring drug withdrawal. 

Liver function test abnormalities in patients taking voriconazole are not unexpected for an azole and can be explained by its extensive hepatic metabolic clearance (12). 

Fungal pneumonia is most likely in the immunocompromized as an oppormnistic infection with aspergillus or histoplasma and can be treated with amphotericin, itraconazole or voriconazole. Amphotericin has to be given intravenously and is toxic to the kidneys itraconazole is given orally or by intravenous infusion and can produce liver toxicity and heart failure voriconazole is given orally or by intravenous infusion and can be toxic to both liver and kidneys. 

Classification and pharmacokinetics The azoles used for systemic mycoses include ke-toconazole, fluconazole, itraconazole, and voriconazole. Oral bioavailability is variable (normal gastric acidity is required). Hueonazole and voriconazole are more reliably absorbed via the oral route than the other azoles. The drugs are distributed to most body tissues, but with the exception of fluconazole, drug levels achieved in the CNS are low. Liver metabolism is responsible for the elimination of ketoconazole, itraconazole, and voriconazole. Fluconazole is eliminated by the kidneys, largely in unchanged form. 

Rifampicin increases the metabolism of the azote antifungals by the liver. However, as fluconazole (unlike ketoconazole, itraconazole and voriconazole) is mainly excreted unchanged in the urine, changes to its metabolism would not be expected to have as marked an etfect as on these other azotes. 

Fluconazole, itraconazole, ketoconazole, posaconazole and voriconazole inhibit the metabolism of the tacrolimus by the gut wall and/or liver by the cytochrome P450 isoenzyme CYP3A4, and/or inhibit the activity of P-glycoprotein so that more tacrolimus is absorbed.Therefore, intravenous tacrolimus is little affected." ... 

Liver In a retrospective review of 200 adult and pediatric recipients of hemopoietic stem cell transplants who took more than two consecutive doses of voriconazole, clinical hepatotoxicity was defined as any rises in liver enzymes (aminotransferases and alkaline phosphatase) that led to withdrawal of voriconazole and biochemical hepatotoxicity as a rise in one or more liver enz5nnes to more than three times the upper limit of the reference range or more than three times the baseline value if abnormal at... 

It is difficult to ascertain the role of each drug in this case, as both voriconazole and bromazepam can cause neurological toxicity and raised liver enzymes. However, this report shows that a very large overdose of voriconazole with high blood concentrations does not necessarily result in severe clinical complications or death, but that delayed hepatotoxicity can occur. 

Carbonara S, Regazzi M, Cirad E, Villani P, Stano F, Cusato M, Heichen M, Monno L. Long-term efficacy and safety of TDM-assisted combination of voriconazole plus efavirenz in an AIDS patient with cryptococcosis and liver cirrhosis. Ann Pharmacother 2009 43 978-84. 

Voriconazole is not recommended for use in combination with efavirenz however, if they are co-administered, the dosage of voriconazole should be increased to 400 mg 12-hourly and the dosage of efavirenz reduced to 300 mg/day, in order to provide systemic exposure similar to standard-dose monotherapy [SEDA-32, 498]. The combination of voriconazole and efavirenz in doses adjusted according to steady-state plasma concentrations has been studied in a 40-year-old man with AIDS, cryptococcosis, and mild liver cirrhosis [154 ]. Adequate concentrations of voriconazole in both plasma and cerebrospinal fluid were obtained and target plasma concentrations of efavirenz were achieved at the final dosage adjustment (oral voriconazole 200 mg bd plus oral efavirenz 300 mg/day). There was stable suppression of cryptococcosis and plasma HIV viremia at long-term follow-up (66 weeks), with no significant adverse events. 

The management of a pharmacokinetic interaction of voriconazole with everolimus has been described in a 65-year-old man who underwent orthotopic liver transplantation complicated by intestinal perforation, sepsis, and acute renal insufficiency [32 ]. He received intravenous fluconazole 400 mg followed by 100 mg/day and oral everolimus 0.75 mg bd the steady-state Cmin of everolimus was satisfactory. On day 72 after transplantation, because of invasive aspergillosis, antifungal therapy was switched to intravenous voriconazole 400 mg bd on the first day followed by 200 mg bd to prevent drug toxicity the dosage of... 

Laboratory values for the liver transaminases AST, ALT and for the cholestatic enzymes gamma-glutamyltrans-ferase (GGT) and AP increased during therapy with voriconazole and decreased after switch to posaconazole. Compared with the upper limit of normal, the mean reduction was 144.6% for AST, 142.3% for ALT, 376% for GGT and 132.7% for AP during posaconazole. 

Liver Hepatotoxicity was retrospectively evaluated in a cohort study in 105 lung transplant recipients taking voriconazole [25 ]. Age less than 40 years, cystic fibrosis, use of azathioprine, history of liver disease and early initiation of voriconazole were associated with hepatotoxicity and in multivariable logistic regression analysis, perioperative initiation of voriconazole was independently associated with hepatotoxicity. 

---