`
`
`VFEND® I.V.
`(voriconazole) for Injection
`
`VFEND® Tablets
`(voriconazole)
`
`
`VFEND®
`
`(voriconazole) for Oral Suspension
`
`
`
`
`
`
`DESCRIPTION
`
`VFEND® (voriconazole), a triazole antifungal agent, is available as a lyophilized powder for
`solution for intravenous infusion, film-coated tablets for oral administration, and as a powder for
`oral suspension. The structural formula is:
`
`
`
`N
`
`N
`
`F
`
`N
`
`CH3
`O H
`
`F
`
`N
`
`N
`
`F
`
`
`
`
`Voriconazole is designated chemically as (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4­
`pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol with an empirical formula of C16H14F3N5O and
`a molecular weight of 349.3.
`
`
`Voriconazole drug substance is a white to light-colored powder.
`
`
`VFEND I.V. is a white lyophilized powder containing nominally 200 mg voriconazole and 3200
`mg sulfobutyl ether beta-cyclodextrin sodium in a 30 mL Type I clear glass vial.
`
`
`VFEND I.V. is intended for administration by intravenous infusion. It is a single-dose,
`unpreserved product. Vials containing 200 mg lyophilized voriconazole are intended for
`reconstitution with Water for Injection to produce a solution containing 10 mg/mL VFEND and
`160 mg/mL of sulfobutyl ether beta-cyclodextrin sodium. The resultant solution is further diluted
`prior to administration as an intravenous infusion (see DOSAGE AND ADMINISTRATION).
`
`
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`Reference ID: 2866932
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`1
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`VFEND Tablets contain 50 mg or 200 mg of voriconazole. The inactive ingredients include
`
` lactose monohydrate, pregelatinized starch, croscarmellose sodium, povidone, magnesium
`stearate and a coating containing hypromellose, titanium dioxide, lactose monohydrate and
`triacetin.
`
`
`VFEND for Oral Suspension is a white to off-white powder providing a white to off-white
`orange-flavored suspension when reconstituted. Bottles containing 45 g powder for oral
`suspension are intended for reconstitution with water to produce a suspension containing 40
`
`mg/mL voriconazole. The inactive ingredients include colloidal silicon dioxide, titanium
`dioxide, xanthan gum, sodium citrate dihydrate, sodium benzoate, anhydrous citric acid, natural
`orange flavor, and sucrose.
`
`
`CLINICAL PHARMACOLOGY
`
`
`Pharmacokinetics
`
`General Pharmacokinetic Characteristics
`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 mg Q12h to 300 mg Q12h leads to a 2.5-fold increase
`in exposure (AUCτ), while increasing the intravenous dose from 3 mg/kg Q12h to 4 mg/kg Q12h
`produces a 2.3-fold increase in exposure (Table 1).
`
`Table 1
`Population Pharmacokinetic Parameters of Voriconazole in Subjects
`
`
`
`300 mg Oral Q12h
`
`50.32
`(74%)
`
`
`3 mg/kg IV Q12h
`
`21.81
`(100%)
`
`
`4 mg/kg IV Q12h
`
`50.40
`(83%)
`
`
`AUCτ* (μg•h/mL)
`(CV%)
`
`
`*Mean AUCτ are predicted values from population pharmacokinetic analysis of data from 236 subjects
`
`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 were similar to those observed in healthy subjects
`(Table 2).
`
`
`200 mg Oral Q12h
`
`19.86
`(94%)
`
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`Reference ID: 2866932
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`Table 2
`Pharmacokinetic Parameters of Voriconazole in Patients at Risk for Aspergillosis
`
`
`
`
`200 mg Oral Q12h
`(n=9)
`20.31
`(69%)
`3.00
`(51%)
`
`300 mg Oral Q12h
`(n=9)
`36.51
`(45%)
`4.66
`(35%)
`
`AUCτ* (μg•h/mL )
`(CV%)
`Cmax* (μg/mL)
`(CV%)
`
`*Geometric mean values on Day 14 of multiple dosing in 2 cohorts of patients
`
`Sparse plasma sampling for pharmacokinetics was conducted in the therapeutic studies in
`patients aged 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
`
`1.60 μg/mL (inter-quartile range 0.28 to 2.73 μg/mL). In 17 adolescent patients for whom mean
`plasma concentrations were calculated following a mean oral maintenance dose of 200 mg Q12h,
`the median of the calculated mean plasma concentrations was 1.16 μg/mL (inter-quartile range
`
`0.85 to 2.14 μg/mL).
`
`When the recommended intravenous or oral loading dose regimens are administered to healthy
`subjects, peak plasma concentrations close to steady state are achieved within the first 24 hours
`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 (Table 3).
`
`
`Table 3
`Pharmacokinetic Parameters of Voriconazole from Loading Dose and Maintenance Dose Regimens
`
`(Individual Studies in Subjects)
`
`
`
`400 mg Q12h on Day 1,
`200 mg Q12h on Days 2 to 10
`(n=17)
`Day 1, 1st dose
`9.31
`(38%)
`
`Day 10
`11.13
`(103%)
`
`6 mg/kg IV** Q12h on Day 1,
`3 mg/kg IV Q12h on Days 2 to 10
`(n=9)
`
`Day 1, 1st dose
`13.22
`(22%)
`
`Day 10
`13.25
`(58%)
`
`
`AUCτ* (μg•h/mL)
`(CV%)
`
`Cmax (μg/mL)
`
`(CV%)
`
`2.30
`(19%)
`
`2.08
`(62%)
`
`4.70
`(22%)
`
`3.06
`(31%)
`
`
`*AUCτ values are calculated over dosing interval of 12 hours
`Pharmacokinetic parameters for loading and maintenance doses summarized for same cohort of subjects
`**IV infusion over 60 minutes
`
`Steady state trough plasma concentrations with voriconazole are achieved after approximately 5
`days of oral or intravenous dosing without a loading dose regimen. However, when an
`intravenous loading dose regimen is used, steady state trough plasma concentrations are
`achieved within 1 day.
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`Reference ID: 2866932
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`Absorption
`
`The pharmacokinetic properties of voriconazole are similar following administration by the
`intravenous 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 Q12h loading dose followed by a 200 mg Q12h
`maintenance dose.
`
`Maximum plasma concentrations (Cmax) are achieved 1-2 hours 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 when administered as a tablet and by 58% and 37%
`respectively when administered as the oral suspension (see DOSAGE AND
`ADMINISTRATION).
`
`
`In healthy subjects, the absorption of voriconazole is not affected by coadministration 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 mg or 300 mg (approximate range: 0.9-15 μg/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 cytochrome P450
`enzymes, CYP2C19, CYP2C9 and CYP3A4 (see CLINICAL PHARMACOLOGY - Drug
`Interactions).
`
`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 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. 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 less than 2% of the dose excreted
`unchanged in the urine. After administration of a single radiolabelled dose of either oral or IV
`voriconazole, preceded by multiple oral or IV dosing, approximately 80% to 83% of the
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`Reference ID: 2866932
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`radioactivity is recovered in the urine. The majority (>94%) of the total radioactivity is excreted
`in the first 96 hours after both oral and intravenous 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
`
`Clinical Efficacy and Safety
`
`
`In 10 clinical trials, the median values for the average and maximum voriconazole plasma
`concentrations in individual patients across these studies (N=1121) was 2.51 μg/mL (inter­
`quartile range 1.21 to 4.44 μg/mL) and 3.79 μg/mL (inter-quartile range 2.06 to 6.31 μg/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).
`
`
`Electrocardiogram
`
`A placebo-controlled, randomized, crossover study to evaluate the effect on the QT interval of
`healthy male and female subjects was conducted with three single oral doses of voriconazole and
`ketoconazole. Serial ECGs and plasma samples were obtained at specified intervals over a 24­
`
`hour post dose observation period. The placebo-adjusted mean maximum increases in QTc from
`baseline after 800, 1200 and 1600 mg of voriconazole and after ketoconazole 800 mg were all
`<10 msec. Females exhibited a greater increase in QTc than males, although all mean changes
`were <10 msec. Age was not found to affect the magnitude of increase in QTc. 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. However, the QT
`effect of voriconazole combined with drugs known to prolong the QT interval is unknown (see
`CONTRAINDICATIONS, PRECAUTIONS-Drug Interactions).
`
`
`Pharmacokinetics in Special Populations
`
`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), after tablet dosing. 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 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.
`
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`Reference ID: 2866932
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`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 subjects 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% to 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 subjects
`was similar and, therefore, no dosage adjustment is necessary for the elderly.
`
`
`Pediatric
`
`A population pharmacokinetic analysis was conducted on pooled data from 35
`immunocompromised pediatric patients aged 2 to <12 years old who were included in two
`pharmacokinetic studies of intravenous voriconazole (single dose and multiple dose). Twenty-
`four of these patients received multiple intravenous maintenance doses of 3 mg/kg and 4 mg/kg.
`A comparison of the pediatric and adult population pharmacokinetic data revealed that the
`predicted average steady state plasma concentrations were similar at the maintenance dose of 4
`
`mg/kg every 12 hours in children and 3 mg/kg every 12 hours in adults (medians of 1.19 μg/mL
`and 1.16 μg/mL in children and adults, respectively) (see PRECAUTIONS, Pediatric Use).
`
`
`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 that 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 AND ADMINISTRATION).
`
`
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`Reference ID: 2866932
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`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 30-50 mL/min), the
`systemic exposure (AUC) and peak plasma concentrations (Cmax) were not significantly different
`from those in 6 subjects with normal renal function.
`
`
`However, in patients with moderate renal dysfunction (creatinine clearance 30-50 mL/min),
`accumulation of the intravenous vehicle, SBECD, occurs. The mean systemic exposure (AUC)
`and peak plasma concentrations (Cmax) of SBECD were increased 4-fold and almost 50%,
`respectively, in the moderately impaired group compared to the normal control group.
`
`
`Intravenous voriconazole should be avoided in patients with moderate or severe renal
`impairment (creatinine clearance <50 mL/min), unless an assessment of the benefit/risk to the
`patient justifies the use of intravenous voriconazole (see DOSAGE AND ADMINISTRATION -
`Dosage Adjustment).
`
`
`A pharmacokinetic study in subjects with renal failure undergoing hemodialysis showed that
`voriconazole is dialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is
`hemodialyzed with clearance of 55 mL/min. A 4-hour 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 cytochrome P450 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 three enzymes may increase or decrease voriconazole
`systemic exposure (plasma concentrations), respectively.
`
`
`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 is contraindicated:
`
`
`Rifampin (potent CYP450 inducer): Rifampin (600 mg once daily) decreased the steady state
`Cmax and AUCτ of voriconazole (200 mg Q12h x 7 days) by an average of 93% and 96%,
`respectively, in healthy subjects. Doubling the dose of voriconazole to 400 mg Q12h does not
`restore adequate exposure to voriconazole during coadministration with rifampin.
`Coadministration of voriconazole and rifampin is contraindicated (see
`CONTRAINDICATIONS, PRECAUTIONS - Drug Interactions).
`
`
`
`Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate): The effect of the
`coadministration of voriconazole and ritonavir (400 mg and 100 mg) was investigated in two
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`Reference ID: 2866932
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`

` separate studies. High-dose ritonavir (400 mg Q12h for 9 days) decreased the steady state Cmax
`
`and AUCτ of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 8 days) by an
`average of 66% and 82%, respectively, in healthy subjects. Low-dose ritonavir (100 mg Q12h
`for 9 days) decreased the steady state Cmax and AUCτ of oral voriconazole (400 mg Q12h for 1
`day, then 200 mg Q12h for 8 days) by an average of 24% and 39%, respectively, in healthy
`subjects. Although repeat oral administration of voriconazole did not have a significant effect on
`steady state Cmax and AUCτ of high-dose ritonavir in healthy subjects, steady state Cmax and
`AUCτ of low-dose ritonavir decreased slightly by 24% and 14% respectively, when administered
`concomitantly with oral voriconazole in healthy subjects. Coadministration of voriconazole
`and high-dose ritonavir (400 mg Q12h) is contraindicated. Coadministration of
`
`voriconazole and low-dose ritonavir (100 mg Q12h) should be avoided, unless an
`assessment of the benefit/risk to the patient justifies the use of voriconazole. (see
`CONTRAINDICATIONS, PRECAUTIONS - Drug Interactions).
`
`St. John’s Wort (CYP450 inducer; P-gp inducer): In an independent published study in
`
`healthy volunteers who were given multiple oral doses of St. John’s Wort (300 mg LI 160 extract
`three times daily for 15 days) followed by a single 400 mg oral dose of voriconazole, a 59%
`decrease in mean voriconazole AUC0-∞ was observed. In contrast, coadministration of single oral
`
`doses of St. John’s Wort and voriconazole had no appreciable effect on voriconazole AUC0-∞.
`
` Because long-term use of St. John’s Wort could lead to reduced voriconazole exposure,
`concomitant use of voriconazole with St. John’s Wort is contraindicated (see
`CONTRAINDICATIONS).
`
`Carbamazepine and long-acting barbiturates (potent CYP450 inducers): Although not studied
`in vitro or in vivo, carbamazepine and long-acting barbiturates (e.g., phenobarbital,
`mephobarbital) are likely to significantly decrease plasma voriconazole concentrations.
`Coadministration of voriconazole with carbamazepine or long-acting barbiturates is
`contraindicated (see CONTRAINDICATIONS, PRECAUTIONS - Drug Interactions).
`
`Significant drug interactions that may require voriconazole dosage adjustment, or frequent
`monitoring of voriconazole-related adverse events/toxicity:
`
`Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Concurrent administration of oral
`voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral fluconazole (400
`mg on day 1, then 200 mg Q24h for 4 days) to 6 healthy male subjects resulted in an increase in
`Cmax and AUCτ of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90%
`
`CI: 40%, 128%), respectively. In a follow-on clinical study involving 8 healthy male subjects,
`reduced dosing and/or frequency of voriconazole and fluconazole did not eliminate or diminish
`this effect. Concomitant administration of voriconazole and fluconazole at any dose is not
`recommended. Close monitoring for adverse events related to voriconazole is recommended if
`voriconazole is used sequentially after fluconazole, especially within 24 hours of the last dose of
`fluconazole. (see PRECAUTIONS - Drug Interactions).
`
`Minor or no significant pharmacokinetic interactions that do not require dosage adjustment:
`
`
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`Reference ID: 2866932
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` Cimetidine (non-specific CYP450 inhibitor and increases gastric pH): Cimetidine (400 mg
`
`Q12h x 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
`Q12h x 7 days to healthy subjects.
`
`
`Ranitidine (increases gastric pH): Ranitidine (150 mg Q12h) had no significant effect on
`voriconazole Cmax and AUCτ following oral doses of 200 mg Q12h x 7 days to healthy subjects.
`
`
`
`Macrolide antibiotics: Coadministration of erythromycin (CYP3A4 inhibitor;1g Q12h for 7
`days) or azithromycin (500 mg qd for 3 days) with voriconazole 200 mg Q12h 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 cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. In these studies,
`the inhibition potency of voriconazole for CYP3A4 metabolic activity was significantly less than
`that of two 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.
`
`
`The systemic exposure of the following drugs is significantly increased or is expected to be
`significantly increased by coadministration of voriconazole and their use is contraindicated:
`
`
`Sirolimus (CYP3A4 substrate): Repeat dose administration of oral voriconazole (400 mg Q12h
`for 1 day, then 200 mg Q12h 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 male subjects. Coadministration of voriconazole and sirolimus is contraindicated
`(see CONTRAINDICATIONS, PRECAUTIONS - Drug 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. Coadministration of voriconazole and terfenadine,
`astemizole, cisapride, pimozide and quinidine is contraindicated (see
`
`CONTRAINDICATIONS, PRECAUTIONS - Drug 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.
`Coadministration of voriconazole with ergot alkaloids is contraindicated (see
`CONTRAINDICATIONS, PRECAUTIONS - Drug Interactions).
`
`
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`Reference ID: 2866932
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`

`Coadministration 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:
`
`
`Alfentanil (CYP3A4 substrate): Coadministration of multiple doses of oral voriconazole (400
`
`mg q12h on day 1, 200 mg q12h on day 2) with a single 20 mcg/kg intravenous dose of
`alfentanil with concomitant naloxone resulted in a 6-fold increase in mean alfentanil AUC0-∞ and
`
`a 4-fold prolongation of mean alfentanil elimination half-life, compared to when alfentanil was
`given alone. An increase in the incidence of delayed and persistent alfentanil-associated nausea
`and vomiting during co-administration of voriconazole and alfentanil was also observed.
`Reduction in the dose of alfentanil or other opiates that are also metabolized by CYP3A4 (e.g.,
`sufentanil), and extended close monitoring of patients for respiratory and other opiate-associated
`adverse events, may be necessary when any of these opiates is coadministered with
`voriconazole. (see PRECAUTIONS – Drug Interactions).
`
`Fentanyl (CYP3A4 substrate): In an independent published study,concomitant use of
`
`voriconazole (400 mg Q12h on Day 1, then 200 mg Q12h on Day 2) with a single intravenous
`dose of fentanyl (5 µg/kg) resulted in an increase in the mean AUC 0-∞ of fentanyl by 1.4-fold
`
`(range 0.81- to 2.04-fold). When voriconazole is co-administered with fentanyl IV, oral or
`transdermal dosage forms, 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. (see PRECAUTIONS – Drug Interactions).
`
`Oxycodone (CYP3A4 substrate): In an independent published study, coadministration of
`
` multiple doses of oral voriconazole (400 mg Q12h ,on Day 1 followed by five doses of 200 mg
`Q12h on Days 2 to 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 2.0-fold (range 1.4- to 2.5-fold). Voriconazole also increased the visual
`effects (heterophoria and miosis) of oxycodone. 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. (see PRECAUTIONS - Drug Interactions).
`
`Cyclosporine (CYP3A4 substrate): In stable renal transplant recipients receiving chronic
`cyclosporine therapy, concomitant administration of oral voriconazole (200 mg Q12h 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, 2.0), 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 one-half 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 PRECAUTIONS - Drug Interactions).
`
`
`
`
`Reference ID: 2866932
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`

`

`Methadone (CYP3A4, CYP2C19, CYP2C9 substrate): Repeat dose administration of oral
`voriconazole (400mg Q12h for 1 day, then 200mg Q12h 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
`
`QD). The Cmax and AUC of (S)-methadone increased by 65% (90% CI: 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 coadministration. Dose reduction of
`methadone may be needed (see PRECAUTIONS - Drug Interactions).
`
`Tacrolimus (CYP3A4 substrate): Repeat oral dose administration of voriconazole (400 mg
`
`Q12h x 1 day, then 200 mg Q12h x 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 one-third 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 PRECAUTIONS -
`Drug Interactions).
`
`
`Warfarin (CYP2C9 substrate): Coadministration of voriconazole (300 mg Q12h x 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
`coadministered and the warfarin dose adjusted accordingly (see PRECAUTIONS - Drug
`Interactions).
`
`
`Oral Coumarin Anticoagulants (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 anti­
`coagulation tests should be monitored at close intervals and the dosage of anticoagulants
`adjusted accordingly (see PRECAUTIONS - Drug 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 the plasma concentrations of statins that are metabolized by CYP3A4. It is
`recommended that dose adjustment of the statin be considered during coadministration.
`Increased statin concentrations in plasma have been associated with rhabdomyolysis (see
`PRECAUTIONS - Drug 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 (e.g., midazolam, triazolam, and alprazolam) and lead to a prolonged
`
`Reference ID: 2866932
`
`11
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`

`

`sedative effect. It is recommended that dose adjustment of the benzodiazepine be considered
`during coadministration (see PRECAUTIONS - Drug 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 coadministration. Dose
`adjustment of the calcium channel blocker may be needed (see PRECAUTIONS - Drug
`Interactions).
`
`
`Sulfonylureas (CYP2C9 su