Vfend

Vfend

voriconazole

Manufacturer:

Pfizer

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Voriconazole.
Description
Film-Coated Tablet: Each tablet contains 50 mg or 200 mg voriconazole.
Powder for Oral Suspension:Each bottle contains 45 g of powder for oral suspension providing 40 mg/mL voriconazole when constituted with water (see Cautions for Usage).
Powder for Solution for Infusion: Each vial contains 200 mg voriconazole, equivalent to a 10 mg/mL solution following reconstitution (see Cautions for Usage).
Excipients/Inactive Ingredients: Film-Coated Tablet: Tablet Core: Lactose monohydrate, pre-gelatinised starch, croscarmellose sodium, povidone, magnesium stearate.
Film-Coat: Hypromellose, titanium dioxide (E171), lactose monohydrate, glycerol triacetate (triacetin).
Powder for Oral Suspension: Colloidal silica, titanium dioxide, xanthan gum, sodium citrate dihydrate, sodium benzoate, anhydrous citric acid, natural orange flavor, sucrose.
Powder for Solution for Infusion: Sulphobutylether beta cyclodextrin sodium, water for injections.
Action
Pharmacology: Pharmacodynamics: Mode of Action: Voriconazole is a triazole antifungal agent. The primary mode of action of voriconazole is the inhibition of fungal cytochrome P-450 mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of voriconazole. Voriconazole has been shown to be more selective for fungal cytochrome P-450 enzymes than various mammalian cytochrome P-450 enzyme systems.
Pharmacokinetic/Pharmacodynamic Relationship: In 10 therapeutic studies, the median for the average and maximum plasma concentrations in individual subjects across the studies was 2,425 ng/mL (inter-quartile range 1,193 to 4,380 ng/mL) and 3,742 ng/mL (inter-quartile range 2,027 to 6,302 ng/mL), respectively. A positive association between mean, maximum or minimum plasma voriconazole concentration and efficacy in therapeutic studies was not found.
Pharmacokinetic-pharmacodynamic analyses of clinical trial data identified positive associations between plasma voriconazole concentrations and both liver function test abnormalities and visual disturbances.
Clinical Experience: Successful outcome in this section is defined as complete or partial response.
Aspergillus Infections-Efficacy in Aspergillosis Patients with Poor Prognosis: Voriconazole has in vitro fungicidal activity against Aspergillus spp. The efficacy and survival benefit of voriconazole compared to conventional amphotericin B in the primary treatment of acute invasive aspergillosis was demonstrated in an open, randomised, multicenter study in 277 immunocompromised patients treated for 12 weeks. Voriconazole was administered intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours followed by a maintenance dose of 4 mg/kg every 12 hours for a minimum of seven days. Therapy could then be switched to the oral formulation at a dose of 200 mg every 12 hours. Median duration of IV voriconazole therapy was 10 days (range 2-85 days). After IV voriconazole therapy, the median duration of PO voriconazole therapy was 76 days (range 2-232 days).
A satisfactory global response (complete or partial resolution of all attributable symptoms, signs, radiographic/bronchoscopic abnormalities present at baseline) was seen in 53% of voriconazole-treated patients compared to 31% of patients treated with comparator. The 84-day survival rate for voriconazole was statistically significantly higher than that for the comparator and a clinically and statistically significant benefit was shown in favor of voriconazole for both time to death and time to discontinuation due to toxicity.
This study confirmed findings from an earlier, prospectively designed study where there was a positive outcome in subjects with risk factors for a poor prognosis, including graft versus host disease, and, in particular, cerebral infections (normally associated with almost 100% mortality).
The studies included cerebral, sinus, pulmonary and disseminated aspergillosis in patients with bone marrow and solid organ transplants, hematological malignancies, cancer and AIDS.
Serious Invasive Candida Infections-Efficacy in Non-Neutropenic Patients: The efficacy of voriconazole compared to the regimen of amphotericin B followed by fluconazole in the primary treatment of candidemia was demonstrated in an open, comparative study. Three hundred and seventy (370) non-neutropenic patients with documented candidemia (positive blood culture and clinical signs of infection) were included in the study, of which 248 were treated with voriconazole. The patient population was seriously ill, with approximately 50% of subjects in the intensive care unit and 40% mechanically ventilated at baseline. The median treatment duration was 15 days in both treatment arms. A successful response (resolution/improvement in all clinical signs and symptoms of infection, blood cultures negative for Candida, infected deep tissue sites negative for Candida) was seen in 41% of patients in both treatment arms 12 weeks after the End of Therapy (EOT).
In this analysis, patients who did not have an assessment 12 weeks after EOT were set to failure. According to a secondary analysis, which compared response rates at the latest time point most relevant to the evaluation of the patient (EOT, or 2, 6, or 12 weeks after EOT), voriconazole and the regimen of amphotericin B followed by fluconazole had response rates of 65% and 71%, respectively.
Serious Refractory Candida Infections: The study comprised 55 patients with serious refractory systemic Candida infections (including candidemia, disseminated and other invasive candidiasis) where prior antifungal treatment, particularly with fluconazole, had been ineffective. Successful response was seen in 24 patients (15 complete, 9 partial responses). In fluconazole-resistant non-albicans species, a successful outcome was seen in 3/3 C. krusei (complete responses) and 6/8 C. glabrata (5 complete, 1 partial response) infections. The clinical efficacy data were supported by limited susceptibility data.
Other Serious Rare Fungal Pathogens: Voriconazole was shown to be effective against the following rare fungal pathogens: Scedosporium spp: Successful response to voriconazole therapy was seen in 16 of 28 patients (55%) with S. apiospermum and in 2 of 7 patients (29%) with S. prolificans infection. In addition, a successful response was seen in 1 of 3 patients with mixed organism infections.
Fusarium spp: Seven of 17 (41%) patients were successfully treated with voriconazole. Of these 7 patients, 3 had eye, 1 had sinus, and 3 had disseminated infection. Four additional patients with fusariosis had an infection caused by several organisms; two of them had a successful outcome.
The majority of patients receiving voriconazole treatment of the previously mentioned rare infections were intolerant of, or refractory to, prior antifungal therapy.
Primary Prophylaxis of Invasive Fungal Infections-Efficacy in Hematopoietic Stem Cell Transplant (HSCT) Recipients Without Prior Proven or Probable Invasive Fungal Infection (IFI): Voriconazole was compared to itraconazole as primary prophylaxis in an open-label, comparative, multicenter study of adult and adolescent allogeneic HSCT recipients without prior proven or probable IFI. Success was defined as the ability to continue study drug prophylaxis for 100 days after HSCT (without stopping for >14 days) and survival with no proven or probable IFI for 180 days after HSCT. The modified intent-to-treat (MITT) group included 465 allogeneic HSCT recipients, with myeloablative (58%) or reduced-intensity (42%) conditioning regimens. Prophylaxis with study drug was started immediately after HSCT: 224 received voriconazole and 241 received itraconazole. The median duration of study drug prophylaxis was 96 days for voriconazole and 68 days for itraconazole in the MITT group.
Success rates and other secondary endpoints are presented in Table 1. (See Table 1).

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Secondary Prophylaxis of IFI–Efficacy in HSCT Recipients With Prior Proven or Probable IFI: Voriconazole was investigated as secondary prophylaxis in an open-label, non-comparative, multicenter study of adult allogeneic HSCT recipients with prior proven or probable IFI. The primary endpoint was the rate of occurrence of proven and probable IFI during the first year after HSCT. The MITT group included 40 patients with prior IFI, including 31 with aspergillosis, 5 with candidiasis, and 4 with other IFI. The median duration of study drug prophylaxis was 95.5 days in the MITT group.
Proven or probable IFIs developed in 7.5% (3/40) of patients during the first year after HSCT, including one candidemia, one scedosporiosis (both relapses of prior IFI), and one zygomycosis. The survival rate at Day 180 was 80.0% (32/40) and at 1 year was 70.0% (28/40).
Duration of Treatment: Intravenous and oral voriconazole allows flexibility in patient care and the possibility of prolonged treatment where indicated. In clinical trials, 714 patients received voriconazole therapy for greater than 12 weeks, with 155 subjects receiving voriconazole for over 6 months.
Clinical Studies in Children: Fifty-three pediatric patients aged 2 to <18 years were treated with voriconazole in two prospective, open-label, non-comparative, multi-center clinical trials. One study enrolled 31 patients with possible, proven or probable invasive aspergillosis (IA), of whom 14 patients had proven or probable IA and were included in the MITT efficacy analyses. The second study enrolled 22 patients with invasive candidiasis including candidaemia (ICC), and esophageal candidiasis (EC) requiring either primary or salvage therapy, of whom 17 were included in the MITT efficacy analyses. Of the total of 31 patients included in the MITT analyses, 14 were 2 to <12 years old (5 patients with IA and 9 with ICC or EC) and 17 were 12 to <18 years old (9 patients with IA and 8 with ICC and EC). The overall rates of global response were 64.3% (9/14) at 6 weeks for patients with IA, 85.7% (6/7) at EOT for patients with ICC and 70% (7/10) at EOT for patients with EC. In subjects with IA, the success rate was 40% (2/5) for patients 2 to <12 years and 77.8% (7/9) for patients 12 to <18 years of age.
Clinical Studies Examining QT Interval: A placebo-controlled, randomized, single-dose, crossover study to evaluate the effect on the QT interval of healthy volunteers was conducted with three oral doses of voriconazole and ketoconazole. The placebo-adjusted mean maximum increases in QTc from baseline after 800, 1,200 and 1,600 mg of voriconazole were 5.1, 4.8, and 8.2 msec, respectively, and 7.0 msec for ketoconazole 800 mg. No subject in any group had an increase in QTc of ≥60 msec from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec.
Pharmacokinetics: General Pharmacokinetic Characteristics: The pharmacokinetics of voriconazole have been characterized in healthy subjects, special populations and patients. During oral administration of 200 mg or 300 mg twice daily for 14 days in patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or hematopoietic tissue), the observed pharmacokinetic characteristics of rapid and consistent absorption, accumulation and non-linear pharmacokinetics were in agreement with those observed in healthy subjects.
The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. Greater than proportional increase in exposure is observed with increasing dose. It is estimated that, on average, increasing the oral dose from 200 mg twice daily to 300 mg twice daily leads to an approximately 2.5-fold increase in exposure (AUCT). The oral maintenance dose of 200 mg (or 100 mg for patients less than 40 kg) achieves a voriconazole exposure similar to 3 mg/kg IV. A 300 mg (or 150 mg for patients less than 40 kg) oral maintenance dose achieves an exposure similar to 4 mg/kg IV. (See Table 2).

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When the recommended intravenous or oral loading dose regimens are administered, plasma concentrations close to steady state are achieved within the first 24 hours of dosing (e.g., 6 mg/kg IV every 12 hours on day 1 followed by 3 mg/kg IV every 12 hours; 400 mg oral every 12 hours on day 1 followed by 200 mg oral every 12 hours). Without the loading dose, accumulation occurs during twice daily multiple dosing with steady-state plasma voriconazole concentrations being achieved by day 6 in the majority of subjects.
Absorption: Voriconazole is rapidly and almost completely absorbed following oral administration, with maximum plasma concentrations (Cmax) achieved 1 to 2 hours after dosing. The oral bioavailability of voriconazole is estimated to be 96%. Bioequivalence was established between the 200 mg tablet and the 40 mg/mL oral suspension when administered as a 400 mg every 12 hours loading dose followed by a 200 mg every 12 hours maintenance dose. When multiple doses of voriconazole are administered with high fat meals, Cmax and AUCT are reduced by 34% and 24%, respectively, when administered as a tablet and by 58% and 37%, respectively, when administered as the oral suspension.
The absorption of voriconazole is not affected by changes in gastric pH.
Distribution: The volume of distribution at steady state for voriconazole is estimated to be 4.6 L/kg, suggesting extensive distribution into tissues. Plasma protein binding is estimated to be 58%.
Cerebrospinal fluid samples from eight patients in a compassionate programme showed detectable voriconazole concentrations in all patients.
Metabolism: In vitro studies showed that voriconazole is metabolized by the hepatic cytochrome P-450 isoenzymes, CYP2C19, CYP2C9 and CYP3A4.
The inter-individual variability of voriconazole pharmacokinetics is high.
In vivo studies indicated that CYP2C19 plays a key role in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism. For example, 15-20% of Asian populations may be expected to be poor metabolizers. For Caucasians and Blacks, the prevalence of poor metabolizers is 3-5%. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor metabolizers have, on average, 4-fold higher voriconazole exposure (AUCT) than their homozygous extensive metabolizer counterparts. Subjects who are heterozygous extensive metabolizers have on average 2-fold higher voriconazole exposure than their homozygous extensive metabolizer counterparts.
The major metabolite of voriconazole is the N-oxide, which accounts for 72% of the circulating radiolabelled metabolites in plasma. This metabolite has minimal antifungal activity and does not contribute to the overall efficacy of voriconazole.
Excretion: Voriconazole is eliminated via hepatic metabolism with less than 2% of the dose excreted unchanged in the urine.
After administration of a radiolabelled dose of voriconazole, approximately 80% of the  radioactivity is recovered in the urine after multiple intravenous dosing and 83% in the urine after multiple oral dosing. The majority (>94%) of the total radioactivity is excreted in the first 96 hours after both oral and intravenous dosing.
The terminal half-life of voriconazole depends on dose and is approximately 6 hours following 200 mg (orally). Because of non-linear pharmacokinetics, the terminal half-life is not useful in the prediction of the accumulation or elimination of voriconazole.
Pharmacokinetics in Special Patient Groups: Gender: In an oral multiple dose study, Cmax and AUCT for healthy young females were 83% and 113% higher, respectively, than in healthy young males (18-45 years), after tablet dosing. In the same study, no significant differences in Cmax and AUCT were observed between healthy elderly males and healthy elderly females (≥65 years). In a similar study, after dosing with the oral suspension, the mean AUC for healthy young females was 45% higher than in healthy young males, whereas the mean Cmax was comparable between genders. The steady-state trough voriconazole concentrations (Cmin) seen in females were 100% and 91% higher than in males receiving the tablet and the oral suspension, respectively.
In the clinical program, no dosage adjustment was made on the basis of gender. The safety profile and plasma concentrations observed in male and female patients were similar. Therefore, no dosage adjustment based on gender is necessary.
Elderly: In an oral multiple dose study Cmax and AUCT in healthy elderly males (≥65 years) were 61% and 86% higher, respectively, than in healthy young males (18-45 years). No significant differences in Cmax and AUCT were observed between healthy elderly females (≥65 years) and healthy young females (18-45 years).
In the therapeutic studies, no dosage adjustment was made on the basis of age. A relationship between plasma concentrations and age was observed. However, the safety profile of voriconazole in young and elderly patients was similar and, therefore, no dosage adjustment is necessary for the elderly.
Pediatrics: The recommended doses in children and adolescent patients are based on a population pharmacokinetic analysis of data pooled from 112 immunocompromised pediatric patients aged 2 to <12 years old and 26 immunocompromised adolescent patients aged 12 to ≤17 years. Multiple intravenous doses of 3, 4, 6, 7 and 8 mg/kg twice daily and multiple oral doses (using the powder for oral suspension) of 4 mg/kg, 6 mg/kg and 200 mg twice daily were evaluated in 3 pediatric pharmacokinetic studies. Intravenous loading doses of 6 mg/kg IV twice daily on day 1 followed by 4 mg/kg intravenous dose twice daily and 300 mg oral tablets twice daily were evaluated in one adolescent pharmacokinetic study. Larger inter-subject variability was observed in pediatric patients compared to adults.
A comparison of the pediatric and adult population pharmacokinetic data indicated that the predicted total exposure (AUCΤ) in children following administration of a 9 mg/kg IV loading dose was comparable to that in adults following a 6 mg/kg IV loading dose. The predicted total exposures in children following IV maintenance doses of 4 and 8 mg/kg twice daily were comparable to those in adults following 3 and 4 mg/kg IV twice daily, respectively. The predicted total exposure in children following an oral maintenance dose of 9 mg/kg (maximum of 350 mg) twice daily was comparable to that in adults following 200 mg oral twice daily. An 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.
The higher intravenous maintenance dose in pediatric patients relative to adults reflects the higher elimination capacity in pediatric patients due to a greater liver mass to body mass ratio. Oral bioavailability may however, be limited in pediatric patients with malabsorption and very low body weight for their age. In that case, intravenous voriconazole administration is recommended.
Voriconazole exposures in the majority of adolescent patients were comparable to those in adults receiving the same dosing regimens. However, lower voriconazole exposure was observed in some young adolescents with low body weight compared to adults. It is likely that these subjects may metabolize voriconazole more similarly to children than to adults. Based on the population pharmacokinetic analysis, 12- to 14-year-old adolescents weighing less than 50 kg should receive children’s doses (see Dosage & Administration).
Renal Impairment: In a single oral dose (200 mg) study in subjects with normal renal function and mild (creatinine clearance 41-60 mL/min) to severe (creatinine clearance <20 mL/min) renal impairment, the pharmacokinetics of voriconazole were not significantly affected by renal impairment. The plasma protein binding of voriconazole was similar in subjects with different degrees of renal impairment. See dosing and monitoring recommendations under Dosage & Administration and Precautions.
In patients with moderate to severe renal dysfunction (serum creatinine levels ≥220 micromol/L (2.5 mg/dL), accumulation of the intravenous vehicle, SBECD, occurs. See dosing and monitoring recommendations under Dosage & Administration and Precautions.
Hepatic Impairment: After a single oral dose (200 mg), AUC was 233% higher in subjects with mild to moderate hepatic cirrhosis (Child-Pugh A and B) compared with subjects with normal hepatic function. Protein binding of voriconazole was not affected by impaired hepatic function.
In a multiple oral dose study, AUCT was similar in subjects with moderate hepatic cirrhosis (Child-Pugh B) given maintenance doses of 100 mg twice daily and subjects with normal hepatic function given 200 mg twice daily. No pharmacokinetic data are available for patients with severe hepatic cirrhosis (Child-Pugh C). For dosing information, refer to use in patients with hepatic impairment (see Dosage & Administration).
Toxicology: Preclinical Safety Data: Repeated-dose toxicity studies with voriconazole indicated the liver to be the target organ. Hepatotoxicity occurred at plasma exposures similar to those obtained at therapeutic doses in humans, in common with other antifungal agents. In rats, mice and dogs, voriconazole also induced minimal adrenal changes. Conventional studies of safety pharmacology, genotoxicity or carcinogenic potential did not reveal a special hazard for humans.
In reproduction studies, voriconazole was shown to be teratogenic in rats and embryotoxic in rabbits at systemic exposures equal to those obtained in humans with therapeutic doses. In the pre- and post-natal development study in rats at exposures lower than those obtained in humans with therapeutic doses, voriconazole prolonged the duration of gestation and labor and produced dystocia with consequent maternal mortality and reduced perinatal survival of pups. The effects on parturition are probably mediated by species-specific mechanisms, involving reduction of estradiol levels, and are consistent with those observed with other azole antifungal agents. Voriconazole administration induced no impairment of male or female fertility in rats at exposures similar to those in humans at therapeutic doses.
Preclinical data on the intravenous vehicle, SBECD indicated that the main effects were vacuolation of urinary tract epithelium and activation of macrophages in the liver and lungs in the repeated-dose toxicity studies.
Microbiology: In vitro, voriconazole displays broad-spectrum antifungal activity with antifungal potency against Candida species (including fluconazole resistant C. krusei and resistant strains of C. glabrata and C. albicans) and fungicidal activity against all Aspergillus species tested. In addition, voriconazole shows in vitro fungicidal activity against emerging fungal pathogens, including those such as Scedosporium or Fusarium which have limited susceptibility to existing antifungal agents.
Clinical efficacy (with partial or complete response, see Clinical Experience as previously mentioned) has been demonstrated for Aspergillus spp including A. flavus, A. fumigatus, A. terreus, A. niger, A. nidulans, Candida spp, including C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. tropicalis and limited numbers of C. dubliniensis, C. inconspicua and C. guilliermondii, Scedosporium spp, including S. apiospermum, S. prolificans and Fusarium spp.
Other treated fungal infections (with often partial or complete response) included isolated cases of Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp, Coccidioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, Penicillium spp including P. marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp including T. beigelii infections.
In vitro activity against clinical isolates has been observed for Acremonium spp, Alternaria spp, Bipolaris spp, Cladophialophora spp, Histoplasma capsulatum, with most strains being inhibited by concentrations of voriconazole in the range 0.05 to 2 μg/mL.
In vitro activity against the following pathogens has been shown, but the clinical significance is unknown: Curvularia spp and Sporothrix spp.
Breakpoints: Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy maybe instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.
The species most frequently involved in causing human infections include C. albicans, C. parapsilosis, C. tropicalis, C. glabrata, and C. krusei, all of which usually exhibit minimum inhibitory concentrations (MICs) of less than 1 mg/L for voriconazole.
However, the in vitro activity of voriconazole against Candida species is not uniform. Specifically, for C. glabrata, the MICs of voriconazole for fluconazole-resistant isolates are proportionally higher than are those of fluconazole-susceptible isolates. Therefore, every attempt should be made to identify Candida to species level. If antifungal susceptibility testing available, the MIC results may be interpreted using breakpoint criteria.
European Committee on Antimicrobial Susceptibility Testing (EUCAST) Breakpoints: Candida Species: The interpretive standards for voriconazole against Candida species are applicable only to tests performed using EUCAST microbroth dilution reference method for minimum inhibitory concentrations (MICs) read at 24 hours. (See Table 3).

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Clinical and Laboratory Standards Institute (CLSI) Breakpoints: Breakpoint Criteria Established by CLSI: Susceptibility Testing Methods: Aspergillus species and other filamentous fungi: No interpretive criteria have been established for Aspergillus species and other filamentous fungi.
Candida Species: The interpretive standards for voriconazole against Candida species are applicable only to tests performed using Clinical and Laboratory Standards Institute (CLSI) microbroth dilution reference method M27 and MIC read at 48 hours or disk diffusion reference method M44 for zone diameter read at 24 hours.
Broth Dilution Techniques: Quantitative methods are used to determine antifungal MICs.
These MICs provide estimates of the susceptibility of Candida species to antifungal agents. MICs should be determined using a standardized procedure at 48 hours. Standardized procedures are based on a microdilution method (broth) with standardized inoculums concentrations and standardized concentrations of voriconazole powder. The MIC values should be interpreted according to the criteria provided in Table 4. (See Table 4).
Diffusion Techniques: Qualitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of Candida species to an antifungal agent. One such standardized procedure requires the use of standardized inoculum concentrations. This procedure uses paper discs impregnated with 1 microgram of voriconazole to test the susceptibility of yeasts to voriconazole. Disc diffusion interpretive criteria are also provided in Table 4. (See Table 4).

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Note 1: Shown are the breakpoints (μg/mL) for voriconazole against Candida species. If MICs are measured using a scale that yields results falling between categories, the next higher category is implied. Thus, an isolate with a voriconazole MIC of 1.5 μg/mL would be placed in the S-DD category.
The susceptible category implies that isolates are inhibited by the usually achievable concentrations of antifungal agent tested when the recommended dosage is used for the site of infection. The susceptible-dose dependent category implies that an infection due to the isolate may be appropriately treated in body sites where the drugs are physiologically concentrated or when a high dosage of drug is used. The resistant category implies that isolates are not inhibited by the usually achievable concentrations of the agent with normal dosage schedules and clinical efficacy of the agent against the isolate has not been reliably shown in treatment studies.
Quality Control: Standardized susceptibility test procedures require the use of quality control organisms to control the technical aspects of the test procedures. Standard voriconazole powder and 1 μg discs should provide the following range of values noted in Table 5. (See Table 5).
NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant. (See Table 5).

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Indications/Uses
Voriconazole is a broad spectrum, triazole antifungal agent and is indicated in adults and children aged 2 years and above as follows: Treatment of invasive aspergillosis; treatment of fluconazole-resistant serious invasive Candida infections (including C. krusei); treatment of serious Candida infections including esophageal candidiasis; treatment of candidemia in non-neutropenic patients and the following Candida infections: disseminated infection in skin and infections in abdomen, kidney, bladder wall and wounds; treatment of serious fungal infections caused by Scedosporium spp and Fusarium spp; prevention of breakthrough fungal infections in febrile high-risk neutropenic patients.
Prophylaxis in patients ≥12 years old who are at high risk of developing invasive fungal infections. The indication is based on a study which includes patients ≥12 years old undergoing haematopoietic stem cell transplantation.
Voriconazole should be administered primarily to immunocompromised patients with progressive, possibly life-threatening infections.
Dosage/Direction for Use
Adults: Therapy must be initiated with the specified intravenous loading dose regimen of voriconazole to achieve adequate plasma concentrations on Day 1. Intravenous treatment should becontinued for at least 7 days before switching to oral treatment (see Pharmacology: Pharmacodynamics under Actions). Once the patient is clinically improved and can tolerate medication given by mouth, the oral tablet form or oral suspension form of voriconazole may be utilized. On the basis of the high oral bioavailability (96%), switching between intravenous and oral administration is appropriate when clinically indicated (see Pharmacology: Pharmacokinetics under Actions).
Detailed information on dosage recommendations is provided in Table 6. (See Table 6).

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Dosage Adjustment: Oral Administration: If patient response is inadequate, the maintenance dose may be increased from 200 mg every 12 hours (similar to 3 mg/kg IV every 12 hours) to 300 mg every 12 hours (similar to 4 mg/kg IV every 12 hours) for oral administration. For patients less than 40 kg the oral dose may be increased from 100 mg to 150 mg every 12 hours.
If patients are unable to tolerate treatment at these higher doses (i.e. 300 mg oral every 12 hours), reduce the oral maintenance dose by 50 mg steps to a minimum of 200 mg every 12 hours (or 100 mg every 12 hours for patients less than 40 kg).
Phenytoin may be co-administered with voriconazole if the maintenance dose of voriconazole is increased from 200 mg to 400 mg orally, every 12 hours (from 100 mg to 200 mg orally, every 12 hours in patients less than 40 kg) (see Precautions and Interactions).
When voriconazole is co-administered with adjusted doses of efavirenz, voriconazole maintenance dose should be increased to 400 mg every 12 hours (see Contraindications, Precautions and Interactions).
Treatment duration depends upon patients' clinical and mycological response.
Intravenous Administration: If patient response at 3 mg/kg every 12 hours is inadequate, the intravenous maintenance dose may be increased to 4 mg/kg every 12 hours.
If patients are unable to tolerate 4 mg/kg every 12 hours, reduce the intravenous maintenance dose to a minimum of 3 mg/kg every 12 hours.
Phenytoin may be co-administered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg intravenously every 12 hours (see Precautions and Interactions).
Treatment duration depends upon patients' clinical and mycological response.
Elderly: No dose adjustment is necessary for elderly patients.
Patients with Renal Impairment: Film-Coated Tablet or Powder for Oral Suspension: The pharmacokinetics of orally administered voriconazole are not affected by renal impairment. Therefore, no adjustment is necessary for oral dosing for patients with mild to severe renal impairment.
Powder for Solution for Infusion: In patients with moderate to severe renal dysfunction (creatinine clearance <50 mL/min), accumulation of the intravenous vehicle, sulphobutylether β-cyclodextrin sodium (SBECD), occurs. Oral voriconazole should be administered to these patients, unless an assessment of the risk benefit to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients and, if increases occur, consideration should be given to changing to oral voriconazole therapy.
Voriconazole is hemodialyzed with a clearance of 121 mL/min. A four-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.
The intravenous vehicle, SBECD, is hemodialyzed with a clearance of 55 mL/min.
Patients with Hepatic Impairment: No dose adjustment is necessary in patients with acute hepatic injury, manifested by elevated liver function tests (ALT, AST). Continued monitoring of liver function tests for further elevations is recommended.
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 A and B) receiving voriconazole.
Voriconazole has not been studied in patients with severe chronic hepatic cirrhosis (Child-Pugh C).
Voriconazole has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and must only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with severe hepatic impairment must be carefully monitored for drug toxicity.
Pediatrics: Use in Children (2 to <12 years) and Young Adolescents (12 to 14 years and <50 kg): The recommended dosing regimen is as follows. (See Table 7).

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It is recommended to initiate the therapy with intravenous regimen, and oral regimen should be considered only after there is a significant clinical improvement. It should be noted that an 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.
The oral dose recommendations for children is based on studies in which voriconazole was administered as the powder for oral suspension formulation. Bioequivalence between the powder for oral suspension and tablets has not been investigated in a pediatric population. Considering the assumed limited gastro-enteric transit time in pediatrics, the absorption of tablets may be different in pediatric compared to adult patients. It is therefore, recommended to use the oral suspension formulation in children aged 2 to <12 years.
Safety and effectiveness in pediatric patients below the age of 2 years has not been established (see Pharmacology: Pharmacodynamics under Actions). Therefore, voriconazole is not recommended for children less than 2 years of age. Use in pediatric patients aged 2 to <12 years with hepatic or renal insufficiency has not been studied (see Pharmacology: Pharmacokinetics under Actions and Adverse Reactions).
Use in All Other Adolescents (12 to 14 Years and ≥50 kg; 15 to 16 Years Regardless of Bodyweight): Voriconazole should be dosed as adults.
Dosage Adjustment: If patient response is inadequate, the dose may be increased by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mg was used initially). If patients are unable to tolerate treatment, reduce the dose by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mg was used initially).
Prophylaxis in Adults and Children: Prophylaxis should be initiated on the day of transplant and may be administered for up to 100 days. It may only be continued up to 180 days after transplantation in case of continuing immunosuppression or graft versus host disease (GvHD) (see Pharmacology: Pharmacodynamics under Actions).
Dosage: The recommended dosing regimen for prophylaxis is the same as for treatment in the respective age groups. Please refer to treatment Tables 6 and 7 previously. (See Tables 6 and 7).
Duration of Prophylaxis: The safety and efficacy of voriconazole use for longer than 180 days has not been adequatelystudied in clinical trials.
Administration: Film-Coated Tabletsor Powder for Oral Suspension: Voriconazole film-coated tablets or oral suspension are to be taken at least one hour before, or one hour following a meal.
Powder for Solution for Infusion: Voriconazole requires reconstitution and dilution (see Cautions for Usage) prior to administration as an intravenous infusion.
Voriconazole powder for solution for infusion is not recommended for bolus injection.
It is recommended that voriconazole be administered at a maximum rate of 3 mg/kg per hour over 1 to 3 hours.
Blood Products and Concentrated Electrolytes: Voriconazole must not be infused concomitantly with any blood product or any short-term infusion of concentrated electrolytes, even if the two infusions are running in separate intravenous lines (or cannulas). Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of voriconazole therapy (see Precautions).
Intravenous Solutions Containing (Non-Concentrated) Electrolytes: Voriconazole can be infused at the same time as other intravenous solutions containing (non-concentrated) electrolytes, but must be infused through a separate line.
Total Parenteral Nutrition (TPN): Voriconazole can be infused at the same time as total parenteral nutrition, but must be infused in a separate line. If infused through a multiple-lumen catheter, TPN needs to be administered using a different port from the one used for voriconazole (see Interactions).
Overdosage
In clinical trials there were three cases of accidental overdose. All occurred in pediatric patients who received up to five times the recommended intravenous dose of voriconazole. A single adverse event of photophobia of 10 minutes duration was reported.
There is no known antidote to voriconazole; it is recommended that treatment of overdose be symptomatic and supportive.
Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. In an overdose, hemodialysis may assist in the removal of voriconazole and SBECD from the body.
Contraindications
Voriconazole is contraindicated in patients with known hypersensitivity to voriconazole or to any of the excipients.
Co-administration of the CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide or quinidine with voriconazole is contraindicated since increased plasma concentrations of these medicinal products can lead to QTc prolongation and rare occurrences of Torsade de pointes (see Interactions).
Co-administration of voriconazole and sirolimus is contraindicated, since voriconazole has been shown to significantly increase plasma concentrations of sirolimus in healthy subjects (see Interactions).
Co-administration of voriconazole with rifabutin, rifampicin, carbamazepine and long-acting barbiturates (e.g., phenobarbital) is contraindicated since these medicinal products are likely to decrease plasma voriconazole concentrations significantly (see Interactions).
Co-administration of standard doses of voriconazole with efavirenz doses of 400 mg QD or higher is contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations (see Precautions; for lower doses, see Interactions).
Co-administration of voriconazole with high-dose ritonavir (400 mg and above twice daily) is contraindicated because ritonavir significantly decreased plasma voriconazole concentrations in healthy subjects at this dose (see Precautions; for lower doses, see Interactions).
Co-administration of ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates, is contraindicated since increased plasma concentrations of these medicinal products can lead to ergotism (see Interactions).
Co-administration of voriconazole with St John's Wort is contraindicated (see Interactions).
Special Precautions
Hypersensitivity: Caution should be used in prescribing voriconazole to patients with hypersensitivity to azoles.
Infusion-Related Reactions: Infusion-related reactions, predominantly flushing and nausea have been observed during administration of the intravenous formulation of voriconazole. Depending on the severity of symptoms, consideration should be given to stopping treatment (see Adverse Reactions).
Cardiac Adverse Events: Some azoles, including voriconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During clinical development and post-marketing surveillance, there have been rare cases of Torsade de pointes in patients taking voriconazole. These cases involve seriously ill patients with multiple confounding risk factors such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medications that may have been contributory. Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions, such as:  Congenital or acquired QT-prolongation; cardiomyopathy, in particular when heart failure is present; sinus bradycardia, existing symptomatic arrhythmias, concomitant medicinal product that is known to prolong QT interval (see Interactions).
Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be monitored and corrected, if necessary, prior to initiation of and during voriconazole therapy (see Dosage & Administration).
A study has been conducted in healthy volunteers which examined the effect on QT interval of single doses of voriconazole up to 4 times the usual daily dose. No subject in any group had an increase in QTc of ≥60 msec from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec (see Pharmacology: Pharmacodynamics under Actions).
Hepatic Toxicity: In clinical trials, there have been cases of serious hepatic reactions during treatment with voriconazole (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly hematological malignancy). Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction has usually been reversible on discontinuation of therapy.
Monitoring of Hepatic Function: Patients receiving voriconazole must be carefully monitored for hepatic toxicity. Clinical management should include laboratory evaluation of hepatic function (specifically AST and ALT) at the initiation of treatment with voriconazole and at least weekly for the first month of treatment. If treatment is continued, monitoring frequency can be reduced to monthly if there are no changes in the liver function tests.
If the liver function tests become markedly elevated, voriconazole should be discontinued, unless the medical judgment of the risk-benefit of the treatment for the patient justifies continued use (see Dosage & Administration).
Visual Adverse Events: There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema. These events occurred primarily in severely ill patients who had underlying conditions and/or concomitant medications which may have caused or contributed to these events (see Adverse Reactions).
Renal Adverse Events: Acute renal failure has been observed in severely ill patients undergoing treatment with voriconazole. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and have concurrent conditions that may result in decreased renal function.
Monitoring of Renal Function: Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine (see Dosage & Administration).
Monitoring of Pancreatic Function: Adults and children with risk factors for acute pancreatitis [e.g., recent chemotherapy, hematopoeitic stem cell transplantation (HSCT)], should be monitored for development of pancreatitis during voriconazole treatment.
Dermatological Adverse Events: Patients have rarely developed exfoliative cutaneous reactions such as, Stevens-Johnson syndrome, during treatment with voriconazole. If a patient develops an exfoliative cutaneous reaction, voriconazole should be discontinued.
In addition, voriconazole has been associated with photosensitivity skin reaction. It is recommended that patients, including children avoid exposure to direct sunlight during voriconazole treatment and use measures such as protective clothing and sunscreen with high sun protection factor (SPF).
Long-Term Treatment: The following severe adverse events have been reported in relation with long-term voriconazole treatment: Squamous Cell Carcinoma of the Skin (SCC): In patients with photosensitivity skin reactions and additional risk factors, squamous cell carcinoma of the skin and melanoma have been reported during long-term therapy. If phototoxic reactions occur, multidisciplinary advice should be sought and the patient should be referred to a dermatologist. Voriconazole discontinuation should be considered. Dermatologic evaluation should be performed on a systematic and regular basis, whenever voriconazole is continued despite the occurrence of phototoxicity-related lesions, to allow early detection and management of premalignant lesions.
If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, voriconazole discontinuation should be considered.
Non-Infectious Periostitis: Periostitis has been reported in transplant patients during long term voriconazole therapy. If a patient develops skeletal pain and radiologic findings compatible with periostitis, voriconazole should be discontinued.
Pediatric Use: Safety and effectiveness in pediatric subjects below the age of two years has not been established (see Pharmacology: Pharmacodynamics under Actions). Voriconazole is indicated for pediatric patients aged two years or older. A higher frequency of liver enzyme elevations was observed in the pediatric population (see Adverse Reactions). Hepatic function should be monitored in both children and adults. Oral bioavailability may be limited in pediatric patients 2 to 12 years with malabsorption and very low body weight for age. In that case, intravenous voriconazole administration is recommended.
The frequency of phototoxicity reactions is higher in the pediatric population. As an evolution towards SCC has been reported, stringent measures for the photoprotection are warranted in this population of patients. In children experiencing photoaging injuries such as lentigines or ephelides, sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation.
Everolimus (CYP3A4 Substrate, P-gp Substrate): Co-administration of voriconazole with everolimus is not recommended because voriconazole is expected to significantly increase everolimus concentrations. Currently there are insufficient data to allow dosing recommendations in this situation (see Interactions).
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibitor): Co-administration of oral voriconazole and oral fluconazole resulted in a significant increase in Cmax and AUCΤ of voriconazole in healthy subjects. The reduced dose and/or frequency of voriconazole and fluconazole that would eliminate this effect have not been established. Monitoring for voriconazole associated adverse events is recommended if voriconazole is used sequentially after fluconazole (see Interactions).
Efavirenz (CYP450 Inducer; CYP3A4 Inhibitor and Substrate): When voriconazole is co-administered with efavirenz the dose of voriconazole should be increased to 400 mg every 12 hours and that of efavirenz should be decreased to 300 mg every 24 hours (see Dosage & Administration, Contraindications and Interactions).
Phenytoin (CYP2C9 Substrate and Potent CYP450 Inducer): Careful monitoring of phenytoin levels is recommended when phenytoin is co-administered with voriconazole. Concomitant use of voriconazole and phenytoin should be avoided unless the benefit outweighs the risk (See Interactions).
Ritonavir (Potent CYP450 Inducer, CYP3A4 Inhibitor and Substrate): Co-administration of voriconazole and low dose ritonavir (100 mg twice daily) should be avoided unless an assessment of the benefit/risk justifies the use of voriconazole (see Interactions; for higher doses, see Contraindications).
Methadone (CYP3A4 Substrate): Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during co-administration. Dose reduction of methadone may be needed (see Interactions).
Short Acting Opiates (CYP3A4 Substrate): Reduction in the dose of alfentanil, fentanyl and other short acting opiates similar in structure to alfentanil and metabolized by CYP3A4 (e.g., sufentanil) should be considered when co-administered with voriconazole (see Interactions). As the half-life of alfentanil is prolonged in a 4-fold manner when alfentanil is co-administered with voriconazole and in an independent published study, concomitant use of voriconazole with fentanyl resulted in an increase in the mean AUC0-∞ of fentanyl by 1.4-fold, frequent monitoring for opiate-associated adverse events (including a longer respiratory monitoring period) may be necessary.
Long Acting Opiates (CYP3A4 Substrate): Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 (e.g., hydrocodone) should be considered when co-administered with voriconazole. Frequent monitoring for opiate-associated adverse events may be necessary (see Interactions).
Effects on Ability to Drive and Use Machines: Voriconazole may cause transient and reversible changes to vision, including blurring, altered/enhanced visual perception, and/or photophobia. Patients must avoid potentially hazardous tasks, such as driving or operating machinery while experiencing these symptoms. Patients should not drive at night while taking voriconazole.
Fertility: In an animal study, no impairment of fertility was demonstrated in male and female rats (See Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Use In Pregnancy & Lactation
Use in Pregnancy: No adequate information on the use of voriconazole in pregnant women is available.
Studies in animals have shown reproductive toxicity at high doses (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). The potential risk to humans is unknown.
Voriconazole must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the fetus.
Women of Child-Bearing Potential: Women of child-bearing potential must always use effective contraception during treatment.
Use in Lactation: The excretion of voriconazole into breast milk has not been investigated. Breastfeeding must be stopped on initiation of treatment with voriconazole.
Adverse Reactions
The safety profile of voriconazole in adults is based on an integrated safety database of more than 2,000 subjects (1,603 adult patients in therapeutic studies). This represents a heterogeneous population, containing patients with hematological malignancy, HIV infected patients with esophageal candidiasis and refractory fungal infections, non-neutropenic patients with candidemia or aspergillosis and healthy volunteers.
In addition, the safety of voriconazole was investigated in 279 patients (including 270 adults) who were treated with voriconazole in prophylaxis studies. The adverse event profile in these prophylaxis studies was similar to the established safety profile from 2,000 subjects in voriconazole clinical trials.
Table 8 includes all causality adverse reactions in 1,873 adults from pooled therapeutic (1,603) and prophylaxis (270) studies. The most commonly reported adverse events were visual impairment, liver function test abnormal, pyrexia, rash, vomiting, nausea, diarrhea, headache, peripheral edema and abdominal pain. The severity of the adverse events was generally mild to moderate. No clinically significant differences were seen when the safety data were analyzed by age, race, or gender. (See Table 8.)

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Visual Impairments: In clinical trials, visual impairments (including blurred vision, photophobia, chloropsia, chromatopsia, color blindness, cyanopsia, eye disorder, halo vision, night blindness, oscillopsia, photopsia, scintillating scotoma, visual acuity reduced, visual brightness, visual field defect, vitreous floaters, and xanthopsia) with voriconazole were very common.
These visual impairments were transient and full reversible, with the majority spontaneously resolving within 60 minutes. There was evidence of attenuation with repeated doses of voriconazole. The visual impairment were generally mild, rarely resulted in discontinuation and were not associated with long-term sequelae. Visual impairments may be associated with higher plasma levels and/or doses.
There have been post-marketing reports of prolonged visual adverse events (see Precautions).
The mechanism of action is unknown, although the site of action is most likely to be within the retina.
In a study in healthy volunteers investigating the impact of voriconazole on retinal function, voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude. The ERG measures electrical currents in the retina. The ERG changes did not progress over 29 days of administration and were fully reversible on withdrawal of voriconazole.
The long-term effect of voriconazole (median 169 days; range 5-353 days) on visual function was evaluated in subjects with paracoccidioidomycosis. Voriconazole had no clinically relevant effect on visual function as assessed by testing of visual acuity, visual fields, color vision and contrast sensitivity. There were no signs of retinal toxicity. 17/35 voriconazole subjects experienced visual adverse events. These events did not lead to discontinuation, were generally mild, occurred during the first week of therapy and resolved during continued voriconazole therapy.
Dermatological Reactions: Dermatological reactions were common in patients treated with voriconazole in clinical trials, but these patients had serious underlying diseases and were receiving multiple concomitant medications. The majority of rashes were of mild to moderate severity. Patients have developed serious cutaneous reactions, including Stevens-Johnson syndrome (uncommon), toxic epidermal necrolysis (rare) and erythema multiforme (rare) during treatment with voriconazole.
If patients develop a rash they should be monitored closely and voriconazole discontinued if lesions progress. Patients receiving long-term voriconazole therapy have developed photosensitive skin reactions (see Precautions).
Dermatological adverse reactions potentially related to phototoxicity (pseudoporphyria, cheilitis, and cutaneous lupus erythematosus) are also reported with voriconazole. Sun avoidance and photoprotection are recommended for all patients. If phototoxicity occurs, voriconazole discontinuation and dermatological evaluation should be considered (see Precautions).
Liver Function Test: The overall incidence of transaminase increases >3 x ULN (not necessarily comprising an adverse event) in the voriconazole clinical program was 18.0% (319/1,768) in adults and 25.8% (73/283) in pediatric subjects who received voriconazole for pooled therapeutic and prophylaxis use. Liver function test abnormalities may be associated with higher plasma levels and/or doses. The majority of abnormal liver function tests either resolved during treatment without dose adjustment or following dose adjustment, including discontinuation of therapy. Voriconazole has been associated with cases of serious hepatic toxicity, in patients with other serious underlying conditions. This includes cases of jaundice, hepatitis and hepatic failure leading to death.
Pediatric Use:
The safety of voriconazole was investigated in 288 pediatric patients aged 2 to <12 years (169) and 12 to <18 years (119) who received voriconazole for prophylaxis (183) and therapeutic use (105). The adverse event profile in these 288 pediatric patients was similar to that in adults. A higher frequency of liver enzyme elevations reported as adverse events (14.2% transaminases increased in pediatrics compared to 5.3% in adults) was observed in pediatric patients as compared to adults. The safety of voriconazole was investigated in additional pediatric patients aged 2 to <12 years who were observed in compassionate use programs (158 pediatric patients). The adverse event profile in these pediatric patients was similar to that observed in adults.
Post-marketing data suggest there might be a higher occurrence of skin reactions in the pediatric population compared to adults.
There have been post-marketing reports of pancreatitis in pediatric patients.
Infusion-Related Reactions: During infusion of the intravenous formulation of voriconazole in healthy subjects, anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus and rash have occurred. Symptoms appeared immediately upon initiating the infusion (see Precautions).
Drug Interactions
Voriconazole is metabolised by, and inhibits the activity of, cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively, and there is potential for voriconazole to increase the plasma concentrations of substances metabolized by these CYP450 isoenzymes.
Unless otherwise specified, drug interaction studies have been performed in healthy adult male subjects using multiple dosing to steady state with oral voriconazole at 200 mg twice daily (BID). These results are relevant to other populations and routes of administration.
Voriconazole should be administered with caution in patients with concomitant medication that is known to prolong QT interval. When there is also potential for voriconazole to increase plasma concentrations of substances metabolized by CYP3A4 isoenzymes (certain antihistamines, quinidine, cisapride, pimozide) co-administration is contraindicated (see Contraindications).
Interaction Table: Interactions between voriconazole and other medicinal products are listed in Tables 9a, 9b and 9c (once daily as "QD", twice daily as "BID", three times daily as "TID" and not determined as "ND"). The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of geometric mean ratio being within (↔), below (↓) or above (↑) the 80-125% range. The asterisk (*) indicates a two-way interaction. AUCτ, AUCt and AUC0-∞ represent an area under the curve over a dosing interval, from time zero to the time with detectable measurement and from time zero to infinity, respectively.
The interactions in Tables 9a, 9b and 9c are presented in the following order: Contraindications, those requiring dose adjustment and careful clinical and/or biological monitoring, and finally those that have no significant pharmacokinetic interaction but may be of clinical interest in this therapeutic field. (See Tables 9a, 9b and 9c).

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Caution For Usage
Special Precautions for Disposal and Other Handling: Film-Coated Tablet: Not applicable.
Powder for Oral Suspension: Constitution Instructions: Tap the bottle to release the powder.
A total of 46 mL of water should be added to the bottle: Measure 23 mL of water by filling the measuring cup to the top of the marked line. Add the water to the bottle. Using the cup measure another 23 mL of water and add this to the bottle. Shake the closed bottle vigorously for about 1 minute. Remove child-resistant cap. Press bottle adaptor into the neck of the bottle. Replace the cap. Write the date of expiration of the constituted suspension on the bottle label (the shelf-life of the constituted suspension is 14 days).
Instructions for Use: Shake the closed bottle of constituted suspension for approximately 10 seconds before each use. Once constituted, VFEND oral suspension should only be administered using the oral syringe supplied with each pack.
Powder for Solution for Infusion: Voriconazole is supplied in single use vials. The vial contents are reconstituted with 19 mL of Water for Injections to obtain a clear solution containing 10 mg/mL of voriconazole and an extractable volume of 20 mL. Discard the vial if vacuum does not pull the diluent into the vial. For administration, the required volume of the reconstituted solution is added to a recommended compatible infusion solution to obtain, where appropriate, a final voriconazole solution containing 0.5-5 mg/mL. (See Table 10).
Dilution: Voriconazole must be infused over 1-2 hours, at a concentration of 5 mg/mL or less.
Therefore, the required volume of the 10 mg/mL voriconazole concentrate should be further diluted as follows (appropriate diluents as follows): Calculate the volume of 10 mg/mL voriconazole concentrate required based on the patient's weight (see Table 10).
In order to allow the required volume of voriconazole concentrate to be added, withdraw and discard at least an equal volume of diluent from the infusion bag or bottle to be used.
The volume of diluent remaining in the bag or bottle should be such that when the 10 mg/mL voriconazole concentrate is added, the final concentration is not less than 0.5 mg/mL nor greater than 5 mg/mL.
Using a suitable size syringe and aseptic technique, withdraw the required volume of voriconazole concentrate from the appropriate number of vials and add to the infusion bag or bottle. Discard partially used vials.
The final voriconazole solution must be infused over 1-2 hours at a maximum rate of 3 mg/kg per hour.

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Voriconazole is a single dose unpreserved sterile lyophile. Therefore, from a microbiological point of view, the product must be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.
The reconstituted solution can be diluted with: 0.9% sodium chloride intravenous infusion, compound sodium lactate intravenous infusion, 5% glucose and compound sodium lactate intravenous infusion, 5% glucose and 0.45% sodium chloride intravenous infusion, 5% glucose intravenous infusion, 5% glucose in 20 mEq potassium chloride intravenous infusion, 0.45% sodium chloride intravenous infusion, 5% glucose and 0.9% sodium chloride intravenous infusion.
The compatibility of voriconazole with diluents other than described previously or in Incompatibilities as follows is unknown.
Incompatibilities: Film-Coated Tablet: Not applicable.
Powder for Oral Suspension: Voriconazole powder for oral suspension and the 40 mg/mL reconstituted oral suspension should not be mixed with any other medication or additional flavoring agent. It is not intended that the suspension be further diluted with water or other vehicles.
Powder for Solution for Infusion: Blood Products and Concentrated Electrolytes: Voriconazole must not be infused concomitantly with any blood product or any short-term infusion of concentrated electrolytes, even if the two infusions are running in separate intravenous lines (or cannulas). Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of voriconazole therapy (see Dosage & Administration and Precautions).
Intravenous Solutions Containing (Non-Concentrated) Electrolytes: Voriconazole can be infused at the same time as other intravenous solutions containing (non-concentrated) electrolytes, but must be infused through a separate line.
Total Parenteral Nutrition (TPN): Voriconazole can be infused at the same time as total parenteral nutrition, but must be infused in a separate line. If infused through a multiple-lumen catheter, TPN needs to be administered using a different port from the one used for voriconazole.
Voriconazole must not be diluted with 4.2% Sodium Bicarbonate Infusion. Compatibility with other concentrations is unknown.
This medicinal product must not be mixed with other medicinal products except those mentioned previously.
Storage
Film-Coated Tablet: Store below 25°C.
Powder for Oral Suspension: Store at 2°C-8°C (in a refrigerator) before constitution.
Constituted Suspension: Do not store above 30°C, do not refrigerate or freeze.
Keep the container tightly closed.
Any remaining suspension should be discarded 14 days after constitution.
The shelf-life of the constituted suspension is 14 days.
Powder for Solution for Infusion: Store at or below 30°C.
Shelf-Life After Reconstitution: 24 hours when stored at 2°C-8°C (36°F-46°F).
MIMS Class
ATC Classification
J02AC03 - voriconazole ; Belongs to the class of triazole derivatives. Used in the systemic treatment of mycotic infections.
Presentation/Packing
FC tab 50 mg (white, round, debossed "Pfizer" on one side and "VOR50" on the reverse) x 10's. 200 mg (white, capsule-shaped, debossed "Pfizer" on one side and "VOR200" on the reverse) x 10's. Powd for oral susp (white to off-white powd providing a white to off-white orange-flavored susp when constituted) 40 mg/mL x 70 mL. Powd for soln for infusion (white lyophilized powd in vial) 200 mg x 1's.
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