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VFEND

voriconazole

Manufacturer:

Pfizer
The information highlighted (if any) are the most recent updates for this brand.
Full Prescribing Info
Contents
Voriconazole.
Description
Each film-coated tablet also contains the following inactive ingredients: Tablet Core: Lactose monohydrate, pregelatinized starch, croscarmellose sodium, povidone, magnesium stearate Film-Coating: Hydroxypropyl methylcellulose, titanium dioxide, lactose monohydrate and triacetin.
The vial also contains sulfobutylether β-cyclodextrin sodium 3200 mg.
Upon reconstitution with water for injections, it produces a solution of 10 mg/mL Vfend and 160 mg/mL of sulfobutyl ether β-cyclodextrin sodium. The resultant solution is further diluted prior to administration as an IV infusion (see Dosage & Administration).
Voriconazole is (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol. It has an empirical formula of C16H14F3N5O and a molecular weight of 349.3.
Voriconazole is a white to light-colored powder.
Action
Pharmacology: Voriconazole is a triazole antifungal agent. The primary mode of action of voriconazole is the inhibition of fungal cytochrome P-450 (CYP450) mediated 14α-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14α-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell wall and may be responsible for the antifungal activity of voriconazole. Voriconazole has been shown to be more selective for fungal CYP450 enzymes than for various mammalian CYP450 enzyme systems.
Clinical Studies: Voriconazole administered orally or parenterally, has been evaluated as primary or salvage therapy in 520 patients ≥12 years with infections caused by Aspergillus spp, Fusarium spp and Scedosporium spp.
Invasive Aspergillosis: Voriconazole was studied in patients for primary therapy of invasive aspergillosis (randomized controlled study 307/602), for primary therapy and salvage therapy of aspergillosis (noncomparative study 304) and for treatment of patients with invasive aspergillosis who were refractory to, or intolerant of, other antifungal therapy (noncomparative study 309/604).
Study 307/602: The efficacy of voriconazole compared to amphotericin B in the primary treatment of acute invasive aspergillosis was demonstrated in 277 patients treated for 12 weeks in Study 307/602. The majority of study patients had underlying hematologic malignancies, including bone marrow transplantation. The study also included patients with solid organ transplantation, solid tumors and AIDS. The patients were mainly treated for definite or probable invasive aspergillosis of the lungs. Other aspergillosis infections included disseminated disease, CNS infections and sinus infections. Diagnosis of definite or probable invasive aspergillosis was made according to criteria modified from those established by the National Institute of Allergy and Infectious Diseases Mycoses Study Group/European Organization for Research and Treatment of Cancer (NIAID MSG/EORTC).
Voriconazole was administered IV with a loading dose of 6 mg/kg every 12 hrs for the first 24 hrs followed by a maintenance dose of 4 mg/kg every 12 hrs for a minimum of 7 days. Therapy could then be switched to the oral formulation at a dose of 200 mg every 12 hrs. Median duration of voriconazole IV therapy was 10 days (range 2-90 days). After voriconazole IV therapy, the median duration of oral voriconazole therapy was 76 days (range 2-232 days).
Patients in the comparator group received conventional amphotericin B as a slow infusion at a daily dose of 1-1.5 mg/kg/day. Median duration of amphotericin IV therapy was 12 days (range 1-85 days). Treatment was then continued with other licensed antifungal therapy (OLAT), including itraconazole and lipid amphotericin B formulations. Although initial therapy with conventional amphotericin B was to be continued for at least 2 weeks, actual duration of therapy was at the discretion of the investigator. Patients who discontinued initial randomized therapy due to toxicity or lack of efficacy were eligible to continue in the study with OLAT treatment.
A satisfactory global response at 12 weeks (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 32% of amphotericin B-treated patients (see Table 1). A benefit of voriconazole compared to amphotericin B on patient survival at Day 84 was seen with a 71% survival rate on voriconazole compared to 58% on amphotericin B (see Table 1).
Table 1 also summarizes the response (success) based on mycological confirmation and species.


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Study 304: The results of this comparative trial (Study 307/602) confirmed the results of an earlier trial in the primary and salvage treatment of patients with acute invasive aspergillosis (Study 304). In this earlier study, an overall success rate of 52% (26/50) was seen in patients treated with voriconazole for primary therapy. Success was seen in 17/29 (59%) with Aspergillus fumigatus infections and 3/6 (50%) patients with infections due to non-fumigatus species [A. flavus (1/1); A. nidulans (0/2); A. niger (2/2); A. terreus (0/1)]. Success in patients who received voriconazole as salvage therapy is presented in Table 2.
Study 309/604: Additional data regarding response rates in patients who were refractory to, or intolerant of, other antifungal agents are also provided in Table 2. Overall mycological eradication for culture-documented infections due to fumigatus and non-fumigatus species of Aspergillus was 36/82 (44%) and 12/30 (40%), respectively, in voriconazole-treated patients. Patients had various underlying diseases and species other than A. fumigatus contributed to mixed infections in some cases.
For patients who were infected with a single pathogen and were refractory to, or intolerant of, other antifungal agents, the satisfactory response rates for voriconazole in Studies 304 and 309/604 are presented in Table 2.


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Nineteen (19) patients had >1 species of Aspergillus isolated. Success was seen in 4/17 (24%) of these patients.
Other Serious Fungal Pathogens: In pooled analyses of patients, voriconazole was shown to be effective against the following additional fungal pathogen.
Scedosporium apiospermum: Successful response to voriconazole therapy was seen in 15 of 24 patients (63%). Three (3) of these patients relapsed within 4 weeks, including 1 patient with pulmonary, skin and eye infections, 1 patient with cerebral disease, and 1 patient with skin infection. Ten (10) patients had evidence of cerebral disease and 6 of these had a successful outcome (1 relapse). In addition, a successful response was seen in 1 of the 3 patients with mixed organism infections.
Fusarium spp: Nine (9) of 21 (43%) patients were successfully treated with voriconazole. Of these 9 patients, 3 had eye infections, 1 had an eye and blood infection, 1 had a skin infection, 1 had a blood infection alone, 2 had sinus infections, and 1 had disseminated infection (pulmonary, skin, hepatosplenic). Three (3) of these patients (1 with disseminated disease, 1 with an eye infection and 1 with a blood infection) had Fusarium solani and were complete successes. Two (2) of these patients relapsed, 1 with a sinus infection and profound neutropenia and 1 postsurgical patient with blood and eye infections.
Microbiology: In vitro and In vivo Activity: Voriconazole has demonstrated in vitro activity against Aspergillus fumigatus isolates as well as A. flavus, A. niger and A. terreus. Variable in vitro activity against Scedosporium apiospermum and Fusarium spp, including Fusarium solani, has been seen. Most of the speciated isolates from clinical studies were Aspergillus fumigatus but clinical efficacy was also seen in a small number of species other than A. fumigatus (see Indications and Clinical Studies: Invasive Aspergillosis).
In vitro susceptibility testing was performed according to the National Committee for Clinical Laboratory Standards (NCCLS) proposed method (M38-P). Voriconazole breakpoints have not been established for any fungi. The relationship between clinical outcome and in vitro susceptibility results remains to be elucidated.
Voriconazole has demonstrated in vivo activity in normal and immunocompromised guinea pigs with established systemic A. fumigatus infections in which the endpoints were prolonged survival of infected animals and reduction of mycological burden from target organs. Activity has also been shown in immunocompromised guinea pigs with pulmonary A. fumigatus infections. Voriconazole demonstrated activity in immunocompromised guinea pigs with systemic infections produced by an A. fumigatus isolate with reduced susceptibility to itraconazole (itraconazole MIC 3.1 mcg/mL). The exact mechanism of resistance was not identified for that particular isolate. In 1 experiment, voriconazole exhibited activity against Scedosporium apiospermum infections in immune competent guinea pigs.
Drug Resistance: Voriconazole drug resistance development has not been adequately studied in vitro against the filamentous fungi, including Aspergillus, Scedosporium and Fusarium spp. The frequency of drug resistance development for the various fungi for which this drug is indicated is not known.
Fungal isolates exhibiting reduced susceptibility to fluconazole or itraconazole may also show reduced susceptibility to voriconazole, suggesting cross-resistance can occur among these azoles. The relevance of cross-resistance and clinical outcome has not been fully characterized. Clinical cases where azole cross-resistance is demonstrated may require alternative antifungal therapy.
Pharmacokinetics: The pharmacokinetics of voriconazole have been characterized in healthy subjects, special populations and patients.
The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. The interindividual variability of voriconazole pharmacokinetics is high. Greater than proportional increase in exposure is observed with increasing dose. It is estimated that, on average, increasing the oral dose in healthy subjects from 200-300 mg every 12 hrs leads to a 2.5-fold increase in exposure (AUCτ) while increasing the IV dose from 3-4 mg/kg every 12 hrs produces a 2.3-fold increase in exposure (see Table 3).


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During oral administration of 200 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 were similar to those observed in healthy subjects (see Table 4).


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Sparse plasma sampling for pharmacokinetics was conducted in the therapeutic studies in patients 12-18 years. In 11 adolescent patients who received a mean voriconazole maintenance dose of 4 mg/kg IV, the median of the calculated mean plasma concentrations was 1.6 mcg/mL (inter-quartile range 0.28-2.73 mcg/mL). In 17 adolescent patients for whom mean plasma concentrations were calculated following a mean oral maintenance oral dose of 200 mg every 12 hrs, the median of the calculated mean plasma concentrations was 1.16 mcg/mL (inter-quartile range 0.85-2.14 mcg/mL).
When the recommended IV or oral loading dose regimens are administered to healthy subjects, peak plasma concentrations close to steady state are achieved within the first 24 hrs of dosing. Without the loading dose, accumulation occurs during twice daily multiple dosing with steady-state peak plasma voriconazole concentrations being achieved by day 6 in the majority of subjects (see Table 5).


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Steady-state trough plasma concentrations with voriconazole are achieved after approximately 5 days of oral or IV dosing without a loading dose regimen. However, when an IV loading dose regimen is used, steady-state trough plasma concentrations are achieved within the day.
Absorption: The pharmacokinetic properties of voriconazole are similar following administration by the IV and oral routes. Based on a population pharmacokinetic analysis of pooled data in healthy subjects (N=207), the oral bioavailability of voriconazole is estimated to be 96% (CV 13%). Bioequivalence was established between the 200 mg tablet and the 40 mg/mL oral suspension when administered as a 400 mg every 12 hrs loading dose followed by a 200 mg every 12 hrs maintenance dose.
Maximum plasma concentrations (Cmax) are achieved 1-2 hrs after dosing. When multiple doses of voriconazole are administered with high fat meals, the mean Cmax and AUCτ are reduced by 34% and 24%, respectively (see Dosage & Administration).
In healthy subjects, the absorption of voriconazole is not affected by co-administration of oral ranitidine, cimetidine, or omeprazole, drugs that are known to increase 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% and was shown to be independent of plasma concentrations achieved following single and multiple oral doses of 200 or 300 mg (approximate range: 0.9-15 mcg/mL). Varying degrees of hepatic and renal insufficiency do not affect the protein-binding of voriconazole.
Metabolism: In vitro studies showed that voriconazole is metabolized by the human hepatic CYP450 enzymes, CYP2C19, CYP2C9 and CYP3A4 (see Effects of Other Drugs on Voriconazole as follows).
In vivo studies indicated that CYP2C19 is significantly involved 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 (AUCτ) than their homozygous extensive metabolizers 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 radiolabeled metabolites in plasma. Since this metabolite has minimal antifungal activity, it does not contribute to the overall efficacy of voriconazole.
Excretion: Voriconazole is eliminated via hepatic metabolism with <2% of the dose excreted unchanged in the urine.
After administration of a single radiolabeled dose of either oral or IV voriconazole, preceded by multiple oral or IV dosing, approximately 80-83% of the radioactivity is recovered in the urine. The majority (>94%) of that total radioactivity is excreted in the first 96 hrs after both oral and IV dosing.
As a result of non-linear pharmacokinetics, the terminal half-life of voriconazole is dose-dependent and therefore not useful in predicting the accumulation or elimination of voriconazole.
Pharmacokinetic-Pharmacodynamic Relationships: In 10 clinical trials, the median values for the average and maximum voriconazole plasma concentrations in individual patients across these studies (N=1121) were 2.51 mcg/mL (inter-quartile range 1.21-4.44 mcg/mL) and 3.79 mcg/mL (inter-quartile range 2.06-6.31 mcg/mL), respectively. A pharmacokinetic-pharmacodynamic analysis of patient data from 6 of these 10 clinical trials (N=280) could not detect a positive association between mean, maximum or minimum plasma voriconazole concentration and efficacy. However, PK/PD analyses of the data from all 10 clinical trials identified positive associations between plasma voriconazole concentrations and rate of both liver function test abnormalities and visual disturbances (see Adverse Reactions).
Pharmacokinetics in Special Patient Groups: Gender: In a multiple oral dose study, the mean Cmax and AUCτ for healthy young females were 83% and 113% higher, respectively, than in healthy young males (18-45 years). In the same study, no significant differences in the mean Cmax and AUCτ were observed between healthy elderly males and healthy elderly females (≥65 years).
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.
Geriatric: In an oral multiple dose study, the mean Cmax and AUCτ in healthy elderly males (≥65 years) were 61% and 86% higher, respectively, than in young males (18-45 years). No significant differences in the mean Cmax and AUCτ were observed between healthy elderly females (≥65 years) and healthy young females (18-45 years).
In the clinical program, no dosage adjustment was made on the basis of age. An analysis of pharmacokinetic data obtained from 552 patients from 10 voriconazole clinical trials showed that the median voriconazole plasma concentrations in the elderly patients (>65 years) were approximately 80-90% higher than those in the younger patients (≤65 years) after either IV or oral administration. However, the safety profile of voriconazole in young and elderly patients was similar and therefore, no dosage adjustment is necessary for the elderly.
Pediatric: The recommended IV dose in pediatric patients is based on a population pharmacokinetic analysis of data pooled from 82 immunocompromised pediatric patients aged 2 to <12 years who were evaluated in three pharmacokinetic studies (examining single IV doses of 3 and 4 mg/kg twice daily, multiple IV doses of 3, 4, 6 and 8 mg/kg twice daily and multiple oral suspension doses of 4 and 6 mg/kg twice daily). The majority of patients received >1 dose level with a maximum duration of dosing of 30 days. A comparison of the pediatric and adult population pharmacokinetic data indicated that in order to obtain comparable exposures to those obtained in adults following intravenous maintenance doses of 4 mg/kg twice daily, intravenous maintenance doses of 7 mg/kg twice daily are required in pediatric patients.
The higher IV 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. In order to obtain comparable exposures to those obtained in adults following IV maintenance doses of 3 mg/kg twice daily, IV maintenance doses of 4 mg/kg twice daily are required in pediatric patients. Based on the population pharmacokinetic analysis, no loading dose or dosage adjustment according to age is warranted in patients aged 2 to <12 years.
The recommended oral dose in pediatrics is based on a population pharmacokinetic analysis data obtained from 47 immunocompromised pediatric patients aged 2 to <12 years who were evaluated in a pharmacokinetic study examining multiple oral suspension doses of 4-6 mg/kg twice daily. A comparison of the pediatric and adult population pharmacokinetic data indicated that in order to obtain comparable exposures to those obtained in adults following a maintenance dose of 200 mg twice daily, the same dose of 200 mg of oral solution twice daily is required in pediatric patients, independent of body weight. In pediatric patients there is a general trend towards low bioavailability at lower body weights and high bioavailability at higher body weights (towards the extent demonstrated in adults). Based on the population pharmacokinetic analysis, no dosage adjustment according to age or weight is warranted in patients aged 2 to <12 years at the 200 mg bid oral solution dosing regimen. A loading dose is not indicated in pediatric patients. Oral bioavailability may however be limited in pediatric patients with malabsorption and very low body weight for their age. In that case, IV voriconazole administration is recommended.
Hepatic Insufficiency: After a single oral dose (200 mg) of voriconazole in 8 patients with mild (Child-Pugh class A) and 4 patients with moderate (Child-Pugh class B) hepatic insufficiency, the mean systemic exposure (AUC) was 3.2-fold higher than in age and weight matched controls with normal hepatic function. There was no difference in mean peak plasma concentrations (Cmax) between the groups. When only the patients with mild (Child-Pugh class A) hepatic insufficiency were compared to controls, there was still a 2.3-fold increase in the mean AUC in the group with hepatic insufficiency compared to controls.
In an oral multiple dose study, AUCτ was similar in 6 subjects with moderate hepatic impairment (Child-Pugh class B) given a lower maintenance dose of 100 mg twice daily compared to 6 subjects with normal hepatic function given the standard 200 mg twice daily maintenance dose. The mean peak plasma concentrations (Cmax) were 20% lower in the hepatically-impaired group.
It is recommended that the standard loading dose regimens be used but the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh class A and B) receiving voriconazole. No pharmacokinetic data are available for patients with severe hepatic cirrhosis (Child-Pugh class C) (see Dosage & Administration).
Renal Insufficiency: In a single oral dose (200 mg) study in 24 subjects with normal renal function and mild to severe renal impairment, systemic exposure (AUC) and peak plasma concentration (Cmax) of voriconazole were not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment.
In a multiple dose study of IV voriconazole (6 mg/kg IV loading dose x 2, then 3 mg/kg IV x 5.5 days) in 7 patients with moderate renal dysfunction [creatinine clearance (CrCl) 30-50 mL/min], the systemic exposure (AUC) and peak plasma concentrations (Cmax) were not significantly different from those in 6 volunteers with normal renal function.
However, in patients with moderate renal dysfunction (CrCl 30-50 mL/min), accumulation of the IV vehicle, SBECD, occurs. The mean systemic exposure (AUC) and peak plasma concentrations (Cmax) of SBECD were increased by 4-fold and almost 50%, respectively, in the moderately impaired group compared to normal control group.
IV voriconazole should be avoided in patients with moderate or severe renal impairment (CrCl <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of IV voriconazole (see Dosage & Administration).
A pharmacokinetic study in subjects with renal failure undergoing hemodialysis showed that voriconazole is dialyzed with clearance of 121 mL/min. The IV vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hr hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.
Drug Interactions: Effects of Other Drugs on Voriconazole: Voriconazole is metabolized by the human hepatic CYP450 enzymes CYP2C19, CYP2C9 and CYP3A4. Results of in vitro metabolism studies indicate that the affinity of voriconazole is highest for CYP2C19, followed by CYP2C9, and is appreciably lower for CYP3A4. Inhibitors or inducers of these 3 enzymes may increase or decrease voriconazole systemic exposure (plasma concentrations), respectively.
Concomitant use of the following agents with voriconazole is contraindicated: St. John's wort (CYP450 inducer; P-gp inducer): In an independent published study in healthy volunteers, St. John's wort exhibited a short initial inhibitory effect followed by induction of voriconazole metabolism. Therefore, concomitant use of voriconazole with St. John's wort is contraindicated.
The systemic exposure to voriconazole is significantly reduced or is expected to be reduced by the concomitant administration of the following agents and their use if contraindicated:
Rifampin (Potent CYP450 Inducer): Rifampin (600 mg once daily) decreased the steady-state Cmax and AUCτ of voriconazole (200 mg every 12 hrs for 7 days) by an average of 93% and 96%, respectively, in healthy subjects. Doubling the dose of voriconazole to 400 mg every 12 hrs does not restore adequate exposure to voriconazole during co-administration with rifampin. Co-administration of voriconazole and rifampin is contraindicated (see Contraindications and Interactions).
Ritonavir (Potent CYP450 Inducer; CYP3A4 Inhibitor and Substrate): The effect of the co-administration of oral voriconazole (200 mg twice daily) and high dose (400 mg) and low dose (100 mg) oral ritonavir was investigated in 2 separate studies in healthy volunteers. High doses of ritonavir (400 mg twice daily) decreased the steady state Cmax and AUCτ of oral voriconazole by an average of 66% and 82%, whereas low doses of ritonavir (100 mg every 12 hrs for 9 days) decreased the steady state Cmax and AUCτ of oral voriconazole (400 mg every 12 hrs for 1 day, then 200 mg every 12 hrs for 8 days) by an average of 24% and 39% respectively, in healthy subjects. Administration of voriconazole did not have a significant effect on mean Cmax and AUCτ of ritonavir in the high dose study, although a minor decrease in steady state Cmax and AUCτ of ritonavir with an average of 25% and 13%, respectively, was observed in the low dose ritonavir interaction study. One outlier subject with raised voriconazole levels was identified in each of the ritonavir interaction studies. Co-administration of voriconazole and high doses of ritonavir (400 mg and above twice daily) is contraindicated.
Co-administration of voriconazole and low dose ritonavir (100 mg twice daily) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Carbamazepine and Long-Acting Barbiturates (Potent CYP450 Inducers): Although not studied in vitro or in vivo, carbamazepine and long-acting barbiturates (eg, phenobarbital, mephobarbital) are likely to significantly decrease plasma voriconazole concentrations. Co-administration of voriconazole with carbamazepine or long-acting barbiturates is contraindicated (see Contraindications and Interactions).
Minor or significant pharmacokinetic interactions that do not require dosage adjustment:
Cimetidine (Nonspecific CYP450 Inhibitor and Increases Gastric pH): Cimetidine (400 mg every 12 hrs for 8 days) increased voriconazole steady-state Cmax and AUCτ by an average of 18% (90% CI: 6%, 32%) and 23% (90% CI: 13%, 33%), respectively, following oral doses of 200 mg every 12 hrs for 7 days to healthy subjects.
Ranitidine (Increases Gastric pH): Ranitidine (150 mg every 12 hrs) had no significant effect on voriconazole Cmax and AUCτ following oral doses of 200 mg every 12 hrs for 7 days to healthy subjects.
Macrolide Antibiotics: Co-administration of erythromycin (CYP3A4 inhibitor; 1 g every 12 hrs for 7 days) or azithromycin (500 mg once daily for 3 days) with voriconazole 200 mg every 12 hrs for 14 days had no significant effect on voriconazole steady-state Cmax and AUCτ in healthy subjects. The effects of voriconazole on the pharmacokinetics of either erythromycin or azithromycin are not known.
Effects of Voriconazole on Other Drugs: In vitro studies with human hepatic microsomes show that voriconazole inhibits the metabolic activity of the CYP450 enzymes CYP2C19, CYP2C9 and CYP3A4. In these studies, the inhibition potency of voriconazole for CYP3A4 metabolic activity was significantly less than that of 2 other azoles, ketoconazole and itraconazole. In vitro studies also show that the major metabolite of voriconazole, voriconazole N-oxide, inhibits the metabolic activity of CYP2C9 and CYP3A4 to a greater extent than that of CYP2C19. Therefore, there is potential for voriconazole and its major metabolite to increase the systemic exposure (plasma concentrations) of other drugs metabolized by these CYP450 enzymes.
Voriconazole should be administered with caution in patients receiving concomitant medication that is known to prolong QT interval. When there is also a potential for voriconazole to increase the plasma levels of substances metabolized by CYP3A4 isoenzymes (eg, certain antihistamines, quinidine, cisapride, pimozide) co-administration is contraindicated.
The systemic exposure of the following drugs is significantly increased or is expected to be significantly increased by co-administration of voriconazole and their use is contraindicated:
Sirolimus (CYP3A4 Substrate): Repeat dose administration of oral voriconazole (400 mg every 12 hrs for 1 day, then 200 mg every 12 hrs for 8 days) increased the Cmax and AUC of sirolimus (2 mg single dose) an average of 7-fold (90% CI: 5.7, 7.5) and 11-fold (90% CI: 9.9, 12.6), respectively, in healthy subjects. Co-administration of voriconazole and sirolimus is contraindicated (see Contraindications and Interactions).
Terfenadine, Astemizole, Cisapride, Pimozide and Quinidine (CYP3A4 Substrates): Although not studied in vitro or in vivo, concomitant administration of voriconazole with terfenadine, astemizole, cisapride, pimozide or quinidine may result in inhibition of the metabolism of these drugs. Increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of torsade de pointes. Co-administration of voriconazole and terfenadine, astemizole, cisapride, pimozide and quinidine is contraindicated (see Contraindications and Interactions).
Ergot Alkaloids: Although not studied in vitro or in vivo, voriconazole may increase the plasma concentration of ergot alkaloids (ergotamine and dihydroergotamine) and lead to ergotism. Co-administration of voriconazole with ergot alkaloids is contraindicated (see Contraindications and Interactions).
Co-administration of voriconazole with the following agents results in increased exposure or is expected to result in increased exposure to these drugs. Therefore, careful monitoring and/or dosage adjustment of these drugs is needed: Cyclosporine (CYP3A4 Substrate): In stable, renal transplant recipients receiving chronic cyclosporine therapy, concomitant administration of oral voriconazole (200 mg every 12 hrs for 8 days) increased cyclosporine Cmax and AUCτ, an average of 1.1 times (90% CI: 0.9, 1.41) and 1.7 times (90% CI: 1.5, 2), respectively, as compared to when cyclosporine was administered without voriconazole. When initiating therapy with voriconazole in patients already receiving cyclosporine, it is recommended that the cyclosporine dose be reduced to ½ of the original dose and followed with frequent monitoring of the cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine levels should be frequently monitored and the dose increased as necessary (see Interactions).
Tacrolimus (CYP3A4 Substrate): Repeat oral dose administration of voriconazole (400 mg every 12 hrs for 1 day then 200 mg every 12 hrs for 6 days) increased tacrolimus (0.1 mg/kg single dose) Cmax and AUCτ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively. When initiating therapy with voriconazole in patients already receiving tacrolimus, it is recommended that the tacrolimus dose be reduced to 1/3 of the original dose and followed with frequent monitoring of the tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus levels should be carefully monitored and the dose increased as necessary (see Interactions).
Methadone (CYP3A4 Substrate): Repeat dose administration of oral voriconazole (400 mg every 12 hrs for 1 day, then 200 mg every 12 hrs for 4 days) increased the Cmax and AUCτ of pharmacologically active R-methadone by 31% (90% CI: 22%, 40%) and 47% (90% CI: 38%, 57%), respectively, in subjects receiving a methadone maintenance dose (30-100 mg once daily). The Cmax and AUC of (S)-methadone increased by 65% (90% Cl: 53%, 79%) and 103% (90% CI: 85%, 124%), respectively. 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.
Short-Acting Opiates (CYP3A4 Substrate): In an independent publication, steady-state administration of oral voriconazole increased the AUC of a single dose of alfentanil by 6-fold. Reduction in the dose of alfentanil and other short acting opiates similar in structure to alfentanil and metabolized by CYP3A4 (eg, sufentanil), should be considered when co-administered with voriconazole.
Fentanyl (CYP3A4 Substrate): In an independent published study, concomitant use of voriconazole (400 mg every 12 hrs on day 1, then 200 mg every 12 hrs on day 2) with a single IV dose of fentanyl (5 mcg/kg) resulted in an increase in the mean AUC0-∞ of fentanyl by 1.4-fold (range 1.12- to 1.6-fold). When voriconazole is co-administered with fentanyl, extended and frequent monitoring of patients for respiratory depression and other fentanyl-associated adverse events is recommended, and fentanyl dosage should be reduced if warranted.
Oxycodone (CYP3A4 Substrate): In an independent published study, co-administration of multiple doses of oral voriconazole (400 mg every 12 hrs, on day 1 followed by 5 doses of 200 mg every 12 hrs on days 2-4) with a single 10 mg oral dose of oxycodone on day 3 resulted in an increase in the mean Cmax and AUC0-∞ of oxycodone by 1.7-fold (range 1.4- to 2.2-fold) and 3.6-fold (range 2.7- to 5.6-fold), respectively. The mean elimination half-life of oxycodone was also increased by 2-fold (range 1.4- to 2.5-fold). A reduction in oxycodone dosage may be needed during voriconazole treatment to avoid opioid related adverse effects. Extended and frequent monitoring for adverse effects associated with oxycodone and other long-acting opiates metabolized by CYP3A4 is recommended.
Warfarin (CYP2C9 Substrate): Co-administration of voriconazole (300 mg every 12 hrs for 12 days) with warfarin (30 mg single dose) significantly increased maximum prothrombin time by approximately 2 times that of placebo in healthy subjects. Close monitoring of prothrombin time or other suitable anticoagulation tests is recommended if warfarin and voriconazole are co-administered and the warfarin dose adjusted accordingly (see Interactions).
Oral Coumarin Anticoagulants eg, Phenprocoumon, Acenocoumarol (CYP2C9, CYP3A4 Substrates): Although not studied in vitro or in vivo, voriconazole may increase the plasma concentrations of coumarin anticoagulants and therefore, may cause an increase in prothrombin time. If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anticoagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly (see Interactions).
Statins (CYP3A4 Substrates): Although not studied clinically, voriconazole has been shown to inhibit lovastatin metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase plasma concentrations of statins that are metabolized by CYP3A4. It is recommended that dose adjustment of the statin be considered during co-administration. Increased statin concentrations in plasma have been associated with rhabdomyolysis (see Interactions).
Benzodiazepines (CYP3A4 Substrates): Although not studied clinically, voriconazole has been shown to inhibit midazolam metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase the plasma concentrations of benzodiazepines that are metabolized by CYP3A4 (eg, midazolam, triazolam, alprazolam) and lead to a prolonged sedative effect. It is recommended that dose adjustment of the benzodiazepine be considered during co-administration (see Interactions).
Calcium-Channel Blockers (CYP3A4 Substrates): Although not studied clinically, voriconazole has been shown to inhibit felodipine metabolism in vitro (human liver microsomes). Therefore, voriconazole may increase the plasma concentrations of calcium-channel blockers that are metabolized by CYP3A4. Frequent monitoring for adverse events and toxicity related to calcium-channel blockers is recommended during co-administration. Dose adjustment of the calcium-channel blocker may be needed (see Interactions).
Sulfonylureas (CYP2C9 Substrates): Although not studied in vitro or in vivo, voriconazole may increase the plasma concentrations of sulfonylureas (eg, tolbutamide, glipizide and glyburide) and therefore cause hypoglycemia. Frequent monitoring of blood glucose and appropriate adjustment (ie, reduction) of the sulfonylurea dosage is recommended during co-administration (see Precautions).
Vinca Alkaloids (CYP3A4 Substrates): Although not studied in vitro or in vivo, voriconazole may increase the plasma concentrations of vinca alkaloids (eg, vincristine and vinblastine) and lead to neurotoxicity. Therefore, it is recommended that dose adjustment of the vinca alkaloid be considered.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDS): Voriconazole increased Cmax and AUC of ibuprofen (400 mg single dose) by 20% and 100%, respectively. Voriconazole increased Cmax and AUC of diclofenac (50 mg single dose) by 114% and 78%, respectively. Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.
No significant pharmacokinetic interactions were observed when voriconazole was co-administered with the following agents. Therefore, no dosage adjustment for these agents is recommended:
Prednisolone (CYP3A4 Substrate):Voriconazole (200 mg every 12 hrs for 30 days) increased Cmax and AUCτ of prednisolone (60 mg single dose) by an average of 11% and 34%, respectively, in healthy subjects.
Digoxin (P-Glycoprotein Mediated Transport): Voriconazole (200 mg every 12 hrs for 12 days) had no significant effect on steady-state Cmax and AUCτ of digoxin (0.25 mg once daily for 10 days) in healthy subjects.
Mycophenolic Acid (UDP-Glucuronyl Transferase Substrate): Voriconazole (200 mg every 12 hrs for 5 days) had no significant effect on the Cmax and AUCτ of mycophenolic acid and its major metabolite, mycophenolic acid glucuronide after administration of a 1 g single oral dose of mycophenolate mofetil.
Two-Way Interactions: Concomitant use of the following agents with voriconazole is contraindicated.
Efavirenz [A Non-Nucleoside Reverse Transcriptase Inhibitor (CYP450 Inducer; CYP3A4 Inhibitor and Substrate)]: In healthy subjects, steady state efavirenz (400 mg oral once daily) decreased the steady state Cmax and AUCτ of voriconazole by an average of 61% and 77%, respectively. In the same study voriconazole at steady state (400 mg oral every 12 hrs for 1 day, then 200 mg oral every 12 hrs for 8 days) increased the steady state Cmax and AUCτ of efavirenz by an average of 38% and 44%, respectively, in the same subjects. Co-administration of standard dose of voriconazole and efavirenz is contraindicated. In a separate study in healthy subjects, voriconazole dose of 300 mg twice daily in combination with low dose efavirenz (300 mg once daily) did not lead to sufficient voriconazole exposure. When voriconazole is co-administered with efavirenz, the voriconazole maintenance dose should be increased to 400 mg twice daily and the efavirenz dose should be reduced by 50% ie, to 300 once daily. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored.
Rifabutin (Potent CYP450 Inducer): Rifabutin (300 mg once daily) decreased the Cmax and AUCτ of voriconazole at 200 mg twice daily by 69% and 78%, respectively. During co-administration with rifabutin, the Cmax and AUCτ of voriconazole at 350 mg twice daily were 96% and 68% of the levels when administered alone at 200 mg twice daily.
At a voriconazole dose of 400 mg twice daily Cmax and AUCτ were 104% and 87% higher, respectively, compared with voriconazole alone at 200 mg twice daily. Voriconazole at 400 mg twice daily increased the Cmax and AUCτ of rifabutin by 195% and 331%, respectively.
If the benefit outweighs the risk, rifabutin may be co-administered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg IV every 12 hrs or from 200-350 mg orally, every 12 hrs (100-200 mg orally, every 12 hrs in patients <40 kg). Careful monitoring of full blood counts and adverse events to rifabutin (eg, uveitis) is recommended when rifabutin is co-administered with voriconazole.
Significant drug interactions that may require dosage adjustments, frequent monitoring of drug levels and/or frequent monitoring of drug-related adverse events/toxicity.
Phenytoin (CYP2C9 Substrate and Potent CYP450 Inducer): Repeat dose administration of phenytoin (300 mg once daily) decreased the steady-state Cmax and AUCτ of orally administered voriconazole (200 mg every 12 hrs for 14 days) by an average of 50% and 70%, respectively, in healthy subjects. Administration of a higher voriconazole dose (400 mg every 12 hrs for 7 days) with phenytoin (300 mg once daily) resulted in comparable steady-state voriconazole Cmax and AUCτ estimates as compared in to when voriconazole was given at 200 mg every 12 hrs without phenytoin.
Phenytoin may be co-administered with voriconazole if the maintenance dose of voriconazole is increased from 4-5 mg/kg IV every 12 hrs or from 200-400 mg orally, every 12 hrs (100-200 mg orally, every 12 hrs in patients <40 kg) (see Dosage & Administration).
Repeat dose administration of voriconazole (400 mg every 12 hrs for 10 days) increased the steady-state Cmax and AUCτ of phenytoin (300 mg once daily) by an average of 70% and 80%, respectively, in healthy subjects. The increase in phenytoin Cmax and AUCτ when co-administered with voriconazole may be expected to be as high as 2 times the Cmax and AUC estimates when phenytoin is given without voriconazole. Therefore, frequent monitoring of plasma phenytoin concentrations and phenytoin-related adverse effects is recommended when phenytoin is co-administered with voriconazole (see Interactions).
Omeprazole (CYP2C19 Inhibitor, CYP2C19 and CYP3A4 Substrate): Co-administration of omeprazole (40 mg once daily for 10 days) with oral voriconazole (400 mg every 12 hrs for 1 day, then 200 mg every 12 hrs for 9 days) increased the steady-state Cmax and AUCτ of voriconazole by an average of 15% (90% CI: 5%, 25%) and 40% (90% CI: 29%, 55%), respectively in healthy subjects. No dosage adjustment of voriconazole is recommended.
Co-administration of voriconazole (400 mg every 12 hrs for 1 day, then 200 mg for 6 days) with omeprazole (40 mg once daily for 7 days) to healthy subjects significantly increased the steady-state Cmax and AUCτ of omeprazole an average of 2-times (90% CI: 1.8, 2.6) and 4-times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole is given without voriconazole. When initiating voriconazole in patients already receiving omeprazole doses ≥40 mg, it is recommended that the omeprazole dose reduced by one-half (see Interactions).
The metabolism of other proton-pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result increased plasma concentrations of these drugs.
Oral Contraceptives (CYP3A4 Substrate): Co-administration of voriconazole and an oral contraceptive (norethisterone 1 mg and ethinylestradiol 0.035 mg; once daily) in healthy female subjects resulted in increases in the Cmax and AUCτ of ethinylestradiol (36% and 61%, respectively) and norethisterone (15% and 53%, respectively). Voriconazole Cmax and AUCτ increased by 14% and 46%, respectively. Oral contraceptives containing doses other than norethisterone 1 mg and ethinylestradiol 0.035 mg have not been studied. As the ratio between norethisterone and ethinylestradiol remained similar during interaction with voriconazole, their contraceptive activity would probably not be affected. Monitoring for adverse events related to oral contraceptives is recommended during co-administration.
No significant pharmacokinetic inteaction was seen and no dosage adjustment of these drugs is recommended:
Indinavir (CYP3A4 Inhibitor and Substrate): Repeat dose administration of indinavir (800 mg 3 times daily for 10 days) had no significant effect on voriconazole Cmax and AUC following repeat dose administration (200 mg 12 hrs daily for 17 days) in healthy subjects.
Repeat dose administration of voriconazole (200 mg every 12 hrs for 7 days) did not have a significant effect on steady-state Cmax and AUCτ of indinavir following repeat dose administrations (800 mg 3 times daily for 7 days) in healthy subjects).
Other Two-Way Interactions Expected to be Significant Based on In vitro Findings: Other HIV Protease Inhibitors (CYP3A4 Substrates and Inhibitors): In vitro studies (human liver microsomes) suggest that voriconazole may inhibit the metabolism of HIV protease inhibitors (eg, saquinavir, amprenavir and nelfinavir). In vitro studies (human liver microsomes) also show that the metabolism of voriconazole may be inhibited by HIV protease inhibitors (eg, ritonavir, saquinavir and amprenavir). Patients should be frequently monitored for drug toxicity during co-administration of voriconazole and HIV protease inhibitors (see Interactions).
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) (CYP3A4 Substrates, Inhibitors or CYP450 Inducers): In vitro studies (human liver microsomes) show that the metabolism of voriconazole may be inhibited by an NNRTI (eg, delavirdine and efavirenz). Although not studied in vitro or in vivo, the metabolism of voriconazole may be induced by an NNRTI eg, efevirenz and nevirapine. In vitro studies (human liver microsomes) show that voriconazole may also inhibit the metabolism of an NNRTI (eg, delavirdine). Patients should be frequently monitored for drug toxicity the co-administration of voriconazole and an NNRTI (see Interactions). Co-administration of voriconazole with efavirenz is contraindicated.
Indications/Uses
Treatment of invasive aspergillosis. In clinical trials, the majority of isolates recovered were Aspergillus fumigatus. There was a small number of cases of culture-proven disease due to species of Aspergillus other than A. fumigatus (see Microbiology: Clinical Studies under Actions).
Treatment of candidemia in non-neutropenic patients; serious invasive Candida infections (including C. krusei); esophageal candidiasis. Treatment of serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp including Fusarium solani in patients intolerant of or refractory to other therapy.
Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.
Dosage/Direction for Use
Vfend tablets should be taken at least 1 hr before or 1 hr following a meal.
Vfend IV for injection requires reconstitution to 10 mg/mL and subsequent dilution to ≤5 mg/mL prior to administration as an infusion, at a maximum rate of 3 mg/kg/hr over 1-2 hrs (see IV administration).
Not for IV bolus injection.
Electrolyte disturbances eg, hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of Vfend therapy (see Precautions).
Adults: Therapy must be initiated with the specific loading dose regimen of IV Vfend to achieve plasma concentrations on Day 1 that are close to steady state. On the basis of high oral bioavailability, switching between IV and oral administration is appropriate when clinically indicated (see Actions).
For the treatment of adults with invasive aspergillosis and infections due to Fusarium spp and Scedosporium apiospermum, the recommended dosing regimen is as follows: Loading dose of 6 mg/kg Vfend IV every 12 hrs for 2 doses, followed by a maintenance of 4 mg/kg Vfend IV every 12 hrs.
Once the patient can tolerate medication given by mouth, the oral tablet form of voriconazole may be utilized. Patients who weigh >40 kg should receive an oral maintenance dose of 200 mg Vfend tablet every 12 hrs. Adult patients who weigh <40 kg should receive an oral maintenance dose of 100 mg every 12 hrs.
Detailed information on dosage recommendations is provided in the following table: (See Table 6.)


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Dosage Adjustment: If patient response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hrs to 300 mg every 12 hrs. For adult patients weighing <40 kg, the oral maintenance dose may be increased from 100 mg every 12 hrs to 150 mg every 12 hrs.
If patient's response at 3 mg/kg every 12 hrs is inadequate, the IV maintenance dose may be increased to 4 mg/kg every 12 hrs. If patients are unable to tolerate treatment, reduce the IV maintenance dose to 3 mg/kg every 12 hrs and the oral maintenance dose by 50 mg steps to a minimum of 200 mg every 12 hrs (or to 100 mg every 12 hrs for adult patients weighing <40 kg).
Phenytoin may be co-administered with Vfend if the maintenance dose of Vfend is increased to 5 mg/kg IV every 12 hrs, or from 200-400 mg every 12 hrs orally (100-200 mg every 12 hrs orally in adult patients weighing <40 kg) (see Actions and Interactions).
When voriconazole is co-administered with adjusted dose of efavirenz, voriconazole maintenance dose should be increased to 400 mg every 12 hrs (see Contraindications, Warnings, Precautions and Interactions).
Duration of therapy should be based on the severity of the patient's underlying disease, recovery from immunosuppression and clinical response.
Elderly: No dose adjustment is necessary for geriatric patients.
Children: Safety and effectiveness in pediatric <2 years has not been established (see Pharmacology under Actions). Therefore, voriconazole is not recommended for children <2 years.
The recommended maintenance dosing regimen in pediatric patients 2 to <12 years is as follows (see Table 7):


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If pediatric patients are unable to tolerate an IV dose of 7 mg/kg twice daily, a dose reduction from 7 mg/kg to 4 mg/kg twice daily may be considered based on the population pharmacokinetic analysis and previous clinical experiences. This provides equivalent exposure to 3 mg/kg twice daily in adults (see previously mentioned texts).
Use in pediatric patients aged 2 to <12 years with hepatic or renal insufficiency has not been studied (see Pharmacokinetics under Actions and Adverse Reactions).
These pediatric dose recommendations are based on studies in which Vfend was administered as the powder oral suspension formulation. Bioequivalence between the powder for oral suspension and tablets has not been investigated in a pediatric population. Considering the assumed limited gastroenteric transit time in pediatrics, the absorption of tablets may be different in pediatric compared to adult patients.
Adolescents (12-16 years) should be dosed as adults.
Patients with Hepatic Insufficiency: In the clinical program, patients were included who had baseline liver function tests (ALT, AST) up to 5 times the upper limit of normal. No dose adjustment is necessary in patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended (see Warnings).
It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B).
Vfend has not been studied in patients with severe hepatic cirrhosis (Child-Pugh Class C) or in patients with chronic hepatitis B or chronic hepatitis C disease. Vfend has been associated with elevations in liver function tests and clinical signs of liver damage eg, jaundice, and should only be used in patients with severe hepatic insufficiency if the benefit outweighs the potential risk. Patients with hepatic insufficiency must be carefully monitored for drug toxicity.
Patients with Renal Insufficiency: The pharmacokinetics of orally administered Vfend are not significantly affected by renal insufficiency. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment (see Pharmacokinetics: Special Populations under Actions).
In patients with moderate to severe renal insufficiency (CrCl <50 mL/min), accumulation of the IV vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of IV 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 clearance of 121 mL/min. The IV vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hr hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.
IV Administration: Vfend for IV injection.
Reconstitution: The powder is reconstituted with 19 mL of Water for Injection to obtain an extractable volume of 20 mL of clear concentrate containing 10 mg/mL of voriconazole. It is recommended that a standard 20 mL (non-automated) syringe be used to ensure that the exact amount (19 mL) of water for injection is dispensed. Discard the vial if a vacuum does not pull the diluent into the vial. Shake the vial until all the powder is dissolved.
Dilution: Vfend must be infused over 1-2 hrs at a concentration of ≤5 mg/mL. Therefore, the required volume of the 10 mg/mL Vfend concentrate should be further diluted as follows (appropriate diluents listed as follows):
Calculate the volume of 10 mg/mL Vfend concentrate required based on the patient's weight (see Table 7).
In order to allow the required volume of Vfend 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 Vfend 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 Vfend concentrate from the appropriate number of vials and add to the infusion bag or bottle. Discard partially used vials.
The final Vfend solution must be infused over 1-2 hrs at a maximum rate of 3 mg/kg/hr. (See Table 8.)


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Vfend is a single-dose unpreserved sterile lyophile. Therefore, from a microbiological point of view, once reconstituted, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hrs at 2°-8°C. This medicinal product is for single use only and any unused solution should be discarded. Only clear solutions without particles should be used.
The reconstitution solutions can be diluted with: 9 mg/mL (0.9%) Sodium Chloride, Lactated Ringer's, 5% Dextrose and Lactated Ringer's, 5% Dextrose and 0.45% Sodium Chloride, 5% Dextrose, 5% Dextrose and 20 mEq Potassium Chloride, 0.45% Sodium Chloride, 5% Dextrose and 0.9% Sodium Chloride.
The compatibility of Vfend IV with diluents other than those described previously is unknown (see Interactions: Incompatibilities).
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Overdosage
In clinical trials, there were 3 cases of accidental overdose. All occurred in pediatric patients who received up to 5 times the recommended IV dose of voriconazole. A single adverse event of photophobia of 10 min duration was reported.
There is no known antidote to voriconazole; it is recommended that treatment of overdosage be symptomatic and supportive.
Voriconazole is hemodialyzed with clearance of 121 mL/min. The IV 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.
The minimum lethal oral dose in mice and rats was 300 mg/kg [equivalent to 4 and 7 times the recommended maintenance dose (RMD), based on body surface area]. At this dose, clinical signs, observed in both mice and rats included salivation, mydriasis, titubation (loss of balance while moving), depressed behavior, prostration, partially closed eyes and dyspnea. Other signs in mice were convulsions, corneal, opacification and swollen abdomen.
Contraindications
Patients with known hypersensitivity to voriconazole or to any of the excipients of Vfend.
There is no information regarding cross-sensitivity between voriconazole and other azole antifungal agents. Caution should be used in prescribing Vfend to patients with hypersensitivity to other azoles.
Co-administration of the CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide or quinidine with voriconazole is contraindicated since increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of torsade de pointes (see Pharmacokinetics: Drug Interactions under Actions and Interactions).
Co-administration of voriconazole with sirolimus is contraindicated because voriconazole significantly increases sirolimus concentrations in healthy subjects (see Pharmacokinetics: Drug Interactions under Actions and Interactions).
Co-administration of voriconazole with rifampin, carbamazepine and long-acting barbiturates is contraindicated since these drugs are likely to decrease plasma voriconazole concentrations significantly (see Pharmacokinetics: Drug Interactions under Actions and Interactions).
Co-administration of voriconazole with ritonavir (400 mg every 12 hrs) is contraindicated because ritonavir significantly decreased plasma voriconazole concentrations in healthy subjects.
Co-administration of voriconazole with ergot alkaloids (ergotamine, dihydroergotamine) is contraindicated because voriconazole may increase the plasma concentration of ergot alkaloids, which may lead to ergotism.
Co-adminsitration of voriconazole with St John’s wort is contraindicated (see Interactions).
Warnings
Hypersensitivity: Caution should be used in prescribing voriconazole to patients with hypersensitivity to other azoles.
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).
Hepatic Toxicity: In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with Vfend (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). 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 (see Precautions: Laboratory Tests and Adverse Reactions: Clinical Laboratory Values).
Monitoring of Hepatic Function: Liver function tests should be evaluated at the start of and during the course of Vfend therapy. Patients who develop abnormal liver function tests during Vfend therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of Vfend must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to Vfend (see Precautions: Laboratory Tests, Dosage & Administration: Dosage Adjustment and Adverse Reactions: Clinical Laboratory Tests).
Galactose Intolerance: Vfend tablets contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
Special Precautions
General: See Warnings and Dosage & Administration.
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 torsades de pointes in patients taking voriconazole. These reports involved seriously ill patients with multiple confounding risk factors eg, history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medications that may have been contributory.
Voriconazole should be administered with caution to patients with these potentially proarrhythmic conditions.
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 millisec from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 millisec (see Pharmacology under Actions) eg, congenital or acquired QT prolongation; cardiomyopathy, in particular when heart failure is present; sinus bradycardia; existing symptomatic arrhythmias; concomitant medication that is known to prolong QT interval.
Rigorous attempts to correct potassium, magnesium and calcium should be made before starting voriconazole.
Infusion-Related Reactions: During infusion of voriconazole IV formulation in healthy subjects, anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus and rash, have occurred uncommonly. Symptoms appeared immediately upon initiating the infusion. Consideration should be given to stopping the infusion should these reactions occur.
Information for Patients: Patients should be advised that Vfend tablets should be taken at least 1 hr before or 1 hr following a meal and that strong, direct sunlight should be avoided during Vfend therapy. Patients should not drive at night while taking Vfend and avoid potentially hazardous tasks, Vfend may cause changes to vision, including blurring and/or photophobia.
Laboratory Tests: Electrolyte disturbances eg, hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of Vfend therapy.
Patient management should include laboratory evaluation of renal (particularly serum creatinine) and hepatic function (particularly liver function tests and bilirubin).
Patients with Hepatic Insufficiency: It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh class A and B) receiving Vfend (see Pharmacology: Hepatic Insufficiency under Actions and Dosage & Administration: Hepatic Insufficiency).
Vfend has not been studied in patients with severe cirrhosis (Child-Pugh class C) or in patients with chronic hepatitis B or chronic hepatitis C disease. Vfend has been associated with elevations in liver function tests and clinical signs of liver damage eg, jaundice, and should only be used in patients with severe hepatic insufficiency if the benefit outweighs the potential risk. Patients with hepatic insufficiency must be carefully monitored for drug toxicity.
Patients with Renal Insufficiency: In patients with moderate to severe renal dysfunction (CrCl <50 mL/min), accumulation of the IV vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of IV 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 (see Pharmacokinetics: Renal Insufficiency under Actions and Dosage & Administration: Renal Insufficiency).
Renal Adverse Events: Acute renal failure has been observed in severely ill patients undergoing treatment with Vfend. 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.
Monitoring of Pancreatic Function: Adults and children with risk factors for acute pancreatitis [eg, recent chemotherapy, hematopoietic stem cell transplantation (HSCT)], should be monitored for development of pancreatitis during voriconazole treatment.
Dermatological Reactions: Patients have rarely developed serious cutaneous reactions eg, Stevens-Johnson syndrome, during treatment with Vfend. If patients develop an exfoliative cutaneous reaction voriconazole should be discontinued. Vfend has been associated with photosensitivity skin reaction, especially during long-term therapy. It is recommended that patients avoid intense or prolonged exposure to direct sunlight during Vfend therapy. 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 a patient develops a skin lesion consistent with squamous cell carcinoma or melanoma, voriconazole discontinuation should be considered.
Effects on the Ability to Drive or Operate Machinery: Voriconazole may cause transient and reversible changes to vision, including blurring, altered/enhanced visual perception and/or photophobia. Patients must avoid potentially hazardous tasks eg, driving or operating machinery while experiencing these symptoms. Patients should not drive at night while taking voriconazole.
Carcinogenicity, Mutagenicity & Impairment of Fertility: Two-year carcinogenicity studies were conducted in rats and mice. Rats were given oral doses of 6, 18 or 50 mg/kg voriconazole, or 0.2, 0.6, or 1.6 times the recommended maintenance dose (RMD) on a mg/m2 basis. Hepatocellular adenomas were detected in females at 50 mg/kg and hepatocellular carcinomas were found in males at 6 and 50 mg/kg. Mice were given oral doses of 10, 30 or 100 mg/kg voriconazole, or 0.1, 0.4 or 1.4 times the RMD on a mg/m2 basis. In mice, hepatocellular adenomas were detected in males and females and hepatocellular carcinomas were detected in males at 1.4 times the RMD of voriconazole.
Voriconazole demonstrated clastogenic activity (mostly chromosome breaks) in human lymphocyte cultures in vitro. Voriconazole was not genotoxic in the Ames test, CHO assay, the mouse micronucleus assay or the DNA repair test (Unscheduled DNA Synthesis assay).
Voriconazole produces a reduction in the pregnancy rates of rats dosed at 50 mg/kg, or 1.6 times the RMD. This was statistically significant only in the preliminary study and not in a larger fertility study.
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. 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 Childbearing Potential: Effective contraception during treatment should be used by women of childbearing potential.
Use in lactation: The excretion of voriconazole in breast milk has not been investigated. Vfend should not be used by nursing mothers unless the benefit clearly outweighs the risk.
A total of 22 patients 12-18 years with invasive aspergillosis were included in the therapeutic studies. Twelve (12) out of 22 (55%) patients had successful response after treatment with a maintenance dose of voriconazole 4 mg/kg every 12 hrs.
Sparse plasma sampling for pharmacokinetics in adolescents was conducted in the therapeutic studies.
Use in children: Safety and effectiveness in pediatric patients <12 years have not been established. Voriconazole is indicated for pediatric patients aged ≥2 years. Hepatic function should be monitored in both children and adults. Oral bioavailability may be limited in pediatric patients 2-12 years with malabsorption and very low body weight for age. In that case, IV voriconazole administration is recommended.
Use in the elderly: In an oral multiple dose study the mean Cmax and AUCτ in healthy elderly males (≥65 years) were 61% and 86% higher, respectively, than in young males (18-45 years). No significant differences in the mean Cmax and AUCτ were observed between healthy elderly females (≥65 years) and healthy young females (18-45 years). An analysis of pharmacokinetic data obtained from 552 patients from 10 voriconazole therapeutic trials showed that voriconazole plasma concentrations in the elderly patients were approximately 80-90% higher than those in younger patients after either IV or oral administration. However, the overall safety profile of the elderly patients was similar to that of the young so no dosage adjustment is recommended (see Pharmacokinetics: Special Populations 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. 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 Childbearing Potential: Effective contraception during treatment should be used by women of childbearing potential.
Use in lactation: The excretion of voriconazole in breast milk has not been investigated. Vfend should not be used by nursing mothers unless the benefit clearly outweighs the risk.
A total of 22 patients 12-18 years with invasive aspergillosis were included in the therapeutic studies. Twelve (12) out of 22 (55%) patients had successful response after treatment with a maintenance dose of voriconazole 4 mg/kg every 12 hrs.
Sparse plasma sampling for pharmacokinetics in adolescents was conducted in the therapeutic studies.
Adverse Reactions
The list as follows includes adverse reactions from therapeutic and/or compassionate/extension studies, if possibly causally related. The most frequently reported adverse events were visual disturbances, fever, 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.
Investigations: Common: Elevated liver function tests (including ASAT, ALAT, alkaline phosphatase, GGT, LDH, bilirubin), increased blood creatinine. Uncommon: Prolonged electrocardiogram QT corrected interval, increased blood urea and increased blood cholesterol.
Cardiac Disorders: Very Common: Peripheral oedema. Uncommon: Ventricular fibrillation, ventricular arrhythmia, syncope, supraventricular arrhythmia, supraventricular tachycardia, tachycardia, bradycardia. Rare: Torsades de pointes, ventricular tachycardia, atrioventricular complete block, bundle branch block, nodal rhythm.
Blood and Lymphatic System Disorders: Common: Pancytopenia, bone marrow depression, leukopenia, thrombocytopenia, purpura, anaemia (including macrocytic, microcytic, normocytic, megaloblastic, aplastic). Uncommon: Disseminated intravascular coagulation, agranulocytosis, lymphadenopathy, eosinophilia, marrow depression.
Nervous System Disorders: Very Common: Headache. Common: Dizziness, confusional state, tremor, agitation, paraesthesia. Uncommon: Brain oedema, ataxia, diplopia, vertigo, hypoaesthesia, hypertonia, nystagmus, syncope, altered tasete perception. Rare: Convulsion, encephalopathy, Guillain-Barre syndrome, extrapyramidal symptoms, oculogyric crisis, hepatic coma, insomnia, somnolence during infusion.
Eye Disorders: Very Common: Visual disturbance (including altered/enhanced visual perception, blurred vision, change color vision, photophobia). Uncommon: Papiloedema, opticneuritis, nystagmus, scleritis, blepharitis, diplopia. Rare: Retinal haemorrhage, optic atrophy, oculogyration, corneal opacity.
Ear and Labyrinth Disorders: Uncommon: Vertigo. Rare: Hypoacusis, tinnitus.
Respiratory, Thoracic and Mediastinal Disorders: Common: Acute respiratory distress syndrome, pulmonary oedema, respiratory distress syndrome, chest pain.
Gastrointestinal Disoders: Very Common: Abdominal pain, nausea, vomiting, diarrhoea. Uncommon: Pancreatitis, peritonitis, duodenitis, gingivitis, glossitis, swollen tongue, dyspepsia, constipation. Rare: Dysgeusia.
Renal and Urinary Disorders: Common: Acute renal failure, haematuria. Uncommon: Nephritis, proteinuria. Rare: Renal tubular necrosis.
Skin and Subcutaneous Tissue Disorders: Very Common: Rash. Common: Exfoliative dermatitis, face oedema, photosensitivity skin reaction, maculo-papular rash, macular rash, papular rash, cheilitis, pruritus, alopecia, erythema, purpura. Uncommon: Stevens-Johnson syndrome, angioneurotic oedema, allergic dermatitis, uricaria, drug hypersensitivity, psoriasis, fixed-drug eruption, eczema. Rare: Toxic epidermal necrolysis, erythema multiforme, discoid lupus erythematosis, angioedema, pseudoporphyria.
Musculoskeletal and Connective Tissue Disoders: Common: Back pain. Uncommon: Arthritis. Rare: Hypertonia.
Endocrine Disorders: Uncommon: Adrenal cortex insufficiency. Rare: Hyperthyroidism, hypothyroidism.
Metabolic and Nutrition System Disorders: Common: Hypoglycaemia, hypokalaemia. Uncommon: Hypercholesteremia.
Infections and Infestation: Common: Gastroenteritis, influenza-like illness. Rare: Pseudomembranous colitis.
Vascular Disoders: Common: Hypotension, thrombophlebitis, phlebitis. Rare: Lymphangitis.
General Disorders and Administrative Site Conditions: Very Common: Pyrexia, fever, peripheral edema. Common: Injection site reaction/inflammation, chills, asthenia, chest pain, flu syndrome.
Immune System Disorders: Common: Sinusitis. Uncommon: Anaphylactoid reaction, hypersensitivity.
Hepatobiliary Disorders: Common: Jaundice, cholestatic jaundice. Uncommon: Hepatic failure, hepatitis, hepatomegaly, cholecystitis, cholelithiasis. Rare: Hepatic coma.
Psychiatric Disorders: Common: Depression, anxiety, hallucination, confusion, agitation. Rare: Insomnia.
*Frequencies are categorized as follows: Very common ≥10%, common from ≥1% to <10%, uncommon from ≥0.1% to <1%, rare from 0.01% to <0.1%.
Visual Disturbances: Voriconazole treatment-related visual disturbances are common. In clinical trials, approximately 30% of patients experienced altered/enhanced visual perception, blurred vision, color vision change and/or photophobia. These visual disturbances were transient and fully reversible, with the majority spontaneously resolving within 60 min. There was evidence of attenuation with repeated doses of voriconazole. The visual disturbances were generally mild, rarely resulted in discontinuation and were not been associated with long-term sequelae. Visual disturbances may be associated with higher plasma concentrations and/or doses.
The mechanism of action of the visual disturbance is unknown, although the site of action is most likely to be within the retina. In a study in healthy volunteers investigating the effect 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.
Dermatological Reactions: Dermatological reactions were common in the patients with voriconazole. The mechanism underlying these dermatologic adverse events remain unknown. In clinical trials, rashes considered related to therapy were reported by 6% (86/1493) of voriconazole-treated patients. The majority of rashes were of mild to moderate severity. Cases of photosensitivity reactions appear to be more likely to occur with long-term treatment. Patients have rarely developed serious cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme during treatment with Vfend. If patients develop a rash, they should be monitored closely and consideration given to discontinuation of Vfend. It is recommended that patients avoid strong, direct sunlight during Vfend therapy.
Less Common Adverse Events: The following adverse events occurred in <2% of all voriconazole-treated patients, including healthy volunteers and patients treated under compassionate use protocols (total N=2090). This listing includes events where causal relationship to voriconazole cannot be ruled out or those which may help the physician in managing the risks to the patients. The list does not include events included in Table 8 and does not include every event reported in the voriconazole clinical program.
Body as a Whole: Abdominal pain, enlarged abdomen, allergic reaction, anaphylactoid reaction (see Precautions), ascites, asthenia, back pain, cellulitis, edema, face edema, flank pain, flu syndrome, graft versus host reaction, granuloma, infection, bacterial infection, fungal infection, injection site pain, injection site infection/inflammation, mucous membrane disorder, multiorgan failure, pain, pelvic pain, peritonitis, sepsis, substernal chest pain.
Cardiovascular: Supraventricular extrasystoles, atrial arrhythmia, atrial fibrillation, complete AV block, bigeminy, bradycardia, bundle branch block, cardiomegaly, cardiomyopathy, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, congestive heart failure, deep thrombophlebitis, endocarditis, extrasystoles, heart arrest, myocardial infarction, nodal arrhythmia, palpitation, phlebitis, postural hypotension, pulmonary embolus, prolonged QT interval, supraventricular tachycardia, syncope, thrombophlebitis, vasodilatation, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia (including Torsade de pointes).
Digestive: Diarrhea and jaundice, anorexia, cheilitis, cholecystitis, cholelithiasis, constipation, duodenal ulcer perforation, duodenitis, dyspepsia, dysphagia, esophageal ulcer, esophagitis, flatulence, gastroenteritis, gastrointestinal hemorrhage, elevated GGT/LDH, gingivitis, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hepatic coma, hepatic failure, hepatitis, intestinal perforation, intestinal ulcer, enlarged liver, melena, mouth ulceration, pancreatitis, parotid gland enlargement, periodontitis, proctitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, stomach ulcer, stomatitis, tongue edema.
Endocrine: Adrenal cortex insufficiency, diabetes insipidus, hyperthyroidism, hypothyroidism.
Hemic and Lymphatic: Agranulocytosis, anemia (macrocytic, megaloblastic, microcytic, normocytic), aplastic anemia, hemolytic anemia, increased bleeding time, cyanosis, DIC, ecchymosis, eosinophilia, hypervolemia, lymphadenopathy, lymphangitis, marrow depression, petechia, purpura, enlarged spleen, thrombotic thrombocytopenic purpura, leucopenia, thrombocytopenia and pancytopenia.
Metabolic and Nutritional: Albuminuria, increased BUN, increased creatinine phosphokinase, edema, decreased glucose tolerance, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperuricemia, hypocalcemia, hypoglycemia, hyponatremia, hypophosphatemia, uremia, hypomagnesemia and peripheral edema.
Musculoskeletal: Arthralgia, arthritis, bone necrosis, bone pain, leg cramps, myalgia, myasthenia, myopathy, osteomalacia, osteoporosis.
Nervous System: Abnormal dreams, acute brain syndrome, agitation, akathisia, amnesia, anxiety, ataxia, brain edema, coma, confusion, convulsion, delirium, dementia, depersonalization, depression, diplopia, encephalitis, encephalopathy, euphoria, extrapyramidal syndrome, grand mal convulsion, Guillain-Barre syndrome, hypertonia, hypesthesia, insomnia, intracranial hypertension, decreased libido, neuralgia, neuropathy, nystagmus, oculogyric crisis, paresthesia, psychosis, somnolence, suicidal ideation, tremor, vertigo, dizziness.
Respiratory System: Increased cough, dyspnea, epistaxis, hemoptysis, hypoxia, lung edema, pharyngitis, pleural effusion, pneumonia, respiratory disorder, respiratory distress syndrome, respiratory tract infection, rhinitis, sinusitis, voice alteration.
Skin and Appendages: Alopecia, angioedema, contact dermatitis, discoid lupus erythematosus, eczema, erythema multiforme, exfoliative dermatitis, fixed drug eruption, furunculosis, herpes simplex, melanosis, photosensitivity skin reaction, psoriasis, skin discoloration, skin disorder, dry skin, Stevens-Johnson syndrome, sweating, toxic epidermal necrolysis, urticaria, maculopapular rash.
Special Senses: Abnormality of accommodation, blepharitis, color blindness, conjunctivitis, corneal opacity, deafness, ear pain, eye pain, dry eyes, keratitis, keratoconjunctivitis, mydriasis, nightblindness, optic atrophy, optic neuritis, otitis externa, papilledema, retinal hemorrhage, retinitis, scleritis, taste loss, taste perversion, tinnitus, uveitis, visual field defect, eye hemorrhage and hypoacusis.
Urogenital: Anuria, blighted ovum, decreased creatinine clearance, dysmenorrhea, dysuria, epididymitis, glycosuria, hemorrhagic cystitis, hematuria, hydronephrosis, impotence, kidney pain, kidney tubular necrosis, metorrhagia, nephritis, nephrosis, oliguria, scrotal edema, urinary incontinence, urinary retention, urinary tract infection, uterine hemorrhage, vaginal hemorrhage.
Clinical Laboratory Values: The overall incidence of clinically significant transaminase abnormalities in the voriconazole clinical program was 12.4% (206/1655) of patients treated with voriconazole. Increased incidence of liver function test abnormalities may be associated with higher plasma concentrations 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 infrequently associated with cases of serious hepatic toxicity including cases of jaundice and rare hepatitis and hepatic failure leading to death. Most of these patients had other serious underlying conditions.
Liver function tests should be evaluated at the start of and during the course of Vfend therapy. Patients who develop abnormal liver function tests during Vfend therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of Vfend must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to Vfend (see Warnings and Precautions: Laboratory Test). Monitoring of hepatic function should be carried out in both children and adults.
Acute renal failure has been observed in severely ill patients undergoing treatment with Vfend. 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. It is recommended that patients are monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.
Drug Interactions
Incompatibilities: Vfend must not be infused in the same line or cannula concomitantly with other drug infusions, including parenteral nutrition eg, Aminofusin 10% Plus. Aminofusin 10% Plus is physically incompatible, with an increase in subvisible particulate matter after 24 hrs storage at 4°C.
Infusions of blood products must not occur simultaneously with Vfend IV.
Infusions of total parenteral nutrition can occur simultaneously with Vfend IV.
Blood Products and Concentrate Electrolyte: Voriconazole must not be infused concomitantly with any blood product or any short-term infusion of concentrated electrolytes, even if the 2 infusions are running in separate IV line (or cannulas). Electrolyte disturbances eg, hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of voriconazole therapy (see Dosage & Administration, Warning and Precautions).
Intravenous Solutions Containing (Non-Concentrated) Electrolytes: Voriconazole can be infused at the same time as other IV 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.
Vfend IV must not be diluted with 4.2% Sodium Bicarbonate Infusion. The mildly alkaline nature of this diluent caused slight degradation of Vfend after 24 hrs storage at room temperature. Although refrigerated storage is recommended following reconstitution, use of this diluent is not recommended as a precautionary measure. Compatibility with other concentrations is unknown.
Storage
Store at a maximum temperature of 30°C.
Unreconstituted vials should be stored at a maximum temperature of 30°C. Vfend is a single dose unpreserved sterile lyophile. From a microbiological point of view, following reconstitution of the lyophile with Water for Injection, the reconstituted solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hrs at 2°-8°C. Chemical and physical in-use stability has been demonstrated for 24 hrs at 2°-8°C. This medicinal product is for single use only and any unused solution should be discarded. Only clear solutions without particles should be used (see Dosage & Administration).
Shelf-Life: Tablet: 3 years. IV: 2 years.
MIMS Class
Antifungals
ATC Classification
J02AC03 - voriconazole ; Belongs to the class of triazole and tetrazole derivatives. Used in the systemic treatment of mycotic infections.
Presentation/Packing
FC tab 200 mg (white, capsule-shaped, debossed with "Pfizer" on one side and "VOR200" on the reverse) x 10's. Powd for inj 200 mg (vial, white, lyophilized, single-dose, unpreserved) x 1's.
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