 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)
` Patients with Hereditary Galactose Intolerance Lapp Lactase
`Deficiency or Glucose-Galactose Malabsorption: Do not use (5.5)
` Arrhythmias and QT Prolongation: Correct potassium, magnesium
`and calcium prior to use; caution patients with proarrhythmic
`conditions (5.6)
` Infusion Related Reactions (including anaphylaxis): Stop the
`infusion (5.7)
` Dermatological Reactions: Discontinue for exfoliative cutaneous
`reactions or phototoxicity. Avoid sunlight due to risk of
`photosensitivity (5.13)
` Skeletal Events: Fluorosis and periostitis with long-term
`voriconazole therapy. Discontinue if these events occur (5.14)
`
`------------------------------ADVERSE REACTIONS---------------------
`Most common adverse reactions (incidence ≥2%): visual
`disturbances, fever, nausea, rash, vomiting, chills, headache, liver
`function test abnormal, tachycardia, hallucinations (6)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer
`Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch
`
`------------------------------DRUG INTERACTIONS---------------------
` 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)
`
`-----------------------USE IN SPECIFIC POPULATIONS-------------
` Pregnancy: Voriconazole can cause fetal harm when administered
`to pregnant woman. Inform pregnant women of risk to the fetus
`(8.1)
` Pediatrics: Safety/effectiveness in patients <12 years has not been
`established (8.4)
` Hepatic impairment: Use half the maintenance dose in patients with
`mild to moderate hepatic impairment (Child-Pugh Class A and B)
`(2.7)
` Renal impairment: Avoid intravenous administration in patients
`with moderate to severe renal impairment (creatinine clearance
`<50 mL/min) (2.8)
`
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA-approved patient labeling.
`
`Revised: 7/2017
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`VFEND safely and effectively. See full prescribing information for
`VFEND.
`
`VFEND® (voriconazole) tablets, for oral use
`VFEND® (voriconazole) for oral suspension
`VFEND® (voriconazole) for injection, for intravenous use
`Initial U.S. Approval: 2002
`
`----------------------------INDICATIONS AND USAGE-----------------
`VFEND is an azole antifungal 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)
`
`Infection
`
`Invasive Aspergillosis
`
`----------------------DOSAGE AND ADMINISTRATION--------------
`Recommended Dosage (2.3)
`Loading dose
`Maintenance Dose
`IV
`IV
`Oral
`4 mg/kg
`200 mg
`6 mg/kg q12h
`q12h
`q12h
`for the first 24
`hours
`3-4 mg/kg
`200 mg
`q12h
`q12h
`
`Candidemia in
`nonneutropenics and
`other deep tissue
`Candida infections
`Scedosporiosis and
`200 mg
`4 mg/kg
`Fusariosis
`q12h
`q12h
`Esophageal
`200 mg
`not
`Candidiasis
`q12h
`evaluated
` 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 reconstitution of oral
`suspension and important administration instructions (2.5, 2.6)
`
`Not Evaluated
`
`---------------------DOSAGE FORMS AND STRENGTHS------------
` Tablets: 50 mg, 200 mg (3)
` For Oral Suspension: 45 grams of powder; after reconstitution 40
`mg/mL (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)
`
`Reference ID: 4131615
`
`-------------------------------CONTRAINDICATIONS-------------------
` Hypersensitivity to voriconazole or its excipients (4)
` Coadministration with terfenadine, astemizole, cisapride, pimozide or
`quinidine, sirolimus due to risk of serious adverse reactions (4, 7)
` Coadministration with rifampin, carbamazepine, long-acting
`barbiturates, efavirenz, ritonavir, rifabutin, ergot alkaloids, and St.
`John’s Wort due to risk of loss of efficacy (4, 7)
`-----------------------WARNINGS AND PRECAUTIONS--------------
` Clinically Significant Drug Interactions: Review patient’s
`concomitant medications (5.1, 7)
`________________________________________________________________________________________________________________________
`
`

`

`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`8.2 Lactation
`
`8.3 Females and Males of Reproductive Potential
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`12.4 Microbiology
`
`12.5 Pharmacogenomics
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`14 CLINICAL STUDIES
`14.1 Invasive Aspergillosis
`
`14.2 Candidemia in Non-neutropenic Patients and Other Deep
`
`Tissue Candida Infections
`
`14.3 Esophageal Candidiasis
`
`14.4 Other Serious Fungal Pathogens
`
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`
`16.2 Storage
`
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing
`information are not listed.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`1.1
`Invasive Aspergillosis
`
`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
`
`1.3 Esophageal Candidiasis
`
`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
`
`2 DOSAGE AND ADMINISTRATION
`Instructions for Use in All Patients
`
`2.1
`2.2 Use of VFEND I.V. With Other Parenteral Drug Products
`
`2.3 Recommended Dosing in Adults
`
`2.4 Dosage Adjustment
`
`2.5
`Intravenous Administration
`
`2.6 Oral Suspension
`
`2.7 Use in Patients With Hepatic Impairment
`
`2.8 Use in Patients With Renal Impairment
`
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Drug Interactions
`
`5.2 Hepatic Toxicity
`
`5.3 Visual Disturbances
`
`5.4 Embryo-Fetal Toxicity
`
`5.5 Galactose Intolerance
`
`5.6 Arrhythmias and QT Prolongation
`
`5.7
`Infusion Related Reactions
`
`5.8 Laboratory Tests
`
`5.9 Patients With Hepatic Impairment
`
`5.10 Patients With Renal Impairment
`
`5.11 Monitoring Renal Function
`
`5.12 Monitoring Pancreatic Function
`
`5.13 Dermatological Reactions
`
`5.14 Skeletal Adverse Events
`
`6 ADVERSE REACTIONS
`6.1 Overview
`
`6.2 Clinical Trial Experience in Adults
`
`6.3 Clinical Laboratory Values
`
`6.4 Postmarketing Experience
`
`7 DRUG INTERACTIONS
`
`Reference ID: 4131615
`
`2
`
`

`

`FULL PRESCRIBING INFORMATION
`1 INDICATIONS AND USAGE
`VFEND is indicated for use in patients 12 years of age and older in the treatment of the following fungal infections:
`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.
`2 DOSAGE AND ADMINISTRATION
`2.1
`Instructions for Use in All Patients
`VFEND Tablets or Oral Suspension should be taken at least one hour before or after 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 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 (5.8)].
`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 (RMD) 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
`3
`
`Reference ID: 4131615
`
`

`

`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.
`
`Infection
`
`Invasive Aspergillosisd
`
`Candidemia in nonneutropenic
`patients and other deep tissue
`Candida infections
`Esophageal Candidiasis
`
`Table 1:
`
`Recommended Dosing Regimen
`
`Loading dose
`IV
`IV
`
`Maintenance Dosea,b
`Oralc
`
`6 mg/kg q12h for the first 24
`hours
`
`6 mg/kg q12h for the first 24
`hours
`
`4 mg/kg q12h
`
`200 mg q12h
`
`3-4 mg/kg q12he
`
`200 mg q12h
`
`f
`
`f
`
`200 mg q12h
`
`Scedosporiosis and Fusariosis
`
`e
`
`4 mg/kg q12h
`
`200 mg q12h
`
`6 mg/kg q12h for the first 24
`hours
`Increase dose when VFEND is co-administered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment (2.7)
`a
`b 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)].
`c Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose.
`d In 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)].
`In 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.
`f Not evaluated in patients with esophageal candidiasis.
`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.
`
`4
`
`Reference ID: 4131615
`
`

`

`Intravenous Administration
`2.5
`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 2).
`In order to allow the required volume of VFEND concentrate to be added, withdraw and discard at least an
`2.
`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.
`Table 2:
`
`Required Volumes of 10 mg/mL VFEND Concentrate
`
`Volume of VFEND Concentrate (10 mg/mL) required for:
`3 mg/kg dose
`4 mg/kg dose
`6 mg/kg dose
`(number of vials)
`(number of vials)
`(number of vials)
`9.0 mL (1)
`12 mL (1)
`18 mL (1)
`10.5 mL (1)
`14 mL (1)
`21 mL (2)
`12.0 mL (1)
`16 mL (1)
`24 mL (2)
`13.5 mL (1)
`18 mL (1)
`27 mL (2)
`15.0 mL (1)
`20 mL (1)
`30 mL (2)
`16.5 mL (1)
`22 mL (2)
`33 mL (2)
`18.0 mL (1)
`24 mL (2)
`36 mL (2)
`19.5 mL (1)
`26 mL (2)
`39 mL (2)
`21.0 mL (2)
`28 mL (2)
`42 mL (3)
`22.5 mL (2)
`30 mL (2)
`45 mL (3)
`24.0 mL (2)
`32 mL (2)
`48 mL (3)
`25.5 mL (2)
`34 mL (2)
`51 mL (3)
`27.0 mL (2)
`36 mL (2)
`54 mL (3)
`28.5 mL (2)
`38 mL (2)
`57 mL (3)
`30.0 mL (2)
`40 mL (2)
`60 mL (3)
`
`Body Weight
`(kg)
`30
`35
`40
`45
`50
`55
`60
`65
`70
`75
`80
`85
`90
`95
`100
`
`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
`
`Reference ID: 4131615
`
`

`

`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 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]).
`Instructions for use
`Shake the closed bottle of reconstituted suspension for approximately 10 seconds before each use. The reconstituted
`oral suspension should only be administered using the oral dispenser supplied with each pack.
`Incompatibilities
`VFEND for Oral Suspension and the 40 mg/mL reconstituted oral suspension should not be mixed with any other
`medication or additional flavoring agent. It is not intended that the suspension be further diluted with water or other
`vehicles.
`2.7 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 impairment must be carefully monitored
`for drug toxicity.
`2.8 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)].
`
`6
`
`Reference ID: 4131615
`
`

`

`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.
`3 DOSAGE FORMS AND STRENGTHS
`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).
`Tablets
`VFEND 50 mg tablets; white, film-coated, round, debossed with “Pfizer” on one side and “VOR50” on the reverse.
`VFEND 200 mg tablets; white, film-coated, capsule shaped, debossed with “Pfizer” on one side and “VOR200” on
`the reverse.
`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.
`4 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 terfenadine, astemizole, cisapride, pimozide or quinidine with VFEND is
`contraindicated because increased plasma concentrations of these drugs can lead to QT prolongation and
`rare occurrences of torsade de pointes [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
` Coadministration of VFEND with sirolimus is contraindicated because VFEND significantly increases
`sirolimus concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
` Coadministration of VFEND with rifampin, carbamazepine and long-acting barbiturates is contraindicated
`because these drugs are likely to decrease plasma voriconazole concentrations significantly [see Drug
`Interactions (7) and Clinical Pharmacology (12.3)].
` Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg q24h or higher is
`contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy
`subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations [see
`Drug Interactions (7) and Clinical Pharmacology (12.3)].
` Coadministration of VFEND with high-dose ritonavir (400 mg q12h) is contraindicated because ritonavir
`(400 mg q12h) significantly decreases plasma voriconazole concentrations. 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 Drug Interactions (7) and Clinical
`Pharmacology (12.3)].
` Coadministration of VFEND with rifabutin is contraindicated since VFEND significantly increases
`rifabutin plasma concentrations and rifabutin also significantly decreases voriconazole plasma
`concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
` 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
`[see Drug Interactions (7) and Clinical Pharmacology (12.3)].
`
`7
`
`Reference ID: 4131615
`
`

`

` Coadministration of VFEND with St. John’s Wort is contraindicated because this herbal supplement may
`decrease voriconazole plasma concentration [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
`5 WARNINGS AND PRECAUTIONS
`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 (5.9) 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 (5.9), Dosage and Administration (2.4, 2.7), 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 [see Use in Specific Populations (8.1)].
`If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of
`the potential hazard to the fetus.
`5.5 Galactose Intolerance
`VFEND tablets contain lactose and should not be given to patients with rare hereditary problems of galactose
`intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
`5.6 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
`8
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`Reference ID: 4131615
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` 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)].
`5.7
`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.
`5.8 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).
`5.9 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 (2.7)].
`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 impairment if the benefit outweighs the potential risk. Patients with hepatic impairment
`must be carefully monitored for drug toxicity.
`5.10 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 (2.8)].
`5.11 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.
`5.12 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.
`5.13 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