New Drug Approvals

Voriconazole: Clinical Pharmacology and Toxicology

Christopher McCoy, PharmD
Department of Pharmacy
Beth Israel Deaconess Medical Center
One Deaconess Road
Boston, MA 02215
Phone: (617) 632-0693
Fax: (617) 632-7024
Email:

Int J Med Toxicol 2003; 6(1): 4


Introduction

Oral triazole antifungal agents, itraconazole and fluconazole, have been associated with a variety of adverse effects, including case reports of hepatotoxicity. Structural dissimilarities account for the differences in spectrum of antifungal activity as well as observed drug related toxicities. Itraconazole is generally reserved for fungal infections caused by Aspergillus spp., both for treatment, prophylaxis and for prolonged courses, and fluconazole for both short and long course treatment and prophylaxis of fungal infections (e.g., candidemia, candiduria, and esophagitis). Other antifungal alternatives include the amphotericin B formulations, standard deoxycholate and three lipid based products for the treatment of infections caused by either Aspergillus or Candida spp. The triazole antifungals have been demonstrated to be less commonly associated with infusion related reactions or nephrotoxicity than amphotericin B deoxycholate. The limitations have been that neither of these agents has been shown to be more effective than amphotericin B in the treatment of invasive aspergillosis, an infection with a high mortality rate, particularly in the immunocompromised patient. Voriconazole is the newest triazole antifungal approved in 2002 by the FDA for the treatment of invasive aspergillosis.

This approval was largely based on an open label trial by Herbrect and colleagues[2], in which a therapeutic benefit was demonstrated among patients treated with voriconazole over amphotericin B. The adverse event profile for voriconazole is somewhat similar to fluconazole with some unique differences, such as acute visual changes. The drug-drug interaction profile for voriconazole is more pronounced than for either fluconazole or itraconazole, as voriconazole is a more potent cytochrome P450 enzyme inhibitor and is more extensively affected by other inhibitors and inducers of this pathway.[3,4,5,6] This new triazole antifungal may require more vigilant monitoring for adverse effects especially following concomitant drug administration when compared to the previously available agents. A review of the clinical pharmacology, pharmacokinetics, and toxicology of voriconazole follows. Voriconazole (Vfend™) is marketed by Pfizer, Inc. and was approved by the United States Food and Drug Administration in May of 2002. The indications for which it is approved are the treatment of invasive aspergillosis and the treatment of serious fungal infections caused by Scedosporium apiospermum and Fusarium species in patients intolerant of, or refractory to, other therapies.[7]

Structure and Pharmacology

Voriconazole is designated chemically as (2R, 3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol with a formula C16H14F3N5O and molecular weight of 349.3 g/mol. Voriconazole is based on a triazole structural foundation similar to that of fluconazole. Side chains are replaced with a fluoropyrimidine group and another methyl group (see Figure 1 and Figure 2). The drug works by inhibiting fungal cytochrome P450 dependent 14α-sterol demethylase and subsequent ergosterol synthesis. Additionally, voriconazole inhibits 24-methylene dihydrolanasterol demethylation, thereby expanding the activity of voriconazole to include Aspergillus and other molds.[8]

Voriconazole exhibits a lower minimal inhibitory concentration (MIC) than fluconazole, itraconazole, and ketoconazole, and an MIC lower than or comparable to amphotericin B against Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, and Candida tropicalis.[9,10,11,12,13,14,15,16,17,18] Candida albicans resistant to fluconazole, when isolated from HIV infected patients, were found to be susceptible to voriconazole although the MICs were higher for both groups.[19,20,21] Voriconazole also exhibits a lower MIC than fluconazole and ketoconazole against Aspergillus species.[22] The mean MIC was similar to or lower than itraconazole and amphotericin B for Aspergillus terreus, Aspergillus fumigatus, Aspergillus flavus, and Aspergillus niger.[23,24,25,26,27,28,29,30] The relative MIC for voriconazole against other hyaline molds including Fusarium species and Scedosporium prolificans appears to be lower than itraconazole and similar to amphotericin B.[31]

Pharmacokinetics

After oral administration, voriconazole is very well absorbed with a bioavailability of approximately 96 percent. The mean peak concentration and area under the curve (AUC) are reduced by 34% and 24%, respectively when administered with a high fat meal.[3] Absorption of the oral tablet occurs quickly, and tmax in high risk patients was achieved at 1.7 to 2.8 hours on day one.[32] The recommended adult oral dose for invasive aspergillosis is 6mg/kg twice a day, IV or PO, for two doses, then 4 mg/kg twice a day. Plasma protein binding is estimated at 58% and is independent of total concentration. Hepatic and renal impairment does not affect the protein binding capacity of voriconazole.[33] Voriconazole is extensively distributed into body tissues as evidenced by a large volume of distribution of 4.6 L/kg. Steady state is reached by 24 hours with the use of a loading dose and by 6 days without a loading dose.[3] Metabolism is saturable, thereby demonstrating non-linear pharmacokinetics when the dose is increased.[34] The mean Cmax and AUC were 1.80 and 1.94 fold higher in subjects receiving voriconazole 300 mg q 12 h than in those receiving 200 mg q 12 h in a pharmacokinetic trial of patients at high risk for fungal infection.[32] In another pharmacokinetic cohort study, of patients receiving intravenous therapy, an increase in voriconazole dose was also associated with disproportionate increases in Cmax and AUC. A 1.7 fold increase in dose resulted in 2.4 and 3.1 fold increases in Cmax and AUC, respectively. For those receiving oral therapy, a doubling of oral dosing resulted in 2.8 and 3.9 fold increases in Cmax and AUC, respectively.[35]

Voriconazole is metabolized by the cytochrome P450 enzyme system, specifically at CYP3A4, 2C9 and 2C19 to relatively inactive metabolites. The enzyme system of 2C19 has been identified as the primary metabolic system.[5,36] Data from the manufacturer indicates that poor metabolizers at 2C19 do not metabolize the drug as well as those patients without this predisposition. Heterozygous extensive (poor) metabolizers have a four-fold increase in voriconazole plasma concentrations as compared with good metabolizers. Heterozygous extensive metabolizers have been identified in up to 3% to 5% of Caucasians and Blacks and 15% to 20% of Asians.[36]

Following either oral or intravenous administration, 80% of voriconazole metabolites are excreted in the urine and up to 20% are enterohepatically cycled into the feces. A small quantity (less than 2%) of unchanged drug is found in the urine. The elimination half-life of the drug is approximately 6.5 hours[37] Voriconazole is a potent inhibitor of the cytochrome P450 isoenzymes 2C9, 2C19 and 3A4.[3,4,5,6]

Special Populations. Elderly patients treated with oral or IV voriconazole had higher (80-90%) median plasma concentrations than that of younger patients (less than 65 years). No dosage adjustment is recommended by the manufacturer.[7] Limited data is available regarding the kinetic profile in pediatric patients. When voriconazole was administered to a pediatric patient at a dose of 5mg/kg orally twice daily, peak and trough concentrations at steady state were found to be similar to adult patients taking 200 mg orally twice daily.[38] In another case, a five-year-old child received oral voriconazole at 3.5 mg/kg twice daily with similar peak and trough measurements.[39]

As voriconazole is primarily metabolized in the liver to inactive metabolites, patients with mild to moderate hepatic insufficiency were found to have mean AUC's 3.2 fold higher than in age- and weight-matched controls with normal hepatic function. The manufacturer recommends that patients with mild to moderate hepatic impairment (Child-Pugh Class A and B) should receive the standard loading dose, but half the maintenance dose. Voriconazole has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).[7] The drug is contraindicated in this category of patients.

When oral voriconazole was administered to patients with mild to moderate renal insufficiency, there was no significant difference in the pharmacokinetics as compared with those with normal renal function. No dosage adjustment is necessary for oral voriconazole in patients with mild-to-moderate renal impairment. However, when patients with moderate renal impairment (CrCl 30-50 mL/min) receive intravenous voriconazole, there is an observed accumulation of the intravenous vehicle, sulfobutyl ether beta-cyclodextrin sodium (SBECD). The mean AUC and peak concentration of this additive was increased four fold and 50%, respectively, in patients with moderate renal impairment compared to normal subjects. The ramifications of this increased exposure is unknown. The manufacturer recommends that intravenous voriconazole not be administered to patients with moderate to severe renal impairment (CrCl less than 50 mL/min), unless the potential benefit to the patient justifies the potential risk.[7] Hemodialysis clearance of voriconazole has been measured at 121 mL/min, not significant enough to warrant any dose adjustment with the standard hemodialysis session.

Clinical Efficacy

Voriconazole was compared with amphotericin B in 391 patients with invasive aspergillosis in an open-label, randomized, multicenter study.[2] Patients were randomized to amphotericin B, 1 to 1.5 mg/kg/day, or voriconazole 6 mg/kg IV for 2 doses followed by 4 mg/kg IV every 12 hours followed by transition to oral voriconazole 200 mg twice daily when possible. Patients could be switched to other antifungal therapies at any point after the initial randomized therapy if deemed a treatment failure or intolerant of the initial therapy. At the predefined 12-week mark, a complete or partial response was achieved in 52.8% of patients randomized to voriconazole and 31.6% of amphotericin B-treated patients (95% CI for the difference: 32.9% to 10.4%). Within a modified intention to treat population, among voriconazole-treated patients, there was a 70.8% survival rate at 12 weeks compared to 57.9% of amphotericin B-treated patients (hazard ratio 0.59; 95% CI 0.4 to 0.88).

In an open label noncomparative trial[40], 116 patients with invasive aspergillosis were treated with voriconazole 6 mg/kg IV twice a day for two doses, then 3 mg/kg IV twice daily for 6 to 27 days, followed by 200 mg orally twice daily for up to 24 weeks. A complete response was observed in 16 patients (14%) and a partial response in 40 patients (34%). Other open label series[41,42], for invasive aspergillosis have demonstrated clinical response particularly in refractory cases.

Voriconazole has also been studied as a treatment for patients with candidal infections including a randomized double dummy comparison with fluconazole in immunocompromised patients with esophageal candidiasis.[43] Candida albicans was the primary pathogen isolated on culture in 91.6% of fluconazole treated patients and 89.5% of voriconazole treated patients. The primary efficacy analysis of clinical success as assessed by esophagoscopy revealed success rates of 98.3% with voriconazole and 95.1% with fluconazole (95% CI -1.0 to 7.5%). The median time to symptomatic cure was 8 days in both treatment groups. In a descriptive case series[44] of 12 patients with AIDS and fluconazole-refractory esophageal candidiasis, a complete clinical response (total disappearance of signs and symptoms) was observed in 50% of the patients after 7 days of therapy and in one additional patient after 2 weeks of therapy. Two of the twelve patients had unchanged symptoms after 7 days of treatment. A blinded study of comparative doses of voriconazole for 7 days in HIV-infected patients with oropharyngeal candidiasis revealed a clinical efficacy rate of 80% to 100% in patients receiving 200 mg once daily and 200 mg twice-daily.[45]

Voriconazole has also been studied in the empiric treatment of febrile neutropenia. In a randomized open label trial of voriconazole versus amphotericin B liposomal[46], 837 patients were randomized after 96 hours of fever and neutropenia on broad-spectrum antibiotics to voriconazole or liposomal amphotericin B. Voriconazole was administered intravenously with a loading dose of 6 mg/kg every 12 hours for two doses, followed by a maintenance dose of 3 mg/kg IV every 12 hours. Liposomal amphotericin B was given at a standing dose of 3mg/kg/day. Doses could be adjusted upwards for both agents when there was evidence for true fungal infection. Therapy was continued up to 72 hours after neutropenia resolved or a maximum of 12 weeks in those with documented invasive fungal infections. Clinical success was defined as no breakthrough fungal infection, survival for 7 days beyond the end of therapy, not discontinuing therapy prematurely, resolution of fever during the period of neutropenia, and successful treatment of any baseline fungal infection. The results demonstrated such success in 26% of voriconazole treated patients and 30.6% of amphotericin B treated patients (p=NS). Among those considered high-risk (e.g., allogeneic transplants or relapsed leukemia), breakthrough fungal infections occurred in 1.4% of patients in the voriconazole group compared to 9.2% of patients in the liposomal amphotericin B group (P=0.003).

A number of case reports of treatment of Scedosporium apiospermum have been published. A 25-year-old male with acute myeloid leukemia who developed disseminated infection with Scedosporium apiospermum despite therapy with amphotericin B lipid complex, was administered voriconazole 400 mg intravenously every 12 hours for two doses followed by 200 mg every 12 hours with marked clinical improvement.[47] An 8-year-old boy was administered oral voriconazole at 5mg/kg every 12 hours for an invasive pulmonary infection due to Scedosporium apiospermum with chronic granulomatous disease. There was a positive clinical response after itraconazole failure and intolerance to intravenous miconazole.[36]

Toxicology

Animal Toxicity Data

Lethal doses for mice and rats ranged from 300 mg/kg administered orally and from 100 mg/kg administered intravenously for single doses. Repeat dose studies in rats, mice, and dogs, revealed hepatotoxic effects. Two-year carcinogenicity studies revealed hepatocellular adenoma in male and female mice at doses of 100 mg/kg daily and in female rats at 50 mg/kg daily. Hepatocellular carcinoma occurred at an increased rate in male mice only at 100 mg/kg daily. Voriconazole administration was teratogenic in rats but was not observed to be mutagenic or clastogenic.[36]

Exposure to voriconazole and subsequent effects on the eye were studied in rats (24 months), mice (24 months) or dogs (12 months). Postmortem examination revealed no histopathological evidence of toxicity to the visual pathways. The nuclear layers in the retina were not affected as compared to a control group in a study of rats and dogs treated for up to 24 and 12 months, respectively.[48] Effects of the excipient SBECD revealed a low acute toxicity with the minimal single lethal dose above 2000 mg/kg in rats. Nephrotoxicity was revealed in repeat dose studies with renal tubular vacuolation and obstruction of renal tubules. Doses of 1000 mg/kg for one month and 600 mg/kg for six months did not produce functional renal changes. Hepatocellular necrosis was noted in rats at doses above three g/kg. In dogs, the maximum exposure dose of 1.5 g/kg revealed no histopathological evidence of toxicity.[36]

Human Toxicity Data

In phase I and II trials (voriconazole N=443, placebo N=135), adverse events that occurred with greater frequency in voriconazole treated patients as compared to those receiving placebo included visual disturbances (abnormal vision, photophobia) [35 versus 12%], headache (30 versus 20%), asthenia (5.4 versus 0.7 %), and infection/ inflammation at the injection site (3.6 versus 0.7%). Asthenia and infection/inflammation at the injection site were not listed as severe and did not require discontinuation of therapy.[3] In addition, those treated with voriconazole experienced ALT increases greater than three times the upper limit of normal more often than those treated with placebo (1.2 versus 0%). AST and total bilirubin increases, however, were similar between the groups. No increases in serum creatinine were noted in the voriconazole group.

In published phase III trials, a similar adverse event profile was noted. In the open label trial for the treatment of aspergillosis[40], of the 137 patients enrolled in the protocol who received at least one dose of drug, a total of 623 adverse events were reported in 125 patients (91%). Of these, the investigator attributed 15% to voriconazole. Five serious adverse events were attributed to the drug, and included hypoglycemia, pneumonitis, liver function test abnormalities, rash, and worsening of psoriasis. The most common adverse events were elevated liver enzymes (16%), visual disturbances (11%), and rash (9%). Six of the 22 patients who developed abnormal liver function or liver failure had increased plasma voriconazole concentrations (greater than 6000 ng/mL). Visual disturbances were described as blurry vision and/or the appearance of wavy or zigzag lines in the visual field. Visual changes occurred within 1 hour after dosing and lasted a few minutes. No patient discontinued therapy for this reason and the magnitude of this effect diminished with continued use of the drug.

In the trial of patients with esophageal candidiasis,[45] patients discontinued voriconazole more often than fluconazole because of laboratory test abnormalities (7 patients [3.5%] vs. 2 patients [1.0%]) or treatment-related adverse events (5 patients [2.5%] vs. 1 patient [0.5%]). An ophthalmologist performed visual acuity, contrast sensitivity, and color perception tests as well as fundoscopy on all patients. Visual adverse events were defined primarily as mild enhancement or alteration of visual perception experienced by 36 patients (18%) taking voriconazole compared with 10 patients (5%) taking fluconazole. This effect was transient, disappearing without medical treatment. No reports of long-term visual sequelae were recorded in any subject. Liver function test abnormalities, measured as increases of >3 times the upper limit of the normal range, were noted more often in the voriconazole group.

In the trial of voriconazole versus amphotericin B liposomal for febrile neutropenia,[46] a safety analysis revealed that voriconazole was associated with more episodes of transient vision changes (22% vs. 1%, P<0.001) and hallucinations (4.3% vs. 0.5%, P<0.001). In the trial of voriconazole versus amphotericin B for invasive aspergillosis[2], these visual disturbances were again more common in the voriconazole treated patients versus amphotericin, 44.8 versus 4.3 percent respectively (p<0.001). Skin reactions were observed in 8.2% of the voriconazole treated group versus 3.2% in the amphotericin B treated group (p=0.05).

Dermatological reactions have also been reported during voriconazole therapy. From pooled data, the incidence of rash was 6% in pre-clinical trials. This included photosensitivity reactions where the incidence increased with longer treatment courses. Serious cutaneous reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme) were noted rarely.[7]

There was one reported death due to cardiac arrhythmia in early trials. Cardiac arrest occurred within 30 minutes of the initial infusion of 540 mg of voriconazole in a 52-year old patient with a history of benign ventricular arrhythmias. The cause of death was attributed to ventricular fibrillation and medullary hypoplasia by the study investigator.[36] Data available from the FDA advisory committee briefing reveal that in the Global Aspergillosis Study (307/602), there were more events of cardiac arrest and syncope in the voriconazole group than the amphotericin B group. From phase I trials of 197 patients, a QTc interval increase of between 30 and 60 msec was noted in 28% of voriconazole treated patients. In clinical trials, there were three cases of accidental overdose in pediatric patients receiving up to five times the recommended intravenous dose of voriconazole. A single adverse event of photophobia of 10 minutes duration was reported.[3]

Drug Interactions

There are multiple pharmacokinetic drug-drug interactions described with voriconazole. Voriconazole is primarily metabolized by the 2C19 isoenzyme system and secondarily by 3A4 and 2C9. Inducers and inhibitors of these enzyme systems significantly affect its clearance. In pharmacokinetic studies of the effects of concomitant medications on voriconazole levels, rifampin and rifabutin significantly reduced the plasma levels of voriconazole through postulated 3A4 induction. The AUC decreased by as much as 98% with rifampin 600 mg daily and 78% with rifabutin 300 mg daily. Doubling of the dose of voriconazole did not overcome this effect.[4] These drugs are contraindicated with voriconazole. Carbamazepine and long-acting barbiturates have been listed among the contraindicated medications as well, based on their effect on other agents. No studies of their true effects on voriconazole metabolism have been done.[36] Phenytoin decreased the AUC of voriconazole by 64% when administered at 300 mg daily. Doubling the dose of voriconazole resulted in an adequate AUC.[5]

Cytochrome P450 enzyme inhibitors have also been studied. Omeprazole, a competitive inhibitor of 2C19 was found to increase the AUC of voriconazole by 41% at a dose of 40 mg per day. The protease inhibitor, indinavir, when given at 800 mg orally three times a day was found to increase voriconazole levels by only 7%. The effects of other protease inhibitors are not known.

The effect of voriconazole inhibitory activity on other drugs has also been observed. Notably, when sirolimus 2 mg was given once to patients on voriconazole 200 mg twice daily, the AUC of sirolimus increased by 1014%. Therefore, sirolimus is contraindicated in patients taking voriconazole. When voriconazole at a dose of 200 mg orally twice a day was given to patients taking rifabutin 300 mg daily, the AUC of rifabutin increased by 331%, and administration of these drugs together is contraindicated. Although not studied, concomitant administration of voriconazole with terfenadine, astemizole, cisapride, pimozide or quinidine is contraindicated, since increased plasma concentrations of these drugs can lead to QTc prolongation and, rarely, torsades de pointes ventricular tachycardia. Although not studied extensively, the concomitant use of ergot alkaloids with voriconazole is also contraindicated due to the expected inhibition of ergot alkaloid metabolism through CYP450 3A4 by voriconazole and the fear of subsequent ergot alkaloid toxicity.

The AUC of cyclosporine is increased by 70% when administered with voriconazole 200 mg twice daily.[3,6] It is recommended to decrease the daily dose of cyclosporine by 50% in patients on voriconazole and check levels of cyclosporine daily thereafter.[3,6] In a double blind placebo controlled crossover trial, seven stable renal transplant patients received placebo or voriconazole 200 mg twice daily with a stable regimen of cyclosporine. The AUC of cyclosporine was increased by a mean of 70% when voriconazole was given.[3,6] Seven other patients who initially started the trial dropped out secondary to toxicities related to increased cyclosporine levels and were not included in the analysis. It may be postulated that this mean increase in AUC would have been higher if these patients were included.[49]

Voriconazole also increases the relative AUC of warfarin at doses of 300 mg twice daily and has been subsequently shown to increase the prothrombin time as a result.[50] The manufacturer recommends daily monitoring of prothrombin time and INR with dose adjustments of warfarin as necessary.[7] Tacrolimus levels are increased when given with voriconazole. The AUC of tacrolimus was increased by 221%. The manufacturer recommends a decrease in dose by 70% for the initial dose with daily monitoring of levels and subsequent dose adjustment of tacrolimus.[7] The AUC of phenytoin was also increased (81%) when 400 mg of voriconazole was given twice daily. The manufacturer recommends frequent monitoring of phenytoin levels when the drugs are administered concomitantly.[5]

While omeprazole can increase voriconazole levels, the opposite effect has been documented. Omeprazole levels were increased by 280% when voriconazole was administered at a dose of 200 mg twice daily. The manufacturer recommends decreasing the dose of omeprazole by 50% when the desired dose exceeds 40 mg per day.[7] Although not yet studied or observed, monitoring of adverse effects is warranted due to the potential for pharmacokinetic drug interactions when one of the following medications is administered with voriconazole: protease inhibitors (e.g., ritonavir, indinavir), nonnucleoside reverse transcriptase inhibitors (e.g., efavirenz, delavirdine), benzodiazepines (e.g., alprazolam, midazolam), HMG CoA reductase inhibitors (e.g., simvastatin, atorvastatin, lovastatin), sulfonylurea antidiabetic agents (e.g., glyburide, glipizide) and calcium channel blockers (e.g., diltiazem).

Management of overdose

Currently, no specific recommendations exist for the management of an acute overdose with voriconazole as human experience is so limited. Recommendations are based on available pharmacokinetic and animal and human toxicity data. Following acute or subacute overdose, the patient should be monitored closely for adverse ophthalmologic, cardiac, and hepatic toxic effects. Initial continuous cardiac monitoring and serial electrocardiograms are recommended in light of the potential for QTc interval prolongation and the theoretical risk for torsades de pointes ventricular tachycardia. Although the duration of cardiac monitoring that is necessary is unknown, clinical (toxic) effects would be expected to last less than 24 hours based on voriconazole pharmacokinetic data. The efficacy of voriconazole adsorption to activated charcoal has not been previously studied. Although gastrointestinal decontamination with activated charcoal is of theoretical benefit following both oral and intravenous voriconazole overdose, its routine administration in overdose is not recommended due to lack of supporting evidence.

Certain patient populations have a greater likelihood of developing toxic effects following both overdose and routine (unadjusted) doses of voriconazole. These patients include those with impaired voriconazole metabolism (the elderly, those with moderate to severe hepatic and renal disease, poor metabolizers at CYP 2C19, 2C9, and 3A4, or those taking medications that inhibit CYP 2C19, 2C9, and 3A4) and those taking drugs that use CYP 2C19, 2C9, and 3A4 for their normal metabolism. The latter group of patients must be observed for toxicity from these drugs whose metabolism is affected (typically decreased) when co-administered with voriconazole. Despite stable dosing, patients could develop toxicity from carbamazepine, cisapride, cyclosporine, diltiazem, glyburide, pimozide, quinidine, tacrolimus, warfarin, and numerous others when coadministered with voriconazole. Close monitoring of electrocardiograms (specifically, QTc intervals), serum drug concentrations, and various laboratory tests (e.g., liver function tests, prothrombin time) may avert unwanted toxic effects from voriconazole and co-administered drugs. The astute clinician should understand the innumerable drug-drug interactions that are possible and be able to recognize the signs and symptoms of toxic effects from other drugs. Heightened awareness may decrease iatrogenic morbidity and mortality.

Conclusion

Voriconazole is the newest triazole antifungal agent available in the United States for the treatment of fungal infections. It is generally well tolerated at therapeutic doses. Overdose experience is currently limited to three cases. Acute and subacute toxic effects may include visual disturbances and liver function test abnormalities. Voriconazole is a potent cytochrome P450 2C19, 2C9 and 3A4 inhibitor. It is also extensively metabolized by these enzyme systems. There are numerous clinically significant drug-drug interactions and the potential for toxic effects following co-administration of voriconazole with other drugs is a greater cause for concern than toxicity following acute overdose. Voriconazole should be used with caution with drugs known to prolong the QT interval and with drugs metabolized by CYP 2C19, 2C9, and 3A4.

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  15. Jabado N, Casanova J, Haddad E, Dulieu F, Fournet JC, Dupont B. Invasive pulmonary infection due to Scedosporium apiospermum in two children with chronic granulomatous disease. Clin Infect Dis 1998; 27:1437-41.
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  19. DuPont B, et al. UK-109,496, a novel, wide-spectrum triazole derivative for the treatment of fungal infections: Clinical efficacy in chronic invasive aspergillosis [abstract]. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 1995:F81; San Francisco.
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  22. Troke PF, et al. UK-109,496, a novel, wide-spectrum triazole derivative for the treatment of fungal infections: Activity in systemic candidiasis models and early clinical efficacy in oropharyngeal candidiasis (OPC) [abstract]. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 1995:F73; San Francisco.
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  25. Ghahramani P, et al. Voriconazole potentiates warfarin-induced prolongation of prothrombin time [abstract]. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2000:24; Toronto. Abstract 846.


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