Vfend 200 MG Injection

Details

Generic Name: VORICONAZOLE

Brand Name: VFEND

Substance Name(s):
VORICONAZOLE

DRUG INTERACTIONS

7 Table 7: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)] 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 RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin (CYP450 Induction) Significantly Reduced Contraindicated Efavirenz (400 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP450 Induction) Significantly Reduced Contraindicated Efavirenz (300 mg q24h) (CYP450 Induction) Slight Decrease in AUC τ When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h High-dose Ritonavir (400 mg q12h) (CYP450 Induction) Significantly Reduced Contraindicated Low-dose Ritonavir (100 mg q12h) (CYP450 Induction) 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 (CYP450 Induction) Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated Long Acting Barbiturates (CYP450 Induction) Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated Phenytoin (CYP450 Induction) Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg) St.

John’s Wort (CYP450 inducer; P-gp inducer) 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 Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole.

Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.

Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction) 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 A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) Careful assessment of voriconazole effectiveness Table 8: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)] Drug/Drug Class (Mechanism of Interaction by Voriconazole) Drug Plasma Exposure (Cmax and AUCτ) Recommendations for Drug Dosage Adjustment/Comments SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition) Significantly Increased Contraindicated Rifabutin (CYP3A4 Inhibition) Significantly Increased Contraindicated Efavirenz (400 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition) Significantly Increased Contraindicated Efavirenz (300 mg q24h) (CYP3A4 Inhibition) Slight Increase in AUCτ When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h 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 (100 mg 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 (CYP3A4 Inhibition) 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 (CYP450 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated Cyclosporine (CYP3A4 Inhibition) 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.

MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg q24h) (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 Fentanyl (CYP3A4 Inhibition) Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND.

Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)] 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 Drug Interactions (7)].

Oxycodone (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND.

Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].

NSAIDsNon-Steroidal Anti-Inflammatory Drug including.

ibuprofen and diclofenac (CYP2C9 Inhibition) Increased Frequent monitoring for adverse events and toxicity related to NSAIDs.

Dose reduction of NSAIDs may be needed [see Drug Interactions (7)].

Tacrolimus (CYP3A4 Inhibition) 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 (CYP2C9 Inhibition) 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 (CYP2C9 Inhibition) Prothrombin Time Significantly Increased Monitor PT or other suitable anti-coagulation tests.

Adjustment of warfarin dosage may be needed.

Omeprazole (CYP2C19/3A4 Inhibition) 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 (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects on Indinavir Exposure No dosage adjustment for indinavir when coadministered with VFEND In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to NNRTI Benzodiazepines (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) 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) (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) 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 (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to calcium channel blockers.

Adjustment of calcium channel blocker dosage may be needed.

Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) 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 (CYP3A4 Inhibition) 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.

Everolimus (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Concomitant administration of voriconazole and everolimus is not recommended.

CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers: Adjust VFEND dosage and monitor for adverse reactions or lack of efficacy (4, 7) VFEND may increase the concentrations and activity of drugs that are CYP3A4, CYP2C9 and CYP2C19 substrates.

Reduce dosage of these other drugs and monitor for adverse reactions (4, 7) Phenytoin or Efavirenz: with co-administration, increase maintenance oral and intravenous dosage of VFEND (2.3 7)

OVERDOSAGE

10 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.

DESCRIPTION

11 VFEND® (voriconazole), an azole antifungal agent is available as a lyophilized powder for solution for intravenous infusion.

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 (2)].

Chemical Structure

CLINICAL STUDIES

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

14.1 Invasive Aspergillosis Voriconazole was studied in patients for primary therapy of invasive aspergillosis (randomized, controlled study 307/602), for primary and salvage therapy of aspergillosis (non-comparative study 304) and for treatment of patients with invasive aspergillosis who were refractory to, or intolerant of, other antifungal therapy (non-comparative study 309/604).

Study 307/602 – Primary Therapy of Invasive Aspergillosis The efficacy of voriconazole compared to amphotericin B in the primary treatment of acute invasive aspergillosis was demonstrated in 277 patients treated for 12 weeks in a randomized, controlled study (Study 307/602).

The majority of study patients had underlying hematologic malignancies, including bone marrow transplantation.

The study also included patients with solid organ transplantation, solid tumors, and AIDS.

The patients were mainly treated for definite or probable invasive aspergillosis of the lungs.

Other aspergillosis infections included disseminated disease, CNS infections and sinus infections.

Diagnosis of definite or probable invasive aspergillosis was made according to criteria modified from those established by the National Institute of Allergy and Infectious Diseases Mycoses Study Group/European Organisation for Research and Treatment of Cancer (NIAID MSG/EORTC).

Voriconazole was administered intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours followed by a maintenance dose of 4 mg/kg every 12 hours for a minimum of seven days.

Therapy could then be switched to the oral formulation at a dose of 200 mg q12h.

Median duration of IV voriconazole therapy was 10 days (range 2–85 days).

After IV voriconazole therapy, the median duration of PO voriconazole therapy was 76 days (range 2–232 days).

Patients in the comparator group received conventional amphotericin B as a slow infusion at a daily dose of 1.0–1.5 mg/kg/day.

Median duration of IV amphotericin therapy was 12 days (range 1–85 days).

Treatment was then continued with other licensed antifungal therapy (OLAT), including itraconazole and lipid amphotericin B formulations.

Although initial therapy with conventional amphotericin B was to be continued for at least two weeks, actual duration of therapy was at the discretion of the investigator.

Patients who discontinued initial randomized therapy due to toxicity or lack of efficacy were eligible to continue in the study with OLAT treatment.

A satisfactory global response at 12 weeks (complete or partial resolution of all attributable symptoms, signs, radiographic/bronchoscopic abnormalities present at baseline) was seen in 53% of voriconazole treated patients compared to 32% of amphotericin B treated patients (Table 14).

A benefit of voriconazole compared to amphotericin B on patient survival at Day 84 was seen with a 71% survival rate on voriconazole compared to 58% on amphotericin B (Table 12).

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

Table 12: Overall Efficacy and Success by Species in the Primary Treatment of Acute Invasive Aspergillosis Study 307/602 Voriconazole Ampho B Amphotericin B followed by other licensed antifungal therapy Stratified Difference (95% CI) Difference and corresponding 95% confidence interval are stratified by protocol n/N (%) n/N (%) Efficacy as Primary Therapy Satisfactory Global Response Assessed by independent Data Review Committee (DRC) 76/144 (53) 42/133 (32) 21.8% (10.5%, 33.0%) p<0.0001 Survival at Day 84 Proportion of subjects alive 102/144 (71) 77/133 (58) 13.1% (2.1%, 24.2%) Success by Species Success n/N (%) Overall success 76/144 (53) 42/133 (32) Mycologically confirmed Not all mycologically confirmed specimens were speciated 37/84 (44) 16/67 (24) Aspergillus spp.Some patients had more than one species isolated at baseline 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 – Primary and Salvage Therapy of Aspergillosis In this non-comparative study, an overall success rate of 52% (26/50) was seen in patients treated with voriconazole for primary therapy.

Success was seen in 17/29 (59%) with Aspergillus fumigatus infections and 3/6 (50%) patients with infections due to non-fumigatus species [A.

flavus (1/1); A.

nidulans (0/2); A.

niger (2/2); A.

terreus (0/1)].

Success in patients who received voriconazole as salvage therapy is presented in Table 13.

Study 309/604 – Treatment of Patients with Invasive Aspergillosis who were Refractory to, or Intolerant of, other Antifungal Therapy Additional data regarding response rates in patients who were refractory to, or intolerant of, other antifungal agents are also provided in Table 15.

In this non-comparative study, overall mycological eradication for culture-documented infections due to fumigatus and non-fumigatus species of Aspergillus was 36/82 (44%) and 12/30 (40%), respectively, in voriconazole treated patients.

Patients had various underlying diseases and species other than A.

fumigatus contributed to mixed infections in some cases.

For patients who were infected with a single pathogen and were refractory to, or intolerant of, other antifungal agents, the satisfactory response rates for voriconazole in studies 304 and 309/604 are presented in Table 13.

Table 13: Combined Response Data in Salvage Patients with Single Aspergillus Species (Studies 304 and 309/604) Success n/N A.

fumigatus 43/97 (44%) 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.

14.2 Candidemia in Non-neutropenic 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 14.

Table 14: Overall Success Rates Sustained From EOT To The Fixed 12-Week Follow-Up Time Point By Baseline PathogenA few patients had more than one pathogen at baseline.

, Patients who did not have a 12-week assessment for any reason were considered a treatment failure.

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 intra-abdominal infections, 5 of 6 patients with kidney and bladder wall infections, 3 of 3 patients with deep tissue abscess or wound infection, 1 of 2 patients with pneumonia/pleural space infections, 2 of 4 patients with skin lesions, 1 of 1 patients with mixed intraabdominal and pulmonary infection, 1 of 2 patients with suppurative phlebitis, 1 of 3 patients with hepatosplenic infection, 1 of 5 patients with osteomyelitis, 0 of 1 with liver infection, and 0 of 1 with cervical lymph node infection.

14.3 Esophageal Candidiasis The efficacy of oral voriconazole 200 mg twice daily compared to oral fluconazole 200 mg once daily in the primary treatment of esophageal candidiasis was demonstrated in Study 150-305, a double-blind, double-dummy study in immunocompromised patients with endoscopically-proven esophageal candidiasis.

Patients were treated for a median of 15 days (range 1 to 49 days).

Outcome was assessed by repeat endoscopy at end of treatment (EOT).

A successful response was defined as a normal endoscopy at EOT or at least a 1 grade improvement over baseline endoscopic score.

For patients in the Intent to Treat (ITT) population with only a baseline endoscopy, a successful response was defined as symptomatic cure or improvement at EOT compared to baseline.

Voriconazole and fluconazole (200 mg once daily) showed comparable efficacy rates against esophageal candidiasis, as presented in Table 15.

Table 15: Success Rates in Patients Treated for Esophageal Candidiasis Population Voriconazole Fluconazole Difference % (95% CI)Confidence Interval for the difference (Voriconazole – Fluconazole) in success rates.

PPPP (Per Protocol) patients had confirmation of Candida esophagitis by endoscopy, received at least 12 days of treatment, and had a repeat endoscopy at EOT (end of treatment).

113/115 (98.2%) 134/141 (95.0%) 3.2 (-1.1, 7.5) ITTITT (Intent to Treat) patients without endoscopy or clinical assessment at EOT were treated as failures.

175/200 (87.5%) 171/191 (89.5%) -2.0 (-8.3, 4.3) Microbiologic success rates by Candida species are presented in Table 16.

Table 16: Clinical and mycological outcome by baseline pathogen in patients with esophageal candidiasis (Study-150-305) PathogenSome patients had more than one species isolated at baseline Voriconazole Fluconazole Favorable endoscopic responsePatients with endoscopic and/or mycological assessment at end of therapy 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 14.4 Other Serious Fungal Pathogens In pooled analyses of patients, voriconazole was shown to be effective against the following additional fungal pathogens: Scedosporium apiospermum – Successful response to voriconazole therapy was seen in 15 of 24 patients (63%).

Three of these patients relapsed within 4 weeks, including 1 patient with pulmonary, skin and eye infections, 1 patient with cerebral disease, and 1 patient with skin infection.

Ten patients had evidence of cerebral disease and 6 of these had a successful outcome (1 relapse).

In addition, a successful response was seen in 1 of 3 patients with mixed organism infections.

Fusarium spp.

– Nine of 21 (43%) patients were successfully treated with voriconazole.

Of these 9 patients, 3 had eye infections, 1 had an eye and blood infection, 1 had a skin infection, 1 had a blood infection alone, 2 had sinus infections, and 1 had disseminated infection (pulmonary, skin, hepatosplenic).

Three of these patients (1 with disseminated disease, 1 with an eye infection and 1 with a blood infection) had Fusarium solani and were complete successes.

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

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 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 0049-4190-01) 16.2 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 (2.1)].

RECENT MAJOR CHANGES

Contraindications, Efavirenz 400 mg q24h or higher (4) 9/2014 Warnings and Precautions, Hepatic Toxicity (5.2) 3/2015 Warnings and Precautions, Arrhythmias/QT Prolongation (5.5) 3/2015 Warnings and Precautions, Dermatological Reactions (5.12) 3/2015

GERIATRIC USE

8.5 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 (12.3)].

DOSAGE FORMS AND STRENGTHS

3 For Injection: lyophilized powder containing 200 mg voriconazole and 3200 mg of sulfobutyl ether beta-cyclodextrin sodium (SBECD); after reconstitution 10 mg/mL of voriconazole and 160 mg/mL of SBECD (3) 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).

MECHANISM OF ACTION

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

INDICATIONS AND USAGE

1 VFEND is indicated for use in patients 12 years of age and older in the treatment of the following fungal infections: VFEND is an azole antifungal drug indicated for use in the treatment of: Invasive aspergillosis (1.1) Candidemia (nonneutropenics) and disseminated candidiasis in skin, abdomen, kidney, bladder wall, and wounds (1.2) Esophageal candidiasis (1.3) Serious infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani, in patients intolerant of, or refractory to, other therapy (1.4) 1.1 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 (14.1) and Clinical Pharmacology (12.4)].

1.2 Candidemia in Non-neutropenic Patients and the Following Candida Infections: Disseminated Infections in Skin and Infections in Abdomen, Kidney, Bladder Wall, and Wounds [see Clinical Studies (14.2) and Clinical Pharmacology (12.4)] 1.3 Esophageal Candidiasis [see Clinical Studies (14.3) and Clinical Pharmacology (12.4)] 1.4 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 (14.4) and Clinical Pharmacology (12.4)] 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.

PEDIATRIC USE

8.4 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 to 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 (12.3)].

There have been postmarketing reports of pancreatitis in pediatric patients.

PREGNANCY

8.1 Pregnancy Pregnancy Category D Voriconazole can cause fetal harm when administered to a pregnant woman and should not be taken in pregnancy except in patients where the benefit to the mother clearly outweighs the potential risk to the fetus.

There are no adequate and well-controlled studies in pregnant women.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patients should be informed of the potential hazard to the fetus [see Warnings and Precautions (5.4)].

Animal Data 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.

NUSRING MOTHERS

8.3 Nursing Mothers It is not known whether voriconazole is excreted in human milk.

Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VFEND, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Clinically Significant Drug Interactions: Review patient’s concomitant medications (5.1,7) Hepatic Toxicity: Serious hepatic reactions reported.

Evaluate liver function tests at start of and during voriconazole therapy (5.2) Visual Disturbances (including optic neuritis and papilledema): Monitor visual function if treatment continues beyond 28 days (5.3) Embryo-Fetal Toxicity: Do not administer to pregnant women unless the benefit to the mother outweighs the risk to the fetus.

Inform pregnant patient of hazard (5.4, 8.1) Arrhythmias and QT Prolongation: Correct potassium, magnesium and calcium prior to use; caution patients with proarrhythmic conditions (5.5) Infusion Related Reactions (including anaphylaxis): Stop the infusion (5.6) Dermatological Reactions: Discontinue for exfoliative cutaneous reactions or phototoxicity.

Avoid sunlight due to risk of photosensitivity (5.12) Skeletal Events: Fluorosis and periostitis reported with long-term voriconazole therapy.

Discontinue if these events occur (5.13) 5.1 Drug Interactions See Table 7 for a listing of drugs that may significantly alter voriconazole concentrations.

Also, see Table 8 for a listing of drugs that may interact with voriconazole resulting in altered pharmacokinetics or pharmacodynamics of the other drug [see Contraindications (4) and Drug Interactions (7)].

5.2 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 Warnings and Precautions (5.8) and Adverse Reactions (6.3)].

Measure serum transaminase levels and bilirubin at the initiation of VFEND therapy and monitor at least weekly for the first month of treatment.

Monitoring frequency can be reduced to monthly during continued use if no clinically significant changes are noted.

If liver function tests become markedly elevated compared to baseline, VFEND should be discontinued unless the medical judgment of the benefit-risk of the treatment for the patient justifies continued use [see Warnings and Precautions (5.8), Dosage and Administration (2.4, 2.6), and Adverse Reactions (6.3)].

5.3 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.

If treatment continues beyond 28 days, visual function including visual acuity, visual field and color perception should be monitored [see Adverse Reactions (6.2)].

5.4 Embryo-Fetal Toxicity Voriconazole can cause fetal harm when administered to a pregnant woman.

In animals, voriconazole administration was associated with teratogenicity, embryotoxicity, increased gestational length, dystocia and embryomortality.

Please refer to section 8.1 (Use in Pregnancy) for additional details.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to the fetus.

5.5 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 potentially proarrhythmic conditions, such as: Congenital or acquired QT-prolongation Cardiomyopathy, in particular when heart failure is present Sinus bradycardia Existing symptomatic arrhythmias Concomitant medicinal product that is known to prolong QT interval [see Contraindications (4), Drug Interactions (7), and Clinical Pharmacology (12.3)] Rigorous attempts to correct potassium, magnesium and calcium should be made before starting and during voriconazole therapy [see Clinical Pharmacology (12.3)].

5.6 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.

5.7 Laboratory Tests Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of and during VFEND therapy.

Patient management should include laboratory evaluation of renal (particularly serum creatinine) and hepatic function (particularly liver function tests and bilirubin).

5.8 Patients With Hepatic Impairment 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 (12.3) and Dosage and Administration (2.6)].

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.

5.9 Patients With Renal Impairment 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 (12.3) and Dosage and Administration (2.7)].

5.10 Monitoring of Renal Function Acute renal failure has been observed in 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.

Patients should be monitored for the development of abnormal renal function.

This should include laboratory evaluation, particularly serum creatinine.

5.11 Monitoring of Pancreatic Function Patients 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.

5.12 Dermatological Reactions Serious exfoliative cutaneous reactions, such as Stevens-Johnson syndrome, have been reported during treatment with VFEND.

If a patient develops an exfoliative cutaneous reaction, VFEND should be discontinued.

VFEND has been associated with photosensitivity skin reaction.

Patients, including children, should avoid exposure to direct sunlight during VFEND treatment and should use measures such as protective clothing and sunscreen with high sun protection factor (SPF).

If phototoxic reactions occur, the patient should be referred to a dermatologist and VFEND discontinuation should be considered.

If VFEND is continued despite the occurrence of phototoxicity-related lesions, dermatologic evaluation should be performed on a systematic and regular basis to allow early detection and management of premalignant lesions.

Squamous cell carcinoma of the skin and melanoma have been reported during long-term VFEND therapy in patients with photosensitivity skin reactions.

If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, VFEND should be discontinued.

The frequency of phototoxicity reactions is higher in the pediatric population.

Because squamous cell carcinoma has been reported in patients who experience photosensitivity reactions, stringent measures for photoprotection are warranted in children.

In children experiencing photoaging injuries such as lentigines or ephelides, sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation.

5.13 Skeletal Adverse Events Fluorosis and periostitis have been reported during long-term voriconazole therapy.

If a patient develops skeletal pain and radiologic findings compatible with fluorosis or periostitis, voriconazole should be discontinued [see Adverse Reactions (6.4)].

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling This product’s label may have been updated.

For current full prescribing information, please visit www.pfizer.com.

DOSAGE AND ADMINISTRATION

2 Recommended Dosage (2.3) 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 nonneutropenics and other deep tissue Candida infections 3–4 mg/kg q12h 200 mg q12h Scedosporiosis and Fusariosis 4 mg/kg q12h 200 mg q12h Esophageal Candidiasis not evaluated not evaluated 200 mg q12h Adult patients weighing less than 40 kg: oral maintenance dose 100 or 150 mg q12 hours See full prescribing information for instructions on reconstitution of lyophilized powder for intravenous use and important administration instructions (2.5) 2.1 Instructions for Use in All Patients 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 to 2 hours.

Do not administer as an IV bolus injection.

2.2 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 and during VFEND therapy [see Warnings and Precautions (5.7)].

Intravenous solutions containing (non-concentrated) electrolytes VFEND I.V.

can be infused at the same time as other intravenous solutions containing (non-concentrated) electrolytes, but must be infused through a separate line.

Total parenteral nutrition (TPN) VFEND I.V.

can be infused at the same time as total parenteral nutrition, but must be infused in a separate line.

If infused through a multiple-lumen catheter, TPN needs to be administered using a different port from the one used for VFEND I.V.

2.3 Recommended Dosing in Adults Invasive aspergillosis and serious fungal infections due to Fusarium spp.

and Scedosporium apiospermum See Table 1.

Therapy must be initiated with the specified loading dose regimen of intravenous VFEND on Day 1 followed by the recommended maintenance dose regimen.

Intravenous treatment should be continued for at least 7 days.

Once the patient has clinically improved and can tolerate medication given by mouth, the oral tablet form or oral suspension form of VFEND may be utilized.

The recommended oral maintenance dose of 200 mg achieves a voriconazole exposure similar to 3 mg/kg IV; a 300 mg oral dose achieves an exposure similar to 4 mg/kg IV.

Switching between the intravenous and oral formulations is appropriate because of the high bioavailability of the oral formulation in adults [see Clinical Pharmacology (12)].

Candidemia in non-neutropenic patients and other deep tissue Candida infections See Table 1.

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 1.

Patients should be treated for a minimum of 14 days and for at least 7 days following resolution of symptoms.

Table 1: Recommended Dosing Regimen Infection Loading dose Maintenance DoseIncrease dose when VFEND is co-administered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment (2.6) , In healthy volunteer studies, the 200 mg oral q12h dose provided an exposure (AUCτ) similar to a 3 mg/kg IV q12h dose; the 300 mg oral q12h dose provided an exposure (AUCτ) similar to a 4 mg/kg IV q12h dose [see Clinical Pharmacology (12)].

IV IV OralAdult patients who weigh less than 40 kg should receive half of the oral maintenance dose.

Invasive AspergillosisIn a clinical study of invasive aspergillosis, the median duration of IV VFEND therapy was 10 days (range 2–85 days).

The median duration of oral VFEND therapy was 76 days (range 2–232 days) [see Clinical Studies (14.1)].

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 q12hIn clinical trials, patients with candidemia received 3 mg/kg IV q12h as primary therapy, while patients with other deep tissue Candida infections received 4 mg/kg q12h as salvage therapy.

Appropriate dose should be based on the severity and nature of the infection.

200 mg q12h Esophageal Candidiasis Not evaluated in patients with esophageal candidiasis.

200 mg q12h Scedosporiosis and Fusariosis 6 mg/kg q12h for the first 24 hours 4 mg/kg q12h 200 mg q12h 2.4 Dosage Adjustment If patient response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours (similar to 3 mg/kg IV q12h) to 300 mg every 12 hours (similar to 4 mg/kg IV q12h).

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 patient is 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 patient is unable to tolerate 4 mg/kg IV q12h, reduce the intravenous maintenance dose to 3 mg/kg q12h.

The maintenance dose of voriconazole should be increased when co-administered with phenytoin or efavirenz [see Drug Interactions (7)].

The maintenance dose of voriconazole should be reduced in patients with mild to moderate hepatic impairment, Child-Pugh Class A and B [see Dosage and Administration (2.7)].

There are no PK data to allow for dosage adjustment recommendations in patients with severe hepatic impairment (Child-Pugh Class C).

Duration of therapy should be based on the severity of the patient’s underlying disease, recovery from immunosuppression, and clinical response.

2.5 Intravenous Administration 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): Calculate the volume of 10 mg/mL VFEND concentrate required based on the patient’s weight (see Table 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.

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.

Table 2: Required Volumes of 10 mg/mL VFEND Concentrate 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.

2.6 Use in Patients With Hepatic Impairment 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 and Precautions (5.9)].

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) [see Clinical Pharmacology (12.3)].

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 impairment if the benefit outweighs the potential risk.

Patients with hepatic insufficiency must be carefully monitored for drug toxicity.

2.7 Use in Patients With Renal Impairment The pharmacokinetics of orally administered VFEND are not significantly affected by renal impairment.

Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment [see Clinical Pharmacology (12.3)].

In patients with moderate or severe renal impairment (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 Warnings and Precautions (5.10)].

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.