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:

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).

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
	200 mg Oral Q12h	300 mg Oral Q12h	3 mg/kg IV Q12h	4 mg/kg IV Q12h
* Mean AUC τ are predicted values from population pharmacokinetic analysis of data from 236 subjects
AUCτ* (µg∙h/mL) (CV%)	19.86 (94%)	50.32 (74%)	21.81 (100%)	50.40 (83%)

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).

Table 2 Pharmacokinetic Parameters of Voriconazole in Patients at Risk for Aspergillosis
	200 mg Oral Q12h (n=9)	300 mg Oral Q12h (n=9)
* Geometric mean values on Day 14 of multiple dosing in 2 cohorts of patients
AUCτ* (µg∙h/mL ) (CV%)	20.31 (69%)	36.51 (45%)
Cmax* (µg/mL) (CV%)	3.00 (51%)	4.66 (35%)

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)		6 mg/kg IV* Q12h on Day 1, 3 mg/kg IV Q12h on Days 2 to 10 (n=9)
	Day 1, 1st dose	Day 10	Day 1, 1st dose	Day 10
* IV infusion over 60 minutes † AUC τ values are calculated over dosing interval of 12 hours Pharmacokinetic parameters for loading and maintenance doses summarized for same cohort of subjects
AUCτ† (µg∙h/mL) (CV%)	9.31 (38%)	11.13 (103%)	13.22 (22%)	13.25 (58%)
Cmax (µg/mL) (CV%)	2.30 (19%)	2.08 (62%)	4.70 (22%)	3.06 (31%)

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