voriconazole 50 mg Tablet, Film Coated, 30-count — NDC 43386-088-03 (Billing 43386-0088-03)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Voriconazole is an antifungal drug [ see Microbiology ( 12.4 )]

12.2Pharmacodynamics Exposure-Response Relationship For Efficacy and Safety In 10 clinical trials (N=1121), the median values for the average and maximum voriconazole plasma concentrations in individual patients across these studies 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, pharmacokinetic/pharmacodynamic 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 ( 6 )] . Cardiac Electrophysiology 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 ( 4 ) and Drug Interactions ( 7 )] .

12.3Pharmacokinetics 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 from 200 mg every 12 hours to 300 mg every 12 hours leads to an approximately 2.5-fold increase in exposure (AUCt); similarly, increasing the intravenous dose from 3 mg/kg every 12 hours to 4 mg/kg every 12 hours produces an approximately 2.5-fold increase in exposure (Table 12). Table 12: Geometric Mean (%CV) Plasma Voriconazole Pharmacokinetic Parameters in Adults Receiving Different Dosing Regimens Note: Parameters were estimated based on non-compartmental analysis from 5 pharmacokinetic studies.

AUC12 = area under the curve over 12 hour dosing interval, Cmax = maximum plasma concentration, Cmin =minimum plasma concentration. CV = coefficient of variation. 6 mg/kg IV (loading dose) 3 mg/kg IV every 12 hours 4 mg/kg IV every 12 hours 400 mg Oral (loading dose) 200 mg Oral every 12 hours 300 mg Oral every 12 hours N 35 23 40 17 48 16 AUC12 (μg∙h/mL) 13.9 (32) 13.7 (53) 33.9 (54) 9.31 (38) 12.4 (78) 34.0 (53) Cmax (μg/mL) 3.13 (20) 3.03 (25) 4.77 (36) 2.30 (19) 2.31 (48) 4.74 (35) Cmin (μg/mL) - 0.46 (97) 1.73 (74) - 0.46 (120) 1.63 (79) When the recommended intravenous loading dose regimen is administered to healthy subjects, plasma concentrations close to steady state are achieved within the first 24 hours of dosing (e.g., 6 mg/kg IV every 12 hours on day 1 followed by 3 mg/kg IV every 12 hours).

Without the loading dose, accumulation occurs during twice daily multiple dosing with steady state plasma voriconazole concentrations being achieved by day 6 in the majority of subjects. Absorption The pharmacokinetic properties of voriconazole are similar follow… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Voriconazole is an antifungal drug [ see Microbiology ( 12.4 )]

12.3Pharmacokinetics 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 from 200 mg every 12 hours to 300 mg every 12 hours leads to an approximately 2.5-fold increase in exposure (AUCt); similarly, increasing the intravenous dose from 3 mg/kg every 12 hours to 4 mg/kg every 12 hours produces an approximately 2.5-fold increase in exposure (Table 12). Table 12: Geometric Mean (%CV) Plasma Voriconazole Pharmacokinetic Parameters in Adults Receiving Different Dosing Regimens Note: Parameters were estimated based on non-compartmental analysis from 5 pharmacokinetic studies.

AUC12 = area under the curve over 12 hour dosing interval, Cmax = maximum plasma concentration, Cmin =minimum plasma concentration. CV = coefficient of variation. 6 mg/kg IV (loading dose) 3 mg/kg IV every 12 hours 4 mg/kg IV every 12 hours 400 mg Oral (loading dose) 200 mg Oral every 12 hours 300 mg Oral every 12 hours N 35 23 40 17 48 16 AUC12 (μg∙h/mL) 13.9 (32) 13.7 (53) 33.9 (54) 9.31 (38) 12.4 (78) 34.0 (53) Cmax (μg/mL) 3.13 (20) 3.03 (25) 4.77 (36) 2.30 (19) 2.31 (48) 4.74 (35) Cmin (μg/mL) - 0.46 (97) 1.73 (74) - 0.46 (120) 1.63 (79) When the recommended intravenous loading dose regimen is administered to healthy subjects, plasma concentrations close to steady state are achieved within the first 24 hours of dosing (e.g., 6 mg/kg IV every 12 hours on day 1 followed by 3 mg/kg IV every 12 hours).

Without the loading dose, accumulation occurs during twice daily multiple dosing with steady state plasma voriconazole concentrations being achieved by day 6 in the majority of subjects. Absorption 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 every 12 hours loading dose followed by a 200 mg every 12 hours maintenance dose. Maximum plasma concentrations (C max ) are achieved 1-2 hours after dosing. When multiple doses of voriconazole are administered with high-fat meals, the mean C max and AUCt are reduced by 34% and 24%, respectively when administered as a tablet and by 58% and 37% respectively when administered as the oral suspension [ see Dosage and Administration ( 2 ) ].

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

4.6L/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 mg/mL). Varying degrees of hepatic and renal impairment do not affect the protein binding of voriconazole.

Elimination Metabolism In vitro studies showed that voriconazole is metabolized by the human hepatic cytochrome P450 enzymes, CYP2C19, CYP2C9 and CYP3A4 [ see Drug Interactions ( 7 ) ]. In vivo studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism [see Clinical Pharmacology ( 12.5 )] .

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 d… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Exposure-Response Relationship For Efficacy and Safety In 10 clinical trials (N=1121), the median values for the average and maximum voriconazole plasma concentrations in individual patients across these studies 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, pharmacokinetic/pharmacodynamic 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 ( 6 )] . Cardiac Electrophysiology 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 ( 4 ) and Drug Interactions ( 7 )] .

14 CLINICAL STUDIES Voriconazole, administered orally or parenterally, has been evaluated as primary or salvage therapy in 520 patients aged 12 years and older with infections caused by Aspergillus spp., Fusarium spp., and Scedosporium spp.

14.1Invasive Aspergillosis (IA) Voriconazole was studied in patients for primary therapy of IA (randomized, controlled study 307/602), for primary and salvage therapy of aspergillosis (non-comparative study 304) and for treatment of patients with IA who were refractory to, or intolerant of, other antifungal therapy (non-comparative study 309/604). Study 307/602 – Primary Therapy of Invasive Aspergillosis The efficacy of voriconazole compared to amphotericin B in the primary treatment of acute IA was demonstrated in 277 patients treated for 12 weeks in a randomized, controlled study (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 IA of the lungs.

Other aspergillosis infections included disseminated disease, CNS infections and sinus infections. Diagnosis of definite or probable IA was made according to criteria modified from those established by the National Institute of Allergy and Infectious Diseases Mycoses Study Group/European Organisation for Research and Treatment of Cancer (NIAID MSG/EORTC). Voriconazole was administered intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours followed by a maintenance dose of 4 mg/kg every 12 hours for a minimum of 7 days.

Therapy could then be switched to the oral formulation at a dose of 200 mg every 12 hours. Median duration of IV voriconazole therapy was 10 days (range 2 - 85 days). After IV voriconazole therapy, the median duration of PO voriconazole therapy was 76 days (range 2 - 232 days).

Patients in the comparator group received conventional amphotericin B as a slow infusion at a daily dose of 1.0 - 1.5 mg/kg/day. Median duration of IV amphotericin therapy was 12 days (range 1 - 85 days). Treatment was then continued with OLAT, including itraconazole and lipid amphotericin B formulations.

Although initial therapy with conventional amphotericin B was to be continued for at least two 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 (Table 15).

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 (Table 13). Table 13 also summarizes the response (success) based on mycological confirmation and species. Table 13: Overall Efficacy and Success by Species in the Primary Treatment of Acute Invasive Aspergillosis Study 307/602 a Assessed by independent Data Review Committee (DRC) b Proportion of subjects alive c Amphotericin B followed by other licensed antifungal therapy d Difference and corresponding 95% confidence interval are stratified by protocol e Not all mycologically confirmed specimens were speciated f Some patients had more than one species isolated at baseline Voriconazole Ampho B c Stratified Difference (95% CI) d n/N (%) n/N (%) Efficacy as Primary Therapy Satisfactory Global Response a 76/144 (53) 42/133 (32) 21.8% (10.5%, 33.0%) p<0.0001 Survival at Day 84 b 102/144 (71) 77/133 (58) 13.1% (2.1%, 24.2%) Success by Species Success n/N (%) Overall success 76/144 (53) 42/133 (32) Mycologically confirmed e 37/84 (44) 16/67 (24) Aspergil… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, 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 RMD on a body surface area 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 body surface area 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 assay, CHO HGPRT assay, the mouse micronucleus assay or the in vivo DNA repair test (Unscheduled DNA Synthesis assay). Voriconazole administration induced no impairment of male or female fertility in rats dosed at 50 mg/kg, or 1.6 times the RMD.