VFEND® I.V. (voriconazole) for Injection VFEND® Tablets (voriconazole) VFEND® (voriconazole) for Oral Suspension
VFEND by
Drug Labeling and Warnings
VFEND by is a Prescription medication manufactured, distributed, or labeled by Cardinal Health. Drug facts, warnings, and ingredients follow.
Drug Details [pdf]
VFEND- voriconazole tablet, film coated
Cardinal Health
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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).
| 200 mg Oral Q12h | 300 mg Oral Q12h | 3 mg/kg IV Q12h | 4 mg/kg IV Q12h | |
|---|---|---|---|---|
|
|
||||
|
AUCτ* (µg∙h/mL) |
19.86 |
50.32 |
21.81 |
50.40 |
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
(n=9) | 300 mg Oral Q12h
(n=9) |
|
|---|---|---|
|
|
||
|
AUCτ* (µg∙h/mL ) |
20.31 |
36.51 |
|
Cmax* (µg/mL) |
3.00 |
4.66 |
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).
| 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 | |
|
Pharmacokinetic parameters for loading and maintenance doses summarized for same cohort of subjects |
||||
|
AUCτ† (µg∙h/mL) |
9.31 |
11.13 |
13.22 |
13.25 |
|
Cmax (µg/mL) |
2.30 |
2.08 |
4.70 |
3.06 |
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.
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 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.
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).
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 × 2, then 3 mg/kg IV × 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 × 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 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).
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 × 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 × 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 × 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).
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).
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).
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 × 1 day, then 200 mg Q12h × 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 × 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 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 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 PRECAUTIONS - Drug Interactions).
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.
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 × 30 days) increased Cmax 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 × 12 days) had no significant effect on steady state Cmax and AUCτ of digoxin (0.25 mg once daily for 10 days) in healthy subjects.
Mycophenolic acid (UDP-glucuronyl transferase substrate): Voriconazole (200 mg Q12h × 5 days) had no significant effect on the Cmax and AUCτ of mycophenolic acid and its major metabolite, mycophenolic acid glucuronide after administration of a 1 g single oral dose of mycophenolate mofetil.
Two-Way Interactions
Concomitant use of the following agents with voriconazole is contraindicated:
Rifabutin (potent CYP450 inducer): Rifabutin (300 mg once daily) decreased the Cmax and AUCτ 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 Cmax and AUCτ 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 Cmax and AUCτ of rifabutin by an average of 3-times (90% CI: 2.2, 4.0) and 4 times (90% CI: 3.5, 5.4), respectively, compared to rifabutin given alone. Coadministration of voriconazole and rifabutin is contraindicated.
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 standard doses of efavirenz must not be coadministered (see PRECAUTIONS – Drug Interactions). Steady state efavirenz (400 mg PO QD) decreased the steady state Cmax and AUCτ 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 Cmax and AUCτ of efavirenz (400 mg PO QD 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 1–7), 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 Q 12h with efavirenz 300 mg Q24h, decreased voriconazole AUCτ by 7% (90% CI: -23%, 13%) and increased Cmax by 23% (90% CI: -1%, 53%); efavirenz AUCτ was increased by 17% (90% CI: 6%, 29%) and Cmax was equivalent.
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.
Phenytoin (CYP2C9 substrate and potent CYP450 inducer): Repeat dose administration of phenytoin (300 mg once daily) decreased the steady state Cmax and AUCτ of orally administered voriconazole (200 mg Q12h × 14 days) by an average of 50% and 70%, respectively, in healthy subjects. Administration of a higher voriconazole dose (400 mg Q12h × 7 days) with phenytoin (300 mg once daily) resulted in comparable steady state voriconazole Cmax and AUCτ 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).
Repeat dose administration of voriconazole (400 mg Q12h × 10 days) increased the steady state Cmax and AUCτ of phenytoin (300 mg once daily) by an average of 70% and 80%, respectively, in healthy subjects. The increase in phenytoin Cmax and AUC when coadministered with voriconazole may be expected to be as high as 2 times the Cmax and AUC estimates when phenytoin is given without voriconazole. Therefore, frequent monitoring of plasma phenytoin concentrations and phenytoin-related adverse effects is recommended when phenytoin is coadministered with voriconazole (see PRECAUTIONS - Drug Interactions).
Omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate): Coadministration of omeprazole (40 mg once daily × 10 days) with oral voriconazole (400 mg Q12h × 1 day, then 200 mg Q12h × 9 days) increased the steady state Cmax and AUCτ of voriconazole by an average of 15% (90% CI: 5%, 25%) and 40% (90% CI: 29%, 55%), respectively, in healthy subjects. No dosage adjustment of voriconazole is recommended.
Coadministration of voriconazole (400 mg Q12h × 1 day, then 200 mg × 6 days) with omeprazole (40 mg once daily × 7 days) to healthy subjects significantly increased the steady state Cmax and AUCτ of omeprazole an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole is given without voriconazole. When initiating voriconazole in patients already receiving omeprazole doses of 40 mg or greater, it is recommended that the omeprazole dose be reduced by one-half (see PRECAUTIONS - Drug Interactions).
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 Cmax and AUCτ 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 Cmax and AUCτ 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 PRECAUTIONS - Drug Interactions).
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 Cmax 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 Cmax and AUCτ 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 PRECAUTIONS - Drug Interactions).
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 CLINICAL PHARMACOLOGY – Drug Interactions, PRECAUTIONS – Drug Interactions). Patients should be frequently monitored for drug toxicity during the coadministration of voriconazole and other NNRTIs (e.g., nevirapine and delavirdine) (see PRECAUTIONS - Drug Interactions). Dose adjustments are required when voriconazole is co-administered with efavirenz (see CLINICAL PHARMACOLOGY - Drug Interactions, PRECAUTIONS - Drug Interactions).
MICROBIOLOGY
Mechanism of Action
Voriconazole is a triazole 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. Voriconazole has been shown to be more selective for fungal cytochrome P-450 enzymes than for various mammalian cytochrome P-450 enzyme systems.
Activity In Vitro
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 µg/mL)1
Candida krusei
Candida parapsilosis
Candida tropicalis
Fusarium spp. including Fusarium solani
Scedosporium apiospermum
The following data are available, but their clinical significance is unknown.
Voriconazole exhibits in vitro minimal inhibitory concentrations (MICs) of 1 µg/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 Methods2,3
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.2,3
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.2 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 4.
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.3 This procedure uses paper disks impregnated with 1 µg of voriconazole to test the susceptibility of yeasts to voriconazole at 24 hours. Disk diffusion interpretive criteria are also provided in Table 4.
| Broth Microdilution at 48 hours
(MIC in µg/mL) | Disk Diffusion at 24 hours
(Zone diameters in mm) |
|||||
|---|---|---|---|---|---|---|
| Susceptible (S) | Intermediate (I) | Resistant (R) | Susceptible (S) | Intermediate (I) | Resistant (R) | |
| NOTE: Shown are the breakpoints (µg/mL) for voriconazole against Candida species. | ||||||
|
Voriconazole |
≤1.0 |
2.0 |
≥4.0 |
≥17 |
14–16 |
≤13 |
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 control the technical aspects of the test procedures. Standard voriconazole powder and 1 µg disks should provide the following range of values noted in Table 5.
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.
| QC Strain | Broth Microdilution (MIC in µg/mL) @ 48-hour | Disk Diffusion (Zone diameter in mm) @ 24- hour |
|---|---|---|
| ATCC is a registered trademark of the American Type Culture Collection. | ||
|
|
||
|
Candida parapsilosis
|
0.03–0.25 |
28–37 |
|
Candida krusei
|
0.12–1.0 |
16–25 |
|
Candida albicans
|
31–42 |
|
Activity In Vivo
Voriconazole was active in normal and/or immunocompromised guinea pigs with systemic and/or pulmonary infections due to A. fumigatus (including an isolate with reduced susceptibility to itraconazole) or Candida species [C.albicans (including an isolate with reduced susceptibility to fluconazole), C. krusei and C. glabrata] in which the endpoints were prolonged survival of infected animals and/or reduction of mycological burden from target organs. In one experiment, voriconazole exhibited activity against Scedosporium apiospermum infections in immune competent guinea pigs.
Drug Resistance
Voriconazole drug resistance development has not been adequately studied in vitro against 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.
INDICATIONS AND USAGE
VFEND is indicated for use in the treatment of the following fungal infections:
Invasive aspergillosis. In clinical trials, the majority of isolates recovered were Aspergillus fumigatus. There was a small number of cases of culture-proven disease due to species of Aspergillus other than A. fumigatus (see CLINICAL STUDIES, MICROBIOLOGY).
Candidemia in nonneutropenic patients and the following Candida infections: disseminated infections in skin and infections in abdomen, kidney, bladder wall, and wounds (see CLINICAL STUDIES, MICROBIOLOGY).
Esophageal candidiasis (see CLINICAL STUDIES, MICROBIOLOGY).
Serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp. including Fusarium solani, in patients intolerant of, or refractory to, other therapy (see CLINICAL STUDIES, MICROBIOLOGY).
Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.
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.
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
The efficacy of voriconazole compared to amphotericin B in the primary treatment of acute invasive aspergillosis was demonstrated in 277 patients treated for 12 weeks in Study 307/602. The majority of study patients had underlying hematologic malignancies, including bone marrow transplantation. The study also included patients with solid organ transplantation, solid tumors, and AIDS. The patients were mainly treated for definite or probable invasive aspergillosis of the lungs. Other aspergillosis infections included disseminated disease, CNS infections and sinus infections. Diagnosis of definite or probable invasive aspergillosis was made according to criteria modified from those established by the National Institute of Allergy and Infectious Diseases Mycoses Study Group/European 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 2–90 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 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 6). 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 6).
Table 6 also summarizes the response (success) based on mycological confirmation and species.
| Voriconazole | Ampho B * | Stratified Difference (95% CI) † | |
|---|---|---|---|
| n/N (%) | n/N (%) | ||
|
|
|||
|
Efficacy as Primary Therapy | |||
|
Satisfactory Global |
76/144 (53) |
42/133 (32) |
21.8% |
|
Survival at Day 84 § |
102/144 (71) |
77/133 (58) |
13.1% |
|
Success by Species | |||
|
Success n/N (%) | |||
|
Overall success |
76/144 (53) |
42/133 (32) | |
|
Mycologically |
37/84 (44) |
16/67 (24) | |
|
Aspergillus spp.# | |||
|
A. fumigatus |
28/63 (44) |
12/47 (26) | |
|
A. flavus |
3/6 |
4/9 | |
|
A. terreus |
2/3 |
0/3 | |
|
A. niger |
1/4 |
0/9 | |
|
A. nidulans |
1/1 |
0/0 | |
Study 304
The results of this comparative trial (Study 307/602) confirmed the results of an earlier trial in the primary and salvage treatment of patients with acute invasive aspergillosis (Study 304). In this earlier study, an overall success rate of 52% (26/50) was seen in patients treated with voriconazole for primary therapy. Success was seen in 17/29 (59%) with Aspergillus fumigatus infections and 3/6 (50%) patients with infections due to non-fumigatus species [A. flavus (1/1); A. nidulans (0/2); A. niger (2/2); A. terreus (0/1)]. Success in patients who received voriconazole as salvage therapy is presented in Table 7.
Study 309/604
Additional data regarding response rates in patients who were refractory to, or intolerant of, other antifungal agents are also provided in Table 7. 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 7.
| Success
n/N |
|
|---|---|
|
|
|
|
A. flavus |
5/12 |
|
A. nidulans |
1/3 |
|
A. niger |
4/5 |
|
A. terreus |
3/8 |
|
A. versicolor |
0/1 |
Nineteen patients had more than one species of Aspergillus isolated. Success was seen in 4/17 (24%) of these patients.
Candidemia in nonneutropenic patients and other deep tissue Candida 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 8.
| Baseline Pathogen | Clinical and Mycological Success (%) | |
|---|---|---|
| Voriconazole | Amphotericin B --> Fluconazole | |
|
|
||
|
C. albicans |
46/107 (43%) |
30/63 (48%) |
|
C. tropicalis |
17/53 (32%) |
1/16 (6%) |
|
C. parapsilosis |
24/45 (53%) |
10/19 (53%) |
|
C. glabrata |
12/36 (33%) |
7/21 (33%) |
|
C. krusei |
1/4 |
0/1 |
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.
Esophageal Candidiasis
The efficacy of oral voriconazole 200 mg bid compared to oral fluconazole 200 mg od 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 od) showed comparable efficacy rates against esophageal candidiasis, as presented in Table 9.
| Population | Voriconazole | Fluconazole | Difference % (95% CI)* |
|---|---|---|---|
|
|
|||
|
PP† |
113/115 (98.2%) |
134/141 (95.0%) |
3.2 (-1.1, 7.5) |
|
ITT‡ |
175/200 (87.5%) |
171/191 (89.5%) |
-2.0 (-8.3, 4.3) |
Microbiologic success rates by Candida species are presented in Table 10.
| Pathogen* | Voriconazole | Fluconazole | ||
|---|---|---|---|---|
| Favorable endoscopic response† | Mycological eradication† | Favorable endoscopic response† | Mycological eradication† | |
| Success/Total (%) | Eradication/Total (%) | Success/Total (%) | Eradication/Total (%) | |
|
|
||||
|
C. albicans |
134/140 (96%) |
90/107 (84%) |
147/156 (94%) |
91/115 (79%) |
|
C. glabrata |
8/8 (100%) |
4/7 (57%) |
4/4 (100%) |
1/4 (25%) |
|
C. krusei |
1/1 |
1/1 |
2/2 (100%) |
0/0 |
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.
CONTRAINDICATIONS
VFEND is contraindicated in patients with known hypersensitivity to voriconazole or its excipients. There is no information regarding cross-sensitivity between VFEND (voriconazole) and other azole antifungal agents. Caution should be used when prescribing VFEND to patients with hypersensitivity to other azoles.
Coadministration of the CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide or quinidine with VFEND are contraindicated since increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of torsade de pointes (see CLINICAL PHARMACOLOGY - Drug Interactions, PRECAUTIONS - Drug Interactions).
Coadministration of VFEND with sirolimus is contraindicated because VFEND significantly increases sirolimus concentrations in healthy subjects (see CLINICAL PHARMACOLOGY - Drug Interactions, PRECAUTIONS - Drug Interactions).
Coadministration of VFEND with rifampin, carbamazepine and long-acting barbiturates is contraindicated since these drugs are likely to decrease plasma voriconazole concentrations significantly (see CLINICAL PHARMACOLOGY - Drug Interactions, PRECAUTIONS - Drug Interactions).
Coadministration of VFEND with high-dose ritonavir (400 mg Q12h) is contraindicated because ritonavir (400 mg Q12h) significantly decreases plasma voriconazole concentrations in healthy subjects. 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 CLINICAL PHARMACOLOGY - Drug Interactions, PRECAUTIONS - Drug Interactions).
Coadministration of VFEND with rifabutin is contraindicated since VFEND significantly increases rifabutin plasma concentrations and rifabutin also significantly decreases voriconazole plasma concentrations (see CLINICAL PHARMACOLOGY - Drug Interactions, PRECAUTIONS - Drug Interactions).
Coadministration of VFEND with ergot alkaloids (ergotamine and dihydroergotamine) is contraindicated because VFEND may increase the plasma concentration of ergot alkaloids, which may lead to ergotism.
Coadministration of VFEND with St. John's Wort is contraindicated (see CLINICAL PHARMACOLOGY - Drug Interactions, PRECAUTIONS - Drug Interactions).
WARNINGS
VISUAL DISTURBANCES
The effect of VFEND on visual function is not known if treatment continues beyond 28 days. There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema. These events occurred primarily in severely ill patients who had underlying conditions and/or concomitant medications which may have caused or contributed to these events. If treatment continues beyond 28 days, visual function including visual acuity, visual field and color perception should be monitored (see PRECAUTIONS – Information for Patients and ADVERSE REACTIONS – Visual Disturbances).
HEPATIC TOXICITY
In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with VFEND (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly hematological malignancy). Hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction has usually been reversible on discontinuation of therapy (see PRECAUTIONS – Laboratory Tests and ADVERSE REACTIONS – Clinical Laboratory Values).
Monitoring of hepatic function
Liver function tests should be evaluated at the start of and during the course of VFEND therapy. Patients who develop abnormal liver function tests during VFEND therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of VFEND must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to VFEND (see PRECAUTIONS - Laboratory Tests, DOSAGE AND ADMINISTRATION - Dosage Adjustment, ADVERSE REACTIONS - Clinical Laboratory Tests).
Pregnancy Category D
Voriconazole can cause fetal harm when administered to a pregnant woman.
Voriconazole was teratogenic in rats (cleft palates, hydronephrosis/hydroureter) from 10 mg/kg (0.3 times the recommended maintenance dose (RMD) on a mg/m2 basis) and embryotoxic in rabbits at 100 mg/kg (6 times the RMD). Other effects in rats included reduced ossification of sacral and caudal vertebrae, skull, pubic and hyoid bone, supernumerary ribs, anomalies of the sternebrae and dilatation of the ureter/renal pelvis. Plasma estradiol in pregnant rats was reduced at all dose levels. Voriconazole treatment in rats produced increased gestational length and dystocia, which were associated with increased perinatal pup mortality at the 10 mg/kg dose. The effects seen in rabbits were an increased embryomortality, reduced fetal weight and increased incidences of skeletal variations, cervical ribs and extrasternebral ossification sites.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
PRECAUTIONS
Arrhythmias and QT Prolongation
Some azoles, including voriconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During clinical development and post-marketing surveillance, there have been rare cases of arrhythmias, (including ventricular arrhythmias such as torsade de pointes), cardiac arrests and sudden deaths in patients taking voriconazole. These cases usually involved seriously ill patients with multiple confounding risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medications that may have been contributory.
Voriconazole should be administered with caution to patients with these potentially proarrhythmic conditions.
Rigorous attempts to correct potassium, magnesium and calcium should be made before starting voriconazole (see CLINICAL PHARMACOLOGY- Pharmacokinetic-Pharmacodynamic Relationships - Electrocardiogram).
Infusion Related Reactions
During infusion of the intravenous formulation of voriconazole in healthy subjects, anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus and rash, have occurred uncommonly. Symptoms appeared immediately upon initiating the infusion. Consideration should be given to stopping the infusion should these reactions occur.
Information for Patients
Patients should be advised:
- that VFEND Tablets or Oral Suspension should be taken at least one hour before, or one hour following, a meal.
- that they should not drive at night while taking VFEND. VFEND may cause changes to vision, including blurring and/or photophobia.
- that they should avoid potentially hazardous tasks, such as driving or operating machinery if they perceive any change in vision.
- that strong, direct sunlight should be avoided during VFEND therapy.
- that VFEND for Oral Suspension contains sucrose and is not recommended for patients with rare hereditary problems of fructose intolerance, sucrase-isomaltase deficiency or glucose-galactose malabsorption.
Laboratory Tests
Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of VFEND therapy.
Patient management should include laboratory evaluation of renal (particularly serum creatinine) and hepatic function (particularly liver function tests and bilirubin).
Drug Interactions
Tables 11 and 12 provide a summary of significant drug interactions with voriconazole that either have been studied in vivo (clinically) or that may be expected to occur based on results of in vitro metabolism studies with human liver microsomes. For more details, see CLINICAL PHARMACOLOGY - Drug Interactions.
| Drug/Drug Class
(Mechanism of Interaction by the Drug) | Voriconazole Plasma Exposure
(Cmax and AUCτ after 200 mg Q12h) | Recommendations for Voriconazole
Dosage Adjustment/Comments |
|---|---|---|
|
|
||
|
Significantly Reduced |
Contraindicated |
|
|
Efavirenz†
|
Significantly Reduced |
When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg Q12h and efavirenz should be decreased to 300 mg Q24h (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION-Dosage Adjustment) |
|
High-dose Ritonavir (400mg Q12h)†
|
Significantly Reduced |
Contraindicated |
|
Low-dose Ritonavir (100mg Q12h)†
|
Reduced |
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 |
|
Carbamazepine |
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction |
Contraindicated |
|
Long Acting Barbiturates |
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction |
Contraindicated |
|
Phenytoin*
|
Significantly Reduced |
Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hrs or from 200 mg to 400 mg orally every 12 hrs (100 mg to 200 mg orally every 12 hrs in patients weighing less than 40 kg) |
|
St. John's Wort |
Significantly Reduced |
Contraindicated |
|
Oral Contraceptives* containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
Increased |
Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives |
|
Other HIV Protease Inhibitors |
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure |
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir |
|
Other NNRTIs‡
|
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to voriconazole |
|
|
|
|
| Drug/Drug Class
(Mechanism of Interaction by Voriconazole) | Drug Plasma Exposure
(Cmax and AUCτ) | Recommendations for Drug Dosage Adjustment/Comments |
|---|---|---|
|
|
||
|
Sirolimus*
|
Significantly Increased |
Contraindicated |
|
Rifabutin*
|
Significantly Increased |
Contraindicated |
|
Efavirenz†
|
Significantly Increased |
When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg Q12h and efavirenz should be decreased to 300 mg Q24h (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION-Dosage Adjustment) |
|
High-dose Ritonavir (400 mg Q12h)†(CYP3A4 Inhibition) |
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ |
Contraindicated because of significant reduction of voriconazole Cmax and AUCτ |
|
Low-dose Ritonavir (100mg Q12h)† |
Slight Decrease in Ritonavir Cmax and AUCτ |
Coadministration of voriconazole and low-dose ritonavir (100 mg Q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
|
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine |
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased |
Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes |
|
Ergot Alkaloids |
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased |
Contraindicated |
|
Cyclosporine*
|
AUCτ Significantly Increased; No Significant Effect on Cmax |
When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. |
|
Methadone‡ (CYP3A4 Inhibition) |
Increased |
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 |
|
Alfentanil (CYP3A4 Inhibition) |
Significantly Increased |
Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary (see CLINICAL PHARMACOLOGY - Drug Interactions). |
|
Tacrolimus*
|
Significantly Increased |
When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. |
|
Phenytoin*
|
Significantly Increased |
Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
|
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)† |
Increased |
Monitoring for adverse events related to oral contraceptives is recommended during coadministration. |
|
Warfarin*
|
Prothrombin Time Significantly Increased |
Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed. |
|
Omeprazole*
|
Significantly Increased |
When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. 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 other proton pump inhibitors. |
|
Other HIV Protease Inhibitors |
In Vivo Studies Showed No Significant Effects on Indinavir Exposure |
No dosage adjustment for indinavir when coadministered with VFEND |
|
Other NNRTIs§
|
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs |
Frequent monitoring for adverse events and toxicity related to NNRTI |
|
Benzodiazepines |
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism |
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed. |
|
HMG-CoA Reductase Inhibitors (Statins) |
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism |
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
|
Dihydropyridine Calcium Channel Blockers |
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism |
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. |
|
Sulfonylurea Oral Hypoglycemics |
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased |
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. |
|
Vinca Alkaloids |
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased |
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
Patients with Hepatic Insufficiency
It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) receiving VFEND (see CLINICAL PHARMACOLOGY - Hepatic Insufficiency, DOSAGE and ADMINISTRATION - Hepatic Insufficiency).
VFEND has not been studied in patients with severe cirrhosis (Child-Pugh Class C). VFEND has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and should only be used in patients with severe hepatic insufficiency if the benefit outweighs the potential risk. Patients with hepatic insufficiency must be carefully monitored for drug toxicity.
Patients with Renal Insufficiency
In patients with moderate to severe renal dysfunction (creatinine clearance <50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and if increases occur, consideration should be given to changing to oral voriconazole therapy (see CLINICAL PHARMACOLOGY - Renal Insufficiency, DOSAGE AND ADMINISTRATION - Renal Insufficiency).
Renal Adverse Events
Acute renal failure has been observed in severely ill patients undergoing treatment with VFEND. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and have concurrent conditions that may result in decreased renal function.
Monitoring of Renal Function
Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.
Monitoring of Pancreatic Function
Adults and children with risk factors for acute pancreatitis (e.g., recent chemotherapy, hematopoietic stem cell transplantation [HSCT]) should be monitored for the development of pancreatitis during VFEND treatment.
Dermatological Reactions
Patients have rarely developed serious cutaneous reactions, such as Stevens-Johnson syndrome, during treatment with VFEND. If patients develop a rash, they should be monitored closely and consideration given to discontinuation of VFEND. VFEND has been infrequently associated with photosensitivity skin reaction, especially during long-term therapy. It is recommended that patients avoid strong, direct sunlight during VFEND therapy.
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 produced a reduction in the pregnancy rates of rats dosed at 50 mg/kg, or 1.6 times the RMD. This was statistically significant only in the preliminary study and not in a larger fertility study.
Women of Childbearing Potential
Women of childbearing potential should use effective contraception during treatment. The coadministration of voriconazole with the oral contraceptive, Ortho-Novum® (35 mcg ethinyl estradiol and 1 mg norethindrone), results in an interaction between these two drugs, but is unlikely to reduce the contraceptive effect. (see CLINICAL PHARMACOLOGY-Drug Interactions-Oral Contraceptives; PRECAUTIONS-Drug Interactions)
Nursing Mothers
The excretion of voriconazole in breast milk has not been investigated. VFEND should not be used by nursing mothers unless the benefit clearly outweighs the risk.
Pediatric Use
Safety and effectiveness in pediatric patients below the age of 12 years have not been established.
A total of 22 patients aged 12–18 years with invasive aspergillosis were included in the therapeutic studies. Twelve out of 22 (55%) patients had successful response after treatment with a maintenance dose of voriconazole 4 mg/kg Q12h.
Sparse plasma sampling for pharmacokinetics in adolescents was conducted in the therapeutic studies (see CLINICAL PHARMACOLOGY - Pharmacokinetics, General Pharmacokinetic Characteristics).
There have been postmarketing reports of pancreatitis in pediatric patients.
Geriatric Use
In multiple dose therapeutic trials of voriconazole, 9.2% of patients were ≥ 65 years of age and 1.8% of patients were ≥ 75 years of age. In a study in healthy subjects, the systemic exposure (AUC) and peak plasma concentrations (Cmax) were increased in elderly males compared to young males. Pharmacokinetic data obtained from 552 patients from 10 voriconazole therapeutic trials showed that voriconazole plasma concentrations in the elderly patients were approximately 80% to 90% higher than those in younger patients after either IV or oral administration. However, the overall safety profile of the elderly patients was similar to that of the young so no dosage adjustment is recommended (see CLINICAL PHARMACOLOGY - Pharmacokinetics in Special Populations).
ADVERSE REACTIONS
Overview
The most frequently reported adverse events (all causalities) in the therapeutic trials were visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, sepsis, peripheral edema, abdominal pain, and respiratory disorder. The treatment-related adverse events which most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances (see hepatic toxicity under WARNINGS and discussion of Clinical Laboratory Values and dermatological and visual adverse events below).
Discussion of Adverse Reactions
The data described in Table 13 reflect exposure to voriconazole in 1655 patients in the therapeutic studies. This represents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy or HIV and non-neutropenic patients. This subgroup does not include healthy subjects and patients treated in the compassionate use and non-therapeutic studies. This patient population was 62% male, had a mean age of 46 years (range 11–90, including 51 patients aged 12–18 years), and was 78% white and 10% black. In the initial regulatory filing, 561 patients had a duration of voriconazole therapy of greater than 12 weeks, with 136 patients receiving voriconazole for over six months. Table 13 includes all adverse events which were reported at an incidence of ≥2% during voriconazole therapy in the all therapeutic studies population, studies 307/602 and 608 combined, or study 305, as well as events of concern which occurred at an incidence of <2%.
In study 307/602, 381 patients (196 on voriconazole, 185 on amphotericin B) were treated to compare voriconazole to amphotericin B followed by other licensed antifungal therapy in the primary treatment of patients with acute invasive aspergillosis. In study 608, 403 patients with candidemia were treated to compare voriconazole (272 patients) to the regimen of amphotericin B followed by fluconazole (131 patients). Study 305 evaluated the effects of oral voriconazole (200 patients) and oral fluconazole (191 patients) in the treatment of esophageal candidiasis. Laboratory test abnormalities for these studies are discussed under Clinical Laboratory Values below.
| Rate ≥ 2% on Voriconazole or Adverse Events of Concern in All Therapeutic Studies Population, Studies 307/602–608 Combined, or Study 305. Possibly Related to Therapy or Causality Unknown* | ||||||
|---|---|---|---|---|---|---|
| All Therapeutic Studies | Studies 307/602 and 608
(IV/ oral therapy) | Study 305
(oral therapy) |
||||
| Voriconazole
N = 1655 | Voriconazole
N = 468 | Ampho B†
N=185 | Ampho B→ Fluconazole
N= 131 | Voriconazole
N = 200 | Fluconazole
N =191 |
|
| N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | |
|
|
||||||
|
Special Senses‡ | ||||||
|
Abnormal vision |
310 (18.7) |
63 (13.5) |
1 (0.5) |
0 |
31 (15.5) |
8 (4.2) |
|
Photophobia |
37 (2.2) |
8 (1.7) |
0 |
0 |
5 (2.5) |
2 (1.0) |
|
Chromatopsia |
20 (1.2) |
2 (0.4) |
0 |
0 |
2 (1.0) |
0 |
|
Body as a Whole | ||||||
|
Fever |
94 (5.7) |
8 (1.7) |
25 (13.5) |
5 (3.8) |
0 |
0 |
|
Chills |
61 (3.7) |
1 (0.2) |
36 (19.5) |
8 (6.1) |
1 (0.5) |
0 |
|
Headache |
49 (3.0) |
9 (1.9) |
8 (4.3) |
1 (0.8) |
0 |
1 (0.5) |
|
Cardiovascular System | ||||||
|
Tachycardia |
39 (2.4) |
6 (1.3) |
5 (2.7) |
0 |
0 |
0 |
|
Digestive System | ||||||
|
Nausea |
89 (5.4) |
18 (3.8) |
29 (15.7) |
2 (1.5) |
2 (1.0) |
3 (1.6) |
|
Vomiting |
72 (4.4) |
15 (3.2) |
18 (9.7) |
1 (0.8) |
2 (1.0) |
1 (0.5) |
|
Liver function tests abnormal |
45 (2.7) |
15 (3.2) |
4 (2.2) |
1 (0.8) |
6 (3.0) |
2 (1.0) |
|
Cholestatic jaundice |
17 (1.0) |
8 (1.7) |
0 |
1 (0.8) |
3 (1.5) |
0 |
|
Metabolic and Nutritional Systems | ||||||
|
Alkaline phosphatase increased |
59 (3.6) |
19 (4.1) |
4 (2.2) |
3 (2.3) |
10 (5.0) |
3 (1.6) |
|
Hepatic enzymes increased |
30 (1.8) |
11 (2.4) |
5 (2.7) |
1 (0.8) |
3 (1.5) |
0 |
|
SGOT increased |
31 (1.9) |
9 (1.9) |
0 |
1 (0.8) |
8 (4.0) |
2 (1.0) |
|
SGPT increased |
29 (1.8) |
9 (1.9) |
1 (0.5) |
2 (1.5) |
6 (3.0) |
2 (1.0) |
|
Hypokalemia |
26 (1.6) |
3 (0.6) |
36 (19.5) |
16 (12.2) |
0 |
0 |
|
Bilirubinemia |
15 (0.9) |
5 (1.1) |
3 (1.6) |
2 (1.5) |
1 (0.5) |
0 |
|
Creatinine increased |
4 (0.2) |
0 |
59 (31.9) |
10 (7.6) |
1 (0.5) |
0 |
|
Nervous System | ||||||
|
Hallucinations |
39 (2.4) |
13 (2.8) |
1 (0.5) |
0 |
0 |
0 |
|
Skin and Appendages | ||||||
|
Rash |
88 (5.3) |
20 (4.3) |
7 (3.8) |
1 (0.8) |
3 (1.5) |
1 (0.5) |
|
Urogenital | ||||||
|
Kidney function abnormal |
10 (0.6) |
6 (1.3) |
40 (21.6) |
9 (6.9) |
1 (0.5) |
1 (0.5) |
|
Acute kidney failure |
7 (0.4) |
2 (0.4) |
11 (5.9) |
7 (5.3) |
0 |
0 |
VISUAL DISTURBANCES
Voriconazole treatment-related visual disturbances are common. In therapeutic trials, approximately 21% of patients experienced abnormal vision, color vision change and/or photophobia. The visual disturbances were generally mild and rarely resulted in discontinuation. Visual disturbances may be associated with higher plasma concentrations and/or doses.
There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema. These events occurred primarily in severely ill patients who had underlying conditions and/or concomitant medications which may have caused or contributed to these events (see WARNINGS).
The mechanism of action of the visual disturbance is unknown, although the site of action is most likely to be within the retina. In a study in healthy subjects investigating the effect of 28-day treatment with voriconazole on retinal function, voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude, a decrease in the visual field, and an alteration in color perception. The ERG measures electrical currents in the retina. The effects were noted early in administration of voriconazole and continued through the course of study drug dosing. Fourteen days after end of dosing, ERG, visual fields and color perception returned to normal (see WARNINGS, PRECAUTIONS – Information For Patients).
Dermatological Reactions
Dermatological reactions were common in the patients treated with voriconazole. The mechanism underlying these dermatologic adverse events remains unknown. In clinical trials, rashes considered related to therapy were reported by 7% (110/1655) of voriconazole-treated patients. The majority of rashes were of mild to moderate severity. Cases of photosensitivity reactions appear to be more likely to occur with long-term treatment. Patients have rarely developed serious cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme during treatment with VFEND. If patients develop a rash, they should be monitored closely and consideration given to discontinuation of VFEND. It is recommended that patients avoid strong, direct sunlight during VFEND therapy.
Less Common Adverse Events
The following adverse events occurred in < 2% of all voriconazole-treated patients in all therapeutic studies (N=1655). This listing includes events where a causal relationship to voriconazole cannot be ruled out or those which may help the physician in managing the risks to the patients. The list does not include events included in Table 13 above and does not include every event reported in the voriconazole clinical program.
Body as a Whole: abdominal pain, abdomen enlarged, allergic reaction, anaphylactoid reaction (see PRECAUTIONS), ascites, asthenia, back pain, chest pain, cellulitis, edema, face edema, flank pain, flu syndrome, graft versus host reaction, granuloma, infection, bacterial infection, fungal infection, injection site pain, injection site infection/inflammation, mucous membrane disorder, multi-organ failure, pain, pelvic pain, peritonitis, sepsis, substernal chest pain
Cardiovascular: atrial arrhythmia, atrial fibrillation, AV block complete, bigeminy, bradycardia, bundle branch block, cardiomegaly, cardiomyopathy, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, congestive heart failure, deep thrombophlebitis, endocarditis, extrasystoles, heart arrest, hypertension, hypotension, myocardial infarction, nodal arrhythmia, palpitation, phlebitis, postural hypotension, pulmonary embolus, QT interval prolonged, supraventricular extrasystoles, supraventricular tachycardia, syncope, thrombophlebitis, vasodilatation, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia (including torsade de pointes)
Digestive: anorexia, cheilitis, cholecystitis, cholelithiasis, constipation, diarrhea, duodenal ulcer perforation, duodenitis, dyspepsia, dysphagia, dry mouth, esophageal ulcer, esophagitis, flatulence, gastroenteritis, gastrointestinal hemorrhage, GGT/LDH elevated, gingivitis, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hepatic coma, hepatic failure, hepatitis, intestinal perforation, intestinal ulcer, jaundice, enlarged liver, melena, mouth ulceration, pancreatitis, parotid gland enlargement, periodontitis, proctitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, stomach ulcer, stomatitis, tongue edema
Endocrine: adrenal cortex insufficiency, diabetes insipidus, hyperthyroidism, hypothyroidism
Hemic and Lymphatic: agranulocytosis, anemia (macrocytic, megaloblastic, microcytic, normocytic), aplastic anemia, hemolytic anemia, bleeding time increased, cyanosis, DIC, ecchymosis, eosinophilia, hypervolemia, leukopenia, lymphadenopathy, lymphangitis, marrow depression, pancytopenia, petechia, purpura, enlarged spleen, thrombocytopenia, thrombotic thrombocytopenic purpura
Metabolic and Nutritional: albuminuria, BUN increased, creatine phosphokinase increased, edema, glucose tolerance decreased, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperuricemia, hypocalcemia, hypoglycemia, hypomagnesemia, hyponatremia, hypophosphatemia, peripheral edema, uremia
Musculoskeletal: arthralgia, arthritis, bone necrosis, bone pain, leg cramps, myalgia, myasthenia, myopathy, osteomalacia, osteoporosis
Nervous System: abnormal dreams, acute brain syndrome, agitation, akathisia, amnesia, anxiety, ataxia, brain edema, coma, confusion, convulsion, delirium, dementia, depersonalization, depression, diplopia, dizziness, encephalitis, encephalopathy, euphoria, Extrapyramidal Syndrome, grand mal convulsion, Guillain-Barré syndrome, hypertonia, hypesthesia, insomnia, intracranial hypertension, libido decreased, neuralgia, neuropathy, nystagmus, oculogyric crisis, paresthesia, psychosis, somnolence, suicidal ideation, tremor, vertigo
Respiratory System: cough increased, dyspnea, epistaxis, hemoptysis, hypoxia, lung edema, pharyngitis, pleural effusion, pneumonia, respiratory disorder, respiratory distress syndrome, respiratory tract infection, rhinitis, sinusitis, voice alteration
Skin and Appendages: alopecia, angioedema, contact dermatitis, discoid lupus erythematosis, eczema, erythema multiforme, exfoliative dermatitis, fixed drug eruption, furunculosis, herpes simplex, maculopapular rash, melanosis, photosensitivity skin reaction, pruritus, psoriasis, skin discoloration, skin disorder, skin dry, Stevens-Johnson syndrome, sweating, toxic epidermal necrolysis, urticaria
Special Senses: abnormality of accommodation, blepharitis, color blindness, conjunctivitis, corneal opacity, deafness, ear pain, eye pain, eye hemorrhage, dry eyes, hypoacusis, keratitis, keratoconjunctivitis, mydriasis, night blindness, optic atrophy, optic neuritis, otitis externa, papilledema, retinal hemorrhage, retinitis, scleritis, taste loss, taste perversion, tinnitus, uveitis, visual field defect
Urogenital: anuria, blighted ovum, creatinine clearance decreased, dysmenorrhea, dysuria, epididymitis, glycosuria, hemorrhagic cystitis, hematuria, hydronephrosis, impotence, kidney pain, kidney tubular necrosis, metrorrhagia, nephritis, nephrosis, oliguria, scrotal edema, urinary incontinence, urinary retention, urinary tract infection, uterine hemorrhage, vaginal hemorrhage
Clinical Laboratory Values
The overall incidence of clinically significant transaminase abnormalities in all therapeutic studies was 12.4% (206/1655) of patients treated with voriconazole. Increased incidence of liver function test abnormalities may be associated with higher plasma concentrations and/or doses. The majority of abnormal liver function tests either resolved during treatment without dose adjustment or following dose adjustment, including discontinuation of therapy.
Voriconazole has been infrequently associated with cases of serious hepatic toxicity including cases of jaundice and rare cases of hepatitis and hepatic failure leading to death. Most of these patients had other serious underlying conditions.
Liver function tests should be evaluated at the start of and during the course of VFEND therapy. Patients who develop abnormal liver function tests during VFEND therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of VFEND must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to VFEND (see WARNINGS and PRECAUTIONS - Laboratory Tests).
Acute renal failure has been observed in severely ill patients undergoing treatment with VFEND. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and have concurrent conditions that may result in decreased renal function. It is recommended that patients are monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.
Tables 14 and 15 and 16 show the number of patients with hypokalemia and clinically significant changes in renal and liver function tests in three randomized, comparative multicenter studies. In study 305, patients with esophageal candidiasis were randomized to either oral voriconazole or oral fluconazole. In study 307/602, patients with definite or probable invasive aspergillosis were randomized to either voriconazole or amphotericin B therapy. In study 608, patients with candidemia were randomized to either voriconazole or the regimen of amphotericin B followed by fluconazole.
| Criteria* | Voriconazole | Fluconazole | |
|---|---|---|---|
| n/N (%) | n /N (%) | ||
| n number of patients with a clinically significant abnormality while on study therapy | |||
| N total number of patients with at least one observation of the given lab test while on study therapy | |||
| ULN upper limit of normal | |||
|
|
|||
|
T. Bilirubin |
>1.5× ULN |
8/185 (4.3) |
7/186 (3.8) |
|
AST |
>3.0× ULN |
38/187 (20.3) |
15/186 (8.1) |
|
ALT |
>3.0× ULN |
20/187 (10.7) |
12/186 (6.5) |
|
Alk phos |
>3.0× ULN |
19/187 (10.2) |
14/186 (7.5) |
| Criteria* | Voriconazole | Amphotericin B† | |||||
|---|---|---|---|---|---|---|---|
| n/N (%) | n/N (%) | ||||||
| n number of patients with a clinically significant abnormality while on study therapy | |||||||
| N total number of patients with at least one observation of the given lab test while on study therapy | |||||||
| ULN upper limit of normal | |||||||
| LLN lower limit of normal | |||||||
|
|
|||||||
|
T. Bilirubin |
>1.5× ULN |
35/180 (19.4) |
46/173 (26.6) |
||||
|
AST |
>3.0× ULN |
21/180 (11.7) |
18/174 (10.3) |
||||
|
ALT |
>3.0× ULN |
34/180 (18.9) |
40/173 (23.1) |
||||
|
Alk phos |
>3.0× ULN |
29/181 (16.0) |
38/173 (22.0) |
||||
|
Creatinine |
>1.3× ULN |
39/182 (21.4) |
102/177 (57.6) |
||||
|
Potassium |
<0.9× LLN |
30/181 (16.6) |
70/178 (39.3) |
||||
| Criteria* | Voriconazole | Amphotericin B followed by Fluconazole | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| n/N (%) | n/N (%) | ||||||||||
| n number of patients with a clinically significant abnormality while on study therapy | |||||||||||
| N total number of patients with at least one observation of the given lab test while on study therapy | |||||||||||
| ULN upper limit of normal | |||||||||||
| LLN lower limit of normal | |||||||||||
|
|
|||||||||||
|
T. Bilirubin |
>1.5× ULN |
50/261 (19.2) |
31/115 (27.0) |
||||||||
|
AST |
>3.0× ULN |
40/261 (15.3) |
16/116 (13.8) |
||||||||
|
ALT |
>3.0× ULN |
22/261 (8.4) |
15/116 (12.9) |
||||||||
|
Alk phos |
>3.0× ULN |
59/261 (22.6) |
26/115 (22.6) |
||||||||
|
Creatinine |
>1.3× ULN |
39/260 (15.0) |
32/118 (27.1) |
||||||||
|
Potassium |
<0.9× LLN |
43/258 (16.7) |
35/118 (29.7) |
||||||||
OVERDOSE
In clinical trials, there were three cases of accidental overdose. All occurred in pediatric patients who received up to five times the recommended intravenous dose of voriconazole. A single adverse event of photophobia of 10 minutes duration was reported.
There is no known antidote to voriconazole.
Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. In an overdose, hemodialysis may assist in the removal of voriconazole and SBECD from the body.
The minimum lethal oral dose in mice and rats was 300 mg/kg (equivalent to 4 and 7 times the recommended maintenance dose (RMD), based on body surface area). At this dose, clinical signs observed in both mice and rats included salivation, mydriasis, titubation (loss of balance while moving), depressed behavior, prostration, partially closed eyes, and dyspnea. Other signs in mice were convulsions, corneal opacification and swollen abdomen.
DOSAGE AND ADMINISTRATION
Administration
VFEND Tablets or Oral Suspension should be taken at least one hour before, or one hour following, a meal.
VFEND I.V. for Injection requires reconstitution to 10 mg/mL and subsequent dilution to 5 mg/mL or less prior to administration as an infusion, at a maximum rate of 3 mg/kg per hour over 1–2 hours (see Intravenous Administration).
NOT FOR IV BOLUS INJECTION
Use of VFEND I.V. with other Parenteral Drug Products
Blood products and concentrated electrolytes
VFEND I.V. must not be infused concomitantly with any blood product or short-term infusion of concentrated electrolytes, even if the two infusions are running in separate intravenous lines (or cannulas). Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of VFEND therapy (see PRECAUTIONS).
Use in Adults
Invasive aspergillosis and serious fungal infections due to Fusarium spp. and Scedosporium apiospermum
For the treatment of adults with invasive aspergillosis and infections due to Fusarium spp. and Scedosporium apiospermum, therapy must be initiated with the specified loading dose regimen of intravenous VFEND to achieve plasma concentrations on Day 1 that are close to steady state. On the basis of high oral bioavailability, switching between intravenous and oral administration is appropriate when clinically indicated (see CLINICAL PHARMACOLOGY). Once the patient can tolerate medication given by mouth, the oral tablet form or oral suspension form of VFEND may be utilized. (See Table 17.)
Candidemia in nonneutropenic patients and other deep tissue Candida infections
See Table 17. Patients should be treated for at least 14 days following resolution of symptoms or following last positive culture, whichever is longer.
Esophageal Candidiasis
See Table 17. Patients should be treated for a minimum of 14 days and for at least 7 days following resolution of symptoms.
| Infection | Loading dose | Maintenance Dose | |
|---|---|---|---|
| IV | IV | Oral* | |
|
|
|||
|
Invasive Aspergillosis |
6 mg/kg q12h for the first 24 hours |
4 mg/kg q12h |
200 mg q12h |
|
Candidemia in nonneutropenic patients and other deep tissue Candida infections |
6 mg/kg q12h for the first 24 hours |
3–4 mg/kg q12h † |
200 mg q12h |
|
Esophageal Candidiasis |
200 mg q12h |
||
|
Scedosporiosis and Fusariosis |
6 mg/kg q12h for the first 24 hours |
4 mg/kg q12h |
200 mg q12h |
Dosage Adjustment
If patient response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours to 300 mg every 12 hours. For adult patients weighing less than 40 kg, the oral maintenance dose may be increased from 100 mg every 12 hours to 150 mg every 12 hours. If patients are unable to tolerate 300 mg orally every 12 hours, reduce the oral maintenance dose by 50 mg steps to a minimum of 200 mg every 12 hours (or to 100 mg every 12 hours for adult patients weighing less than 40 kg).
If patients are unable to tolerate 4 mg/kg IV, reduce the intravenous maintenance dose to 3 mg/kg every 12 hours.
Phenytoin may be coadministered with VFEND if the intravenous maintenance dose of VFEND is increased to 5 mg/kg every 12 hours, or the oral maintenance dose is increased from 200 mg to 400 mg every 12 hours (100 mg to 200 mg every 12 hours in adult patients weighing less than 40 kg) (see CLINICAL PHARMACOLOGY, PRECAUTIONS - Drug Interactions).
When voriconazole is coadministered with efavirenz, the voriconazole maintenance dose should be increased to 400 mg Q12h and the efavirenz dose should be decreased to 300 mg Q24h. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored (see CLINICAL PHARMACOLOGY and PRECAUTIONS – Drug Interactions).
Duration of therapy should be based on the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response.
Use in Patients with Hepatic Insufficiency
In the clinical program, patients were included who had baseline liver function tests (ALT, AST) up to 5 times the upper limit of normal. No dose adjustment is necessary in patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended (see WARNINGS).
It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B).
VFEND has not been studied in patients with severe hepatic cirrhosis (Child-Pugh Class C) or in patients with chronic hepatitis B or chronic hepatitis C disease. VFEND has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and should only be used in patients with severe hepatic insufficiency if the benefit outweighs the potential risk. Patients with hepatic insufficiency must be carefully monitored for drug toxicity.
Use in Patients with Renal Insufficiency
The pharmacokinetics of orally administered VFEND are not significantly affected by renal insufficiency. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment (see CLINICAL PHARMACOLOGY - Special Populations).
In patients with moderate or severe renal insufficiency (creatinine clearance <50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral voriconazole therapy (see DOSAGE and ADMINISTRATION).
Voriconazole is hemodialyzed 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.
Intravenous Administration
VFEND I.V. For Injection
Reconstitution
The powder is reconstituted with 19 mL of Water For Injection to obtain an extractable volume of 20 mL of clear concentrate containing 10 mg/mL of voriconazole. It is recommended that a standard 20 mL (non-automated) syringe be used to ensure that the exact amount (19.0 mL) of Water for Injection is dispensed. Discard the vial if a vacuum does not pull the diluent into the vial. Shake the vial until all the powder is dissolved.
Dilution
VFEND must be infused over 1–2 hours, at a concentration of 5 mg/mL or less. Therefore, the required volume of the 10 mg/mL VFEND concentrate should be further diluted as follows (appropriate diluents listed below):
- 1. Calculate the volume of 10 mg/mL VFEND concentrate required based on the patient's weight (see Table 18).
- 2. In order to allow the required volume of VFEND concentrate to be added, withdraw and discard at least an equal volume of diluent from the infusion bag or bottle to be used. The volume of diluent remaining in the bag or bottle should be such that when the 10 mg/mL VFEND concentrate is added, the final concentration is not less than 0.5 mg/mL nor greater than 5 mg/mL.
- 3. Using a suitable size syringe and aseptic technique, withdraw the required volume of VFEND concentrate from the appropriate number of vials and add to the infusion bag or bottle. Discard Partially Used Vials.
The final VFEND solution must be infused over 1–2 hours at a maximum rate of 3 mg/kg per hour.
| Body Weight
(kg) | Volume of VFEND Concentrate (10 mg/mL) required for: | ||
|---|---|---|---|
| 3 mg/kg dose
(number of vials) | 4 mg/kg dose
(number of vials) | 6 mg/kg dose
(number of vials) |
|
|
30 |
9.0 mL (1) |
12 mL (1) |
18 mL (1) |
|
35 |
10.5 mL (1) |
14 mL (1) |
21 mL (2) |
|
40 |
12.0 mL (1) |
16 mL (1) |
24 mL (2) |
|
45 |
13.5 mL (1) |
18 mL (1) |
27 mL (2) |
|
50 |
15.0 mL (1) |
20 mL (1) |
30 mL (2) |
|
55 |
16.5 mL (1) |
22 mL (2) |
33 mL (2) |
|
60 |
18.0 mL (1) |
24 mL (2) |
36 mL (2) |
|
65 |
19.5 mL (1) |
26 mL (2) |
39 mL (2) |
|
70 |
21.0 mL (2) |
28 mL (2) |
42 mL (3) |
|
75 |
22.5 mL (2) |
30 mL (2) |
45 mL (3) |
|
80 |
24.0 mL (2) |
32 mL (2) |
48 mL (3) |
|
85 |
25.5 mL (2) |
34 mL (2) |
51 mL (3) |
|
90 |
27.0 mL (2) |
36 mL (2) |
54 mL (3) |
|
95 |
28.5 mL (2) |
38 mL (2) |
57 mL (3) |
|
100 |
30.0 mL (2) |
40 mL (2) |
60 mL (3) |
VFEND I.V. for Injection is a single dose unpreserved sterile lyophile. Therefore, from a microbiological point of view, once reconstituted, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2° to 8°C (36° to 46°F). This medicinal product is for single use only and any unused solution should be discarded. Only clear solutions without particles should be used.
The reconstituted solution can be diluted with:
9 mg/mL (0.9%) Sodium Chloride USP
Lactated Ringers USP
5% Dextrose and Lactated Ringers USP
5% Dextrose and 0.45% Sodium Chloride USP
5% Dextrose USP
5% Dextrose and 20 mEq Potassium Chloride USP
0.45% Sodium Chloride USP
5% Dextrose and 0.9% Sodium Chloride USP
The compatibility of VFEND I.V. with diluents other than those described above is unknown (see Incompatibilities below).
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Incompatibilities
VFEND I.V. must not be diluted with 4.2% Sodium Bicarbonate Infusion. The mildly alkaline nature of this diluent caused slight degradation of VFEND after 24 hours storage at room temperature. Although refrigerated storage is recommended following reconstitution, use of this diluent is not recommended as a precautionary measure. Compatibility with other concentrations is unknown.
VFEND for Oral Suspension
Reconstitution
Tap the bottle to release the powder. Add 46 mL of water to the bottle. Shake the closed bottle vigorously for about 1 minute. Remove child-resistant cap and push bottle adaptor into the neck of the bottle. Replace the cap. Write the date of expiration of the reconstituted suspension on the bottle label (the shelf-life of the reconstituted suspension is 14 days at controlled room temperature 15–30°C [59–86°F]).
HOW SUPPLIED
Powder for Solution for Injection
VFEND I.V. for Injection is supplied in a single use vial as a sterile lyophilized powder equivalent to 200 mg VFEND and 3200 mg sulfobutyl ether beta-cyclodextrin sodium (SBECD).
Individually packaged vials of 200 mg VFEND I.V.
(NDC: 0049-3190-28)
Tablets
VFEND 50 mg tablets; white, film-coated, round, debossed with "Pfizer" on one side and "VOR50" on the reverse.
Bottles of 30 (NDC: 0049-3170-30)
VFEND 200 mg tablets; white, film-coated, capsule shaped, debossed with "Pfizer" on one side and "VOR200" on the reverse.
Bottles of 30 (NDC: 0049-3180-30)
Powder for Oral Suspension
VFEND for Oral Suspension is supplied in 100 mL high density polyethylene (HDPE) bottles. Each bottle contains 45 g of powder for oral suspension. Following reconstitution, the volume of the suspension is 75 mL, providing a usable volume of 70 mL (40 mg voriconazole/mL). A 5 mL oral dispenser and a press-in bottle adaptor are also provided.
(NDC: 0049-3160-44)
STORAGE
VFEND I.V. for Injection unreconstituted vials should be stored at 15° – 30°C (59° – 86°F) [see USP Controlled Room Temperature]. VFEND is a single dose unpreserved sterile lyophile. From a microbiological point of view, following reconstitution of the lyophile with Water for Injection, the reconstituted solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2° to 8°C (36° to 46°F). Chemical and physical in-use stability has been demonstrated for 24 hours at 2° to 8°C (36° to 46°F). This medicinal product is for single use only and any unused solution should be discarded. Only clear solutions without particles should be used (see DOSAGE AND ADMINISTRATION - Intravenous Administration).
VFEND Tablets should be stored at 15° – 30°C (59° – 86°F) [see USP Controlled Room Temperature].
VFEND Powder for Oral Suspension should be stored at 2° – 8°C (36° – 46° F) (in a refrigerator) before reconstitution. The shelf-life of the powder for oral suspension is 18 months.
The reconstituted suspension should be stored at 15° – 30°C (59° – 86°F) [see USP Controlled Room Temperature]. Do not refrigerate or freeze. Keep the container tightly closed. The shelf-life of the reconstituted suspension is 14 days. Any remaining suspension should be discarded 14 days after reconstitution.
REFERENCES
- 1. Clinical Laboratory Standards Institute. Reference method for broth dilution antifungal susceptibility testing of conidium-forming filamentous fungi. Approved Standard M38-P. Clinical Laboratory Standards Institute, Villanova, Pa.
- 2. Clinical Laboratory Standards Institute. Reference method for broth dilution antifungal susceptibility testing of yeasts. Approved Standard M27-A. Clinical Laboratory Standards Institute, Villanova, Pa.
- 3. Clinical Laboratory Standards Institute. Method for antifungal disk diffusion susceptibility testing of yeasts. Approved guideline M44-A. Clinical Laboratory Standards Institute, Villanova, Pa.
PATIENT INFORMATION
VFEND ® (VEE-fend)
(voriconazole IV injection, tablets, liquid)
Read the Patient Information that comes with VFEND before you start taking it and each time you get a refill. There may be new information. This information does not replace talking with your doctor about your condition or treatment.
What is VFEND?
VFEND is a prescription medicine that treats certain serious fungal infections in your blood and body; these infections are called "aspergillosis," "esophageal candidiasis," "Scedosporium," "Fusarium," and "candidemia.".
VFEND is for adults and children over 12 years of age.
What should I tell my doctor before taking VFEND?
Tell your doctor about all your health conditions, including if you:
- have or ever had an abnormal heart rate or rhythm. Your doctor may order a test to check your heart (EKG) before starting VFEND.
- have liver or kidney problems. Your doctor may do blood tests to make sure you can take VFEND.
- have trouble digesting dairy products, lactose, or regular table sugar. VFEND tablets contain lactose (milk sugar). VFEND liquid contains sucrose (table sugar).
- had an allergic reaction to any other medicine, such as hives, wheezing, or swelling of your face or throat.
- are pregnant or planning to become pregnant while taking this medication. VFEND can harm your unborn baby. Women who can become pregnant should use effective birth control while taking VFEND.
- are breast-feeding. It is not known if VFEND passes into breast milk. You and your doctor will need to decide if VFEND is right for you while you are nursing.
Know what medications you are taking. Be sure to tell your doctor about all the medications that you are taking, including prescription medicines, non-prescription medicines, vitamins, and herbal remedies. Keep a list of them with you to show your doctor or pharmacist.
Who should not take VFEND?
Do NOT take VFEND if you are taking the medicines listed below. Serious or life-threatening side effects from these medicines, or a decrease in the effect of VFEND could result if any of these medicines are taken together with VFEND. Tell your doctor right away if you are taking any of these medications:
- terfenadine (Seldane®)
- astemizole (Hismanal®)
- cisapride (Propulsid®)
- pimozide (Orap®)
- sirolimus (Rapamune®)
- carbamazepine (Tegretol®)
- rifampin (Rifadin®)
- rifabutin (Mycobutin®)
- St. John's Wort (herbal supplement)
- quinidine (like Quinaglute®)
- ergotamine, dihydroergotamine, methysergide (Sansert®), and bromocriptine (Parlodel®)
- long-acting barbiturates like phenobarbital (Luminal®)
- ritonavir (Norvir®) and efavirenz (Sustiva®) (Some doses of ritonavir and efavirenz can be taken at the same time as VFEND, but you must check with your doctor first)
If you have questions or are uncertain about your medications, talk with your doctor or pharmacist.
Do not take VFEND if you are allergic to anything in it. The active ingredient is voriconazole. There is a list of what is in VFEND at the end of this leaflet.
Can I take other medicines with VFEND?
VFEND and many medicines can interact with each other and some should not be taken together (see "Who should not take VFEND?"). Other medicines may need the dose adjusted when taken with Vfend. Knowing the medicines that you are taking is important. Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins and herbal supplements. Keep a list of them with you to show your doctor or pharmacist. Do not take any new medicine without talking with your doctor.
How do I take VFEND?
- VFEND comes in I.V. (intravenous) form, or as a tablet or liquid.
- VFEND I.V. Your doctor or nurse may give you VFEND through a needle in your vein (intravenous, I.V.). It takes 1 to 2 hours to get each dose.
- VFEND tablets. Take the tablets as your doctor tells you. Take your dose at least 1 hour before or at least 1 hour after meals.
- VFEND liquid. Take the liquid as your doctor tells you. Take it at least 1 hour before or at least 1 hour after meals.
- VFEND is usually taken every 12 hours. Follow your doctor's instructions on when to take it. If you miss a dose of VFEND, take it as soon as you remember. If it is more than 6 hours since you missed your dose, wait. Do not take the missed dose. Take VFEND at the next regular dosing time. Do not take double doses.
- If you take too much VFEND or develop serious reactions, call your doctor or poison control center, or go to the nearest emergency room.
What should I avoid while taking VFEND?
- Avoid night driving, because VFEND may cause vision problems like blurry vision.
- Avoid all driving or using dangerous machinery, if you have any change in your eyesight.
- Avoid bright sunlight. Your skin may burn more easily. Your eyes may hurt in bright sunlight.
What are possible side effects of VFEND?
VFEND may cause serious or life threatening side effects. Call your doctor right away if you have any of the following symptoms:
- Serious changes in heart rate or rhythm, including heart stopping (cardiac arrest). People who have certain heart conditions or who take certain other medicines have a higher chance for this problem.
- Eyesight (vision) changes. These changes include blurred vision, color vision change, and being sensitive to light while you are taking VFEND. These changes are generally mild. Vision side effects lasting for more than one month have been reported by some patients. Your doctor should monitor your eyesight if you take VFEND for more than 28 days.
- Liver problems. VFEND can cause liver problems that usually go away when you stop VFEND. It can also cause very serious liver problems. Your doctor should test your liver function while you are taking VFEND. Call your doctor if you have any of these symptoms of liver problems, you:
-
- itch, or your skin or eyes turn yellow
- feel more tired than usual
- feel like you have the flu
- have nausea or vomiting
-
Kidney problems. Your doctor may check your kidney function while you are taking VFEND. Your doctor will decide if you can keep taking it or if you need a lower dose. Call your doctor if you have any of these symptoms of kidney problems:
- no appetite, feeling very tired
- changes in thinking, seizures, or trouble breathing
- nausea and vomiting, or itching
- Serious allergic reactions can happen with VFEND injection. These include sweating, fast heartbeats, chest tightness, trouble breathing, nausea, itching, and rash. Your doctor should stop your VFEND infusion if you have any of these symptoms.
- Serious skin reactions. If you get a skin rash or hives, sores in your mouth, or your skin blisters and peels, stop using VFEND. Call your doctor right away.
Common side effects with VFEND include eyesight changes, rash, vomiting, nausea, diarrhea, headache, chills, fever, infection in your blood, swelling in your arms and legs, stomach pains, and breathing problems.
These are not all the side effects with VFEND. For more information, ask your doctor or pharmacist.
How do I store VFEND?
- Store VFEND tablets and liquid at room temperature, 59° to 86° F (15°to 30°C). Do not refrigerate or freeze. The liquid should be discarded after 14 days. Keep all containers tightly closed.
- I.V. VFEND should be given by your nurse or doctor.
- Keep VFEND, as well as all other medicines, out of the reach of children.
General information about VFEND
Doctors can prescribe medicines for conditions that are not in this leaflet. Use VFEND only for what your doctor prescribed. Do not give it to other people, even if they have the same symptoms you have. It may harm them.
This leaflet gives the most important information about VFEND. For more information, talk with your doctor. You can ask your doctor or pharmacist for information about VFEND that is written for health professionals.
What is in VFEND?
Active ingredient: voriconazole
Inactive ingredients:
VFEND IV: sulfobutyl ether beta-cyclodextrin sodium
VFEND tablets: lactose monohydrate, pregelatinized starch, croscarmellose sodium, povidone, magnesium stearate, and a coating containing hypromellose, titanium dioxide, lactose monohydrate, and triacetin
VFEND liquid: colloidal silicon dioxide, titanium dioxide, xanthan gum, sodium citrate dihydrate, sodium benzoate, anhydrous citric acid, natural orange flavor, and sucrose
Rx Only
Trademarks are the property of their respective owners.
LAB-0311-5.0
March 2008
VFEND 50 mg and 200 mg tablets are available from Cardinal Health in unit dose packages of 30.
50 mg, unit dose package of 30 tablets, NDC: 55154-2730-4
200 mg, unit dose package of 30 tablets, NDC: 55154-2725-4
Cardinal Health
Zanesville OH 43701
IU37363861109
| VFEND
voriconazole tablet, film coated |
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| VFEND
voriconazole tablet, film coated |
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| Labeler - Cardinal Health (603638201) |