Voriconazole

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.

Voriconazole drug substance is a white to off-white powder.

Voriconazole tablets contain 50 mg or 200 mg of voriconazole. The inactive ingredients include croscarmellose sodium, lactose monohydrate, magnesium stearate, polyethylene glycol, polyvinyl alcohol, povidone, pregelatinized starch, talc, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Voriconazole is an antifungal drug [see Microbiology (12.4)]

12.3 Pharmacokinetics

General Pharmacokinetic Characteristics

The pharmacokinetics of voriconazole have been characterized in healthy subjects, special populations and patients.

During oral administration of 200 mg or 300 mg twice daily for 14 days in patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or hematopoietic tissue), the observed pharmacokinetic characteristics were similar to those observed in healthy subjects.

The pharmacokinetics of voriconazole are nonlinear 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 q12h to 300 mg q12h leads to an approximately a 2.5 fold increase in exposure (AUC_τ); similarly, increasing the intravenous dose from 3 mg/kg q12h to 4 mg/kg q12h produces an approximately a 2.5 fold increase in exposure (Table 9).

Table 9

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, C_max = maximum plasma concentration, C_min = minimum plasma concentration. CV = coefficient of variation

Sparse plasma sampling for pharmacokinetics was conducted in the therapeutic studies in patients aged 12 to 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 to 2.73 mcg/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 mcg/mL (inter-quartile range 0.85 to 2.14 mcg/mL).

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 q12h on day 1 followed by 3 mg/kg IV q12h). 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 q12h loading dose followed by a 200 mg q12h maintenance dose.

Maximum plasma concentrations (C_max) are achieved 1 to 2 hours after dosing. When multiple doses of voriconazole are administered with high-fat meals, the mean C_max 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 (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 4.6 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 to 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 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. For example, 15 to 20% of Asian populations may be expected to be poor metabolizers. For Caucasians and Blacks, the prevalence of poor metabolizers is 3 to 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 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 mcg/mL (inter-quartile range 1.21 to 4.44 mcg/mL) and 3.79 mcg/mL (inter-quartile range 2.06 to 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, 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)].

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 (4) and Drug Interactions (7)].

Pharmacokinetics in Special Populations

Gender

In a multiple oral dose study, the mean C_max and AUC_τ for healthy young females were 83% and 113% higher, respectively, than in healthy young males (18 to 45 years), after tablet dosing. In the same study, no significant differences in the mean C_max and AUC_τ 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 C_max was comparable between genders. The steady-state trough voriconazole concentrations (C_min) seen in females were 100% and 91% higher than in males receiving the tablet and the oral suspension, respectively.

In the clinical program, no dosage adjustment was made on the basis of gender. The safety profile and plasma concentrations observed in male and female subjects were similar. Therefore, no dosage adjustment based on gender is necessary.

Geriatric

In an oral multiple dose study the mean C_max and AUC_τ in healthy elderly males (≥ 65 years) were 61% and 86% higher, respectively, than in young males (18 to 45 years). No significant differences in the mean C_max and AUC_τ were observed between healthy elderly females (≥ 65 years) and healthy young females (18 to 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 [see Use in Special Populations (8.5)].

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 pediatric patients and 3 mg/kg every 12 hours in adults (medians of 1.19 mcg/mL and 1.16 mcg/mL in pediatric patients and adults, respectively) [see Use in Specific Populations (8.4)].

Hepatic Impairment

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 (C_max) 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, AUC_τ 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 (C_max) 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 (2.7)].

Renal Impairment

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 (C_max) 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 to 50 mL/min), the systemic exposure (AUC) and peak plasma concentrations (C_max) were not significantly different from those in 6 subjects with normal renal function.

However, in patients with moderate renal dysfunction (creatinine clearance 30 to 50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. The mean systemic exposure (AUC) and peak plasma concentrations (C_max) 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 (2.8)].

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 C_max and AUC_τ 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 (4) and Warnings and Precautions (5.1)].

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 separate studies. High dose ritonavir (400 mg q12h for 9 days) decreased the steady state C_max and AUC_τ 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 C_max and AUC_τ 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 C_max and AUC_τ of high-dose ritonavir in healthy subjects, steady state C_max and AUC_τ 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 (4) and Warnings and Precautions (5.1)].

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 AUC_{0 to ∞} was observed. In contrast, coadministration of single oral doses of St. John’s Wort and voriconazole had no appreciable effect on voriconazole AUC_{0 to ∞}. 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 (4)].

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 (4) and Warnings and Precautions (5.1)].

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 C_max and AUC_τ 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 Warnings and Precautions (5.1)].

Minor or no significant pharmacokinetic interactions that do not require dosage adjustment:

Cimetidine (non-specific CYP450 inhibitor and increases gastric pH)

Cimetidine (400 mg q12h x 8 days) increased voriconazole steady state C_max and AUC_τ 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 C_max and AUC_τ 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 q24h for 3 days) with voriconazole 200 mg q12h for 14 days had no significant effect on voriconazole steady state C_max and AUC_τ 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 C_max 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 (4) and Warnings and Precautions (5.1)].

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 (4) and Warnings and Precautions (5.1)].

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 (4) and Warnings and Precautions (5.1)].

Everolimus (CYP3A4 substrate, P-gp substrate)

Although not studied in vitro or in vivo, voriconazole may increase plasma concentrations of everolimus, which could potentially lead to exacerbation of everolimus toxicity. Currently there are insufficient data to allow dosing recommendations in this situation. Therefore, coadministration of voriconazole with everolimus is not recommended [see Drug Interactions ( 7)].

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 AUC_{0 to ∞} 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 coadministration 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 Warnings and Precautions (5.1)].

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 mcg/kg) resulted in an increase in the mean AUC_{0 to ∞} of fentanyl by 1.4 fold (range 0.81 to 2.04 fold). When voriconazole is coadministered 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 Warnings and Precautions (5.1)].

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 C_max and AUC_{0 to ∞} 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). 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 Warnings and Precautions (5.1)].

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 C_max and AUC_τ 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 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 Warnings and Precautions (5.1)].

Methadone (CYP3A4, CYP2C19, CYP2C9 substrate)

Repeat dose administration of oral voriconazole (400 mg q12h for 1 day, then 200 mg q12h for 4 days) increased the C_max and AUC_τ 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 to 100 mg q24h). The C_max 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 Warnings and Precautions (5.1)].

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) C_max and AUC_τ 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 Warnings and Precautions (5.1)].

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 are recommended if warfarin and voriconazole are coadministered and the warfarin dose adjusted accordingly [see Warnings and Precautions (5.1)].

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 Warnings and Precautions (5.1)].

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 Warnings and Precautions (5.1)].

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 sedative effect. It is recommended that dose adjustment of the benzodiazepine be considered during coadministration [see Warnings and Precautions (5.1)].

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 Warnings and Precautions (5.1)].

Sulfonylureas (CYP2C9 substrates)

Although not studied in vitro or in vivo, voriconazole may increase plasma concentrations of sulfonylureas (e.g., tolbutamide, glipizide, and glyburide) and therefore cause hypoglycemia. Frequent monitoring of blood glucose and appropriate adjustment (i.e., reduction) of the sulfonylurea dosage is recommended during coadministration [see Warnings and Precautions (5.1)].

Vinca Alkaloids (CYP3A4 substrates)

Although not studied in vitro or in vivo, voriconazole may increase the plasma concentrations of the vinca alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity. Therefore, it is recommended that dose adjustment of the vinca alkaloid be considered [see Warnings and Precautions (5.1)].

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs; CYP2C9 substrates)

In two independent published studies, single doses of ibuprofen (400 mg) and diclofenac (50 mg) were coadministered with the last dose of voriconazole (400 mg q12h on Day 1, followed by 200 mg q12h on Day 2). Voriconazole increased the mean C_max and AUC of the pharmacologically active isomer, S (+)-ibuprofen by 20% and 100%, respectively. Voriconazole increased the mean C_max and AUC of diclofenac by 114% and 78%, respectively.

A reduction in ibuprofen and diclofenac dosage may be needed during concomitant administration with voriconazole. Patients receiving voriconazole concomitantly with other NSAIDs (e.g., celecoxib, naproxen, lornoxicam, meloxicam) that are also metabolized by CYP2C9 should be carefully monitored for NSAID-related adverse events and toxicity, and dosage reduction should be made if warranted [see Warnings and Precautions (5.1)].

No significant pharmacokinetic interactions were observed when voriconazole was coadministered with the following agents. Therefore, no dosage adjustment for these agents is recommended:

Prednisolone (CYP3A4 substrate)

Voriconazole (200 mg q12h x 30 days) increased C_max and AUC 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 q12h x 12 days) had no significant effect on steady state C_max and AUC_τ of digoxin (0.25 mg once daily for 10 days) in healthy subjects.

Mycophenolic acid (UDP-glucuronyl transferase substrate)

Voriconazole (200 mg q12h x 5 days) had no significant effect on the C_max and AUC_τ 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:

Rifabutin (potent CYP450 inducer)

Rifabutin (300 mg once daily) decreased the C_max and AUC_τ of voriconazole at 200 mg twice daily by an average of 67% (90% CI: 58%, 73%) and 79% (90% CI: 71%, 84%), respectively, in healthy subjects. During coadministration with rifabutin (300 mg once daily), the steady state C_max and AUC_τ of voriconazole following an increased dose of 400 mg twice daily were on average approximately 2 times higher, compared with voriconazole alone at 200 mg twice daily. Coadministration of voriconazole at 400 mg twice daily with rifabutin 300 mg twice daily increased the C_max and AUC_τ of rifabutin by an average of 3 times (90% CI: 2.2, 4) and 4 times (90% CI: 3.5, 5.4), respectively, compared to rifabutin given alone. Coadministration of voriconazole and rifabutin is contraindicated [see Contraindications (4)].

Significant drug interactions that may require dosage adjustment, frequent monitoring of drug levels and/or frequent monitoring of drug-related adverse events/toxicity:

Efavirenz, a non-nucleoside reverse transcriptase inhibitor (CYP450 inducer; CYP3A4 inhibitor and substrate)

Standard doses of voriconazole and efavirenz (400 mg q24h or higher) must not be coadministered [see Drug Interactions (7)]. Steady state efavirenz (400 mg PO q24h) decreased the steady state C_max and AUC_τ of voriconazole (400 mg PO q12h for 1 day, then 200 mg PO q12h for 8 days) by an average of 61% and 77%, respectively, in healthy male subjects. Voriconazole at steady state (400 mg PO q12h for 1 day, then 200 mg q12h for 8 days) increased the steady state C_max and AUC_τ of efavirenz (400 mg PO q24h for 9 days) by an average of 38% and 44%, respectively, in healthy subjects.

The pharmacokinetics of adjusted doses of voriconazole and efavirenz were studied in healthy male subjects following administration of voriconazole (400 mg PO q12h on Days 2 to 7) with efavirenz (300 mg PO q24h on Days 1 to 7), relative to steady state administration of voriconazole (400 mg for 1 day, then 200 mg PO q12h for 2 days) or efavirenz (600 mg q24h for 9 days). Coadministration of voriconazole 400 mg q12h with efavirenz 300 mg q24h, decreased voriconazole AUC_τ by 7% (90% CI: -23%, 13%) and increased C_max by 23% (90% CI: -1%, 53%); efavirenz AUC_τ was increased by 17% (90% CI: 6%, 29%) and C_max was equivalent.

Coadministration of standard doses of voriconazole and efavirenz (400 mg q24h or higher) is contraindicated.
Voriconazole may be coadministered with efavirenz if the voriconazole maintenance dose is increased to 400 mg q12h and the efavirenz dose is decreased to 300 mg q24h. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored [see Dosage and Administration (2.4), Contraindications (4), and Drug Interactions (7)].

Phenytoin (CYP2C9 substrate and potent CYP450 inducer)

Repeat dose administration of phenytoin (300 mg once daily) decreased the steady state C_max and AUC_τ of orally administered voriconazole (200 mg q12h x 14 days) by an average of 50% and 70%, respectively, in healthy subjects. Administration of a higher voriconazole dose (400 mg q12h x 7 days) with phenytoin (300 mg once daily) resulted in comparable steady state voriconazole C_max and AUC_τ estimates as compared to when voriconazole was given at 200 mg q12h without phenytoin.

Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased from 4 mg/kg to 5 mg/kg intravenously every 12 hours or from 200 mg to 400 mg orally, every 12 hours (100 mg to 200 mg orally, every 12 hours in patients less than 40 kg) [see Dosage and Administration (2.4) and Drug Interactions (7)].

Repeat dose administration of voriconazole (400 mg q12h x 10 days) increased the steady state C_max and AUC_τ of phenytoin (300 mg once daily) by an average of 70% and 80%, respectively, in healthy subjects. The increase in phenytoin C_max and AUC when coadministered with voriconazole may be expected to be as high as 2 times the C_max 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 coadministered with voriconazole [see Warnings and Precautions (5.1)].

Omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate)

Coadministration of omeprazole (40 mg once daily x 10 days) with oral voriconazole (400 mg q12h x 1 day, then 200 mg q12h x 9 days) increased the steady state C_max and AUC_τ 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.

Coadministration of voriconazole (400 mg q12h x 1 day, then 200 mg x 6 days) with omeprazole (40 mg once daily x 7 days) to healthy subjects significantly increased the steady state C_max and AUC_τ 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 of 40 mg or greater, it is recommended that the omeprazole dose be reduced by one-half [see Warnings and Precautions (5.1)].

The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of these drugs.

Oral Contraceptives (CYP3A4 substrate; CYP2C19 inhibitor)

Coadministration of oral voriconazole (400 mg q12h for 1 day, then 200 mg q12h for 3 days) and oral contraceptive (Ortho-Novum1/35^® consisting of 35 mcg ethinyl estradiol and 1 mg norethindrone, q24h) to healthy female subjects at steady state increased the C_max and AUC_τ of ethinyl estradiol by an average of 36% (90% CI: 28%, 45%) and 61% (90% CI: 50%, 72%), respectively, and that of norethindrone by 15% (90% CI: 3%, 28%) and 53% (90% CI: 44%, 63%), respectively in healthy subjects. Voriconazole C_max and AUC_τ increased by an average of 14% (90% CI: 3%, 27%) and 46% (90% CI: 32%, 61%), respectively. Monitoring for adverse events related to oral contraceptives, in addition to those for voriconazole, is recommended during coadministration [see Warnings and Precautions (5.1)].

No significant pharmacokinetic interaction was seen and no dosage adjustment of these drugs is recommended:

Indinavir (CYP3A4 inhibitor and substrate)

Repeat dose administration of indinavir (800 mg TID for 10 days) had no significant effect on voriconazole C_max and AUC following repeat dose administration (200 mg q12h for 17 days) in healthy subjects.

Repeat dose administration of voriconazole (200 mg q12h for 7 days) did not have a significant effect on steady state C_max and AUC_τ of indinavir following repeat dose administration (800 mg TID for 7 days) in healthy subjects.

Other Two-Way Interactions Expected to be Significant Based on In Vitro and In Vivo 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 (e.g., saquinavir, amprenavir and nelfinavir). In vitro studies (human liver microsomes) also show that the metabolism of voriconazole may be inhibited by HIV protease inhibitors (e.g., saquinavir and amprenavir). Patients should be frequently monitored for drug toxicity during the coadministration of voriconazole and HIV protease inhibitors [see Warnings and Precautions (5.1)].

Other Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (CYP3A4 substrates, inhibitors or CYP450 inducers)

In vitro studies (human liver microsomes) show that the metabolism of voriconazole may be inhibited by a NNRTI (e.g., delavirdine). The findings of a clinical voriconazole-efavirenz drug interaction study in healthy male subjects suggest that the metabolism of voriconazole may be induced by a NNRTI. This in vivo study also showed that voriconazole may inhibit the metabolism of a NNRTI [see Drug Interactions (7) and Warnings and Precautions (5.9)]. Patients should be frequently monitored for drug toxicity during the coadministration of voriconazole and other NNRTIs (e.g., nevirapine and delavirdine) [see Warnings and Precautions (5.1)]. Dose adjustments are required when voriconazole is coadministered with efavirenz [see Drug Interactions (7) and Warnings and Precautions (5.1)].

12.4 Microbiology

Mechanism of Action

Voriconazole is an azole antifungal agent. The primary mode of action of voriconazole is the inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell wall and may be responsible for the antifungal activity of voriconazole.

Drug Resistance

Voriconazole drug resistance development has not been adequately studied in vitro against Candida, Aspergillus, Scedosporium and Fusarium species. 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.

Activity In Vitro and In Vivo

Voriconazole has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections:

Aspergillus fumigatus

Aspergillus flavus

Aspergillus niger

Aspergillus terreus

Candida albicans

Candida glabrata (In clinical studies, the voriconazole MIC₉₀ was 4 mcg/mL)*

Candida krusei

Candida parapsilosis

Candida tropicalis

Fusarium spp. including Fusarium solani

Scedosporium apiospermum

*In clinical studies, voriconazole MIC₉₀ for C. glabrata baseline isolates was 4 mcg/mL; 13/50 (26%) C. glabrata baseline isolates were resistant (MIC ≥ 4 mcg/mL) to voriconazole. However, based on 1054 isolates tested in surveillance studies the MIC₉₀ was 1 mcg/mL (see Table 12).

The following data are available, but their clinical significance is unknown.

Voriconazole exhibits in vitro minimal inhibitory concentrations (MICs) of 1 mcg/mL or less against most (≥ 90%) isolates of the following microorganisms; however, the safety and effectiveness of voriconazole in treating clinical infections due to these Candida species have not been established in adequate and well-controlled clinical trials:

Candida lusitaniae

Candida guilliermondii

Susceptibility Testing Methods^1,2

Aspergillus species and other filamentous fungi

No interpretive criteria have been established for Aspergillus species and other filamentous fungi.

Candida species

The interpretive standards for voriconazole against Candida species are applicable only to tests performed using Clinical Laboratory and Standards Institute (CLSI) microbroth dilution reference method M27 for MIC read at 48 hours or disk diffusion reference method M44 for zone diameter read at 24 hours.^1,2

Broth Microdilution Techniques –Quantitative methods are used to determine antifungal minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida spp. to antifungal agents. MICs should be determined using a standardized procedure at 48 hours.¹ Standardized procedures are based on a microdilution method (broth) with standardized inoculum concentrations and standardized concentrations of voriconazole powder. The MIC values should be interpreted according to the criteria provided in Table 10.

Diffusion Techniques –Qualitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One such standardized procedure requires the use of standardized inoculum concentrations.¹ This procedure uses paper disks impregnated with 1 mcg of voriconazole to test the susceptibility of yeasts to voriconazole at 24 hours. Disk diffusion interpretive criteria are also provided in Table 10.

Table 10

Susceptibility Interpretive Criteria for Voriconazole^1,2

NOTE: Shown are the breakpoints (mcg/mL) for voriconazole against Candida species.

The susceptible category implies that isolates are inhibited by the usually achievable concentrations of antifungal agent tested when the recommended dosage is used for the site of infection. The intermediate category implies that an infection due to the isolate may be appropriately treated in body sites where the drugs are physiologically concentrated or when a high dosage of drug is used. The resistant category implies that isolates are not inhibited by the usually achievable concentrations of the agent with normal dosage schedules and clinical efficacy of the agent against the isolate has not been reliably shown in treatment studies.

Quality Control

Standardized susceptibility test procedures require the use of quality control organisms to ensure the accuracy of the technical aspects of the test procedures. Standard voriconazole powder and 1 mcg disks should provide the following range of values noted in Table 11.

NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant.

Table 11

Acceptable Quality Control Ranges for Voriconazole to be Used in Validation of Susceptibility Test Results

 * Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive
interlaboratory variation during initial quality control studies.
ATCC is a registered trademark of the American Type Culture Collectio

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, 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 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 assay, CHO assay, the mouse micronucleus assay or the 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 (recommended maintenance dose).

13.2 Teratogenic Effects

Pregnancy Category D [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1)]. 

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.

14.1 Invasive Aspergillosis

Voriconazole was studied in patients for primary therapy of invasive aspergillosis (randomized, controlled study 307/602), for primary and salvage therapy of aspergillosis (non-comparative study 304) and for treatment of patients with invasive aspergillosis 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 invasive aspergillosis 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 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 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 seven days. Therapy could then be switched to the oral formulation at a dose of 200 mg q12h. Median duration of IV voriconazole therapy was 10 days (range 2 to 85 days). After IV voriconazole therapy, the median duration of PO voriconazole therapy was 76 days (range 2 to 232 days).

Patients in the comparator group received conventional amphotericin B as a slow infusion at a daily dose of 1 to 1.5 mg/kg/day. Median duration of IV amphotericin therapy was 12 days (range 1 to 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 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 14). 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 12).

Table 12 also summarizes the response (success) based on mycological confirmation and species.

Table 12

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

Study 304 – Primary and Salvage Therapy of Aspergillosis

In this non-comparative 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 13.

Study 309/604 – Treatment of Patients With Invasive Aspergillosis who were Refractory to, or Intolerant of, other Antifungal Therapy

Additional data regarding response rates in patients who were refractory to, or intolerant of, other antifungal agents are also provided in Table 15. In this non-comparative study, 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 13.

Table 13

Combined Response Data in Salvage Patients With Single Aspergillus Species

(Studies 304 and 309/604)

Nineteen patients had more than one species of Aspergillus isolated. Success was seen in 4/17 (24%) of these patients.

14.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue Infections

Voriconazole was compared to the regimen of amphotericin B followed by fluconazole in Study 608, an open label, comparative study in nonneutropenic patients with candidemia associated with clinical signs of infection. Patients were randomized in 2:1 ratio to receive either voriconazole (n = 283) or the regimen of amphotericin B followed by fluconazole (n = 139). Patients were treated with randomized study drug for a median of 15 days. Most of the candidemia in patients evaluated for efficacy was caused by C. albicans (46%), followed by C. tropicalis (19%), C. parapsilosis (17%), C. glabrata (15%), and C. krusei (1%).

An independent Data Review Committee (DRC), blinded to study treatment, reviewed the clinical and mycological data from this study, and generated one assessment of response for each patient. A successful response required all of the following: resolution or improvement in all clinical signs and symptoms of infection, blood cultures negative for Candida, infected deep tissue sites negative for Candida or resolution of all local signs of infection, and no systemic antifungal therapy other than study drug. The primary analysis, which counted DRC-assessed successes at the fixed time point (12 weeks after End of Therapy [EOT]), demonstrated that voriconazole was comparable to the regimen of amphotericin B followed by fluconazole (response rates of 41% and 41%, respectively) in the treatment of candidemia. Patients who did not have a 12 week assessment for any reason were considered a treatment failure.

The overall clinical and mycological success rates by Candida species in Study 150-608 are presented in Table 14.

Table 14

Overall Success Rates Sustained From EOT to the Fixed 12 Week Follow-up Time Point by Baseline Pathogen^a,b

^a A few patients had more than one pathogen at baseline.
^b Patients who did not have a 12 week assessment for any reason were considered a treatment failure.

In a secondary analysis, which counted DRC-assessed successes at any time point (EOT, or 2, 6, or 12 weeks after EOT), the response rates were 65% for voriconazole and 71% for the regimen of amphotericin B followed by fluconazole.

In Studies 608 and 309/604 (non-comparative study in patients with invasive fungal infections who were refractory to, or intolerant of, other antifungal agents), voriconazole was evaluated in 35 patients with deep tissue Candida infections. A favorable response was seen in 4 of 7 patients with intraabdominal infections, 5 of 6 patients with kidney and bladder wall infections, 3 of 3 patients with deep tissue abscess or wound infection, 1 of 2 patients with pneumonia/pleural space infections, 2 of 4 patients with skin lesions, 1 of 1 patients with mixed intraabdominal and pulmonary infection, 1 of 2 patients with suppurative phlebitis, 1 of 3 patients with hepatosplenic infection, 1 of 5 patients with osteomyelitis, 0 of 1 with liver infection, and 0 of 1 with cervical lymph node infection.

14.3 Esophageal Candidiasis

The efficacy of oral voriconazole 200 mg twice daily compared to oral fluconazole 200 mg once daily in the primary treatment of esophageal candidiasis was demonstrated in Study 150-305, a double-blind, double-dummy study in immunocompromised patients with endoscopically proven esophageal candidiasis. Patients were treated for a median of 15 days (range 1 to 49 days). Outcome was assessed by repeat endoscopy at end of treatment (EOT). A successful response was defined as a normal endoscopy at EOT or at least a 1 grade improvement over baseline endoscopic score. For patients in the Intent to Treat (ITT) population with only a baseline endoscopy, a successful response was defined as symptomatic cure or improvement at EOT compared to baseline. Voriconazole and fluconazole (200 mg once daily) showed comparable efficacy rates against esophageal candidiasis, as presented in Table 15.

Table 15

Success Rates in Patients Treated for Esophageal Candidiasis

^a Confidence Interval for the difference (Voriconazole – Fluconazole) in success rates.
^b PP (Per Protocol) patients had confirmation of Candida esophagitis by endoscopy, received at least 12 days of
treatment, and had a repeat endoscopy at EOT (end of treatment).
^c ITT (Intent to Treat) patients without endoscopy or clinical assessment at EOT were treated as failures.

Microbiologic success rates by Candida species are presented in Table 16.

Table 16

Clinical and Mycological Outcome by Baseline Pathogen in Patients with Esophageal Candidiasis (Study 150-305)

^a Some patients had more than one species isolated at baseline.

^b Patients with endoscopic and/or mycological assessment at end of therapy.

14.4 Other Serious Fungal Pathogens

In pooled analyses of patients, voriconazole was shown to be effective against the following additional fungal pathogens:

Scedosporium apiospermum - Successful response to voriconazole therapy was seen in 15 of 24 patients (63%). Three 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 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 3 patients with mixed organism infections.

Fusarium spp. - Nine 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 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 of these patients relapsed, 1 with a sinus infection and profound neutropenia and 1 post surgical patient with blood and eye infections.

15 REFERENCES

• 1.Clinical Laboratory Standards Institute (CLSI). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts. Approved Standard M27-A3. Clinical Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898, USA, 2008.
  
• 2.Clinical Laboratory Standards Institute (CLSI). Method for Antifungal Disk Diffusion Susceptibility Testing of Yeasts. Approved Guideline M44-A2. Clinical Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898, USA, 2009.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Voriconazole Tablets, 50 mg are available as white to off-white, round shaped, unscored, film-coated tablets, debossed with “TEVA” on one side and “5289” on the other side and packaged in bottles of 30 tablets.

Voriconazole Tablets, 200 mg are available as white to off-white, oval shaped, unscored, film-coated tablets, debossed with “TEVA” on one side and “5290” on the other side and packaged in bottles of 30 tablets.

16.2 Storage

Voriconazole Tablets should be stored at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling

Manufactured In Israel By:

TEVA PHARMACEUTICAL IND. LTD.

Jerusalem, 91010, Israel

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

All brand names are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA.

Rev. F 4/2014

PATIENT INFORMATION

VORICONAZOLE (Vor-ih-CON-ah-zole) TABLETS

Read the patient information that comes with voriconazole before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your condition or treatment.

What is voriconazole?

Voriconazole is a prescription medicine used to treat certain serious fungal infections in your blood and body. These infections are called “aspergillosis,” “esophageal candidiasis,” “Scedosporium,” “Fusarium,” and “candidemia.”

It is not known if voriconazole is safe and effective in children younger than 12 years old.

Who should not take voriconazole?

Do not take voriconazole if you:

• • are allergic to voriconazole or any of the ingredients in voriconazole tablets. See the end of this leaflet for a complete list of ingredients in voriconazole tablets.
• • are taking any of the following medicines:
• •cisapride (Propulsid^®)
• •pimozide (Orap^®)
• •quinidine (like Quinaglute^®)
• •sirolimus (Rapamune^®)
• •rifampin (Rifadin^®)
• •carbamazepine (Tegretol^®)
• •long-acting barbiturates like phenobarbital (Luminal^®)
• •efavirenz (Sustiva^®)
• •ritonavir (Norvir^®)
• •rifabutin (Mycobutin^®)
• •ergotamine, dihydroergotamine (ergot alkaloids)
• •St. John’s Wort (herbal supplement)

Ask your healthcare provider or pharmacist if you are not sure if you are taking any of the medicines listed above.

Do not start taking a new medicine without talking to your healthcare provider or pharmacist.

What should I tell my healthcare provider before taking voriconazole?

Before you take voriconazole, tell your healthcare provider if you:

• •have or ever had an abnormal heart rate or rhythm. Your healthcare provider may order a test to check your heart (EKG) before starting voriconazole.
• •have liver or kidney problems. Your healthcare provider may do blood tests to make sure you can take voriconazole.
• •have trouble digesting dairy products or lactose (milk sugar). Voriconazole tablets contain lactose.
• •are pregnant or plan to become pregnant. Voriconazole can harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant. Women who can become pregnant should use effective birth control while taking voriconazole.
• •are breastfeeding or plan to breastfeed. It is not known if voriconazole passes into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take voriconazole.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.

Voriconazole may affect the way other medicines work, and other medicines may affect how voriconazole works.

Know what medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.

How should I take voriconazole?

• • Voriconazole may be prescribed to you as:
  • •Voriconazole tablets
• •Take voriconazole tablets exactly as your healthcare provider tells you to.
• •Take voriconazole tablets at least 1 hour before or at least 1 hour after meals.
• •If you take too much voriconazole, call your healthcare provider or go to the nearest hospital emergency room.

What should I avoid while taking voriconazole?

• •You should not drive at night while taking voriconazole. Voriconazole can cause changes in your vision such as blurring or sensitivity to light.
• •Do not drive or operate machinery, or do other dangerous activities until you know how voriconazole affects you.
• •Avoid direct sunlight. Voriconazole can make your skin sensitive to the sun and the light from sunlamps and tanning beds. You could get a severe sunburn. Use sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight. Talk to your healthcare provider if you get sunburn.

What are possible side effects of voriconazole?

Voriconazole may cause serious side effects including:

• • liver problems. Symptoms of liver problems may include:
• •itchy skin
• •yellowing of your eyes
• •feeling very tired
• •flu-like symptoms
• •nausea or vomiting
• • vision changes. Symptoms of vision changes may include:
• •blurred vision
• •changes in the way you see colors
• •sensitivity to light (photophobia)
• • serious heart problems. Voriconazole may cause changes in your heart rate or rhythm, including your heart stopping (cardiac arrest).
• • allergic reactions. Symptoms of an allergic reaction may include:
• •fever
• •sweating
• •feels like your heart is beating fast (tachycardia)
• •chest tightness
• •trouble breathing
• •feel faint
• •nausea
• •itching
• •skin rash
• • kidney problems. Voriconazole may cause new or worse problems with kidney function, including kidney failure. Your healthcare provider should check your kidney function while you are taking voriconazole. Your healthcare provider will decide if you can keep taking voriconazole
• • serious skin reactions. Symptoms of serious skin reactions may include:
• •rash or hives
• •mouth sores
• •blistering or peeling of your skin
• •trouble swallowing or breathing

Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the symptoms listed above.

The most common side effects of voriconazole include:

• •vision changes
• •rash
• •vomiting
• •nausea
• •headache
• •fast heart beat (tachycardia)
• •hallucinations (seeing or hearing things that are not there)
• •abnormal liver function tests

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of voriconazole. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store voriconazole?

• •Store voriconazole tablets at room temperature, 20° to 25°C (68° to 77°F).
• •Keep voriconazole tablets in a tightly closed container.
• •Safely throw away medicine that is out of date or no longer needed.
• • Keep voriconazole, as well as all other medicines, out of the reach of children.

General information about the safe and effective use of voriconazole

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use voriconazole for a condition for which it was not prescribed. Do not give voriconazole to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information leaflet summarizes the most important information about voriconazole. If you would like more information, talk to your healthcare provider. You can ask your healthcare provider or pharmacist for information about voriconazole that is written for health professionals.

For more information about voriconazole tablets call 1-888-838-2872.

What are the ingredients of voriconazole?

Active ingredient: voriconazole

Inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, polyethylene glycol, polyvinyl alcohol, povidone, pregelatinized starch, talc, and titanium dioxide

Manufactured In Israel By:

TEVA PHARMACEUTICAL IND. LTD.

Jerusalem, 91010, Israel

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA.

Rev. D 4/2014

PRINCIPAL DISPLAY PANEL