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, Oral Suspension, and I.V.
`Initial U.S. Approval: 2002
`
`
`
`
`----------------------------INDICATIONS AND USAGE-----------------
`VFEND is a triazole 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 spp. including Fusarium solani, in patients intolerant of, or
`
`
`refractory to, other therapy (1.4)
`
`
`----------------------DOSAGE AND ADMINISTRATION--------------
`
` Recommended Dosing Regimen (2)
`Loading dose
`Infection
`
` IVa
`
` Invasive Aspergillosise
`6 mg/kg q12h
`for the first 24
`hours
`6 mg/kg q12h
`for the first 24
`hours
`
`
` Maintenance Dosea,b,c
`
` Orald
`IV
`200 mg
`4 mg/kg
`q12h
`q12h
`
`3-4 mg/kg
`q12hf
`
`
`200 mg
`q12h
`
`not evaluated
`
`not
`evaluated
`4 mg/kg
`q12h
`
`200 mg
`q12h
`200 mg
`q12h
`
`• To prevent loss of VFEND efficacy, do not use with rifampin,
`
`carbamazepine, long-acting barbiturates, ritonavir, rifabutin, ergot
`alkaloids, and St. John’s Wort (4, 7)
`-----------------------WARNINGS AND PRECAUTIONS--------------
`Drug Interactions (5.1): review patient’s concomitant medications.
`Several drugs may significantly alter voriconazole concentrations.
`
`
`Voriconazole may alter PK or PD of several drugs (7)
`Hepatic Toxicity (5.2): serious hepatic reactions have been reported.
`Evaluate liver function tests at the start of and during the course of
`
`voriconazole therapy
`
`Visual Disturbances (5.3): monitor visual function if treatment
`
`continues beyond 28 days
`
`Pregnancy Category D (5.4): do not administer to pregnant women
`Galactose Intolerance (5.5): do not administer to patients with
`
`galactose intolerance, Lapp lactase deficiency or glucose-galactose
`
`malabsorption
`Arrhythmias and QT Prolongation (5.6): administer with caution to
`patients with proarrhythmic conditions
`Infusion Related Reactions (5.7): anaphylactoid reactions have been
`reported
`Dermatological Reactions (5.13): exfoliative cutaneous reactions and
`photosensitivity have been reported
`
`Skeletal Events (5.14): fluorosis and periostitis have been reported
`
`with long-term voriconazole therapy
`
`------------------------------ADVERSE REACTIONS---------------------
`Most frequent (all causalities, 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---------------------
` • Inhibitors and inducers of CYP3A4, CYP2C9, and CYP2C19 may
`
`
`alter VFEND concentrations. Adjust the VFEND dose and monitor
`
` for adverse events or lack of efficacy (4, 7)
`
` • VFEND may increase the concentrations and activity of drugs that
`
` are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce doses of
`
` and monitor for lack of efficacy or adverse events associated with
`
`
`
` drugs that are substrates of these enzymes (4, 7)
`
`-----------------------USE IN SPECIFIC POPULATIONS-------------
`
`• Pregnant or nursing women: VFEND should not be used in
`pregnant or nursing women (8.1, 8.3)
`
`
` • 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)
`
`
`
`Revised: 10/2011
`
`
`
`Candidemia in
`nonneutropenics and
`other deep tissue
`Candida infections
`Esophageal
`Candidiasis
`Scedosporiosis and
`Fusariosis
`
`c
`
`
`e
`
`
`6 mg/kg q12h
`for the first 24
`hours
`
` a See full prescribing information for IV administration instructions (2.5)
`
`b
`Increase dose when VFEND is co-administered with phenytoin or efavirenz
`
`(7); Decrease dose in patients with hepatic impairment (2.7)
`Oral and intravenous maintenance doses do not produce the same
`
`voriconazole exposures. A 200 mg oral dose provides an exposure similar to
`
`a 3 mg/kg IV dose; 300 mg oral dose provides an exposure similar to a
`4 mg/kg IV dose.
`
`d Adult patients who weigh less than 40 kg should receive half of the oral
`
`maintenance dose.
`In a clinical study, the median duration of IV VFEND therapy was 10 days;
`
`the median duration of oral VFEND therapy was 76 days.
`
`f Patients with candidemia received 3 mg/kg q12h; patients with other deep
`
`tissue Candida infections received 4 mg/kg q12h.
`
`
`---------------------DOSAGE FORMS AND STRENGTHS------------
`
` Powder for Solution for Injection: 200 mg voriconazole and 3200 mg
` sulfobutyl ether beta-cyclodextrin sodium (SBECD). (3)
`
`
`
` • Film-coated tablets: 50 mg, 200 mg voriconazole. (3)
`
`
`• Powder for Oral Suspension: 40 mg voriconazole/mL. (3)
`-------------------------------CONTRAINDICATIONS-------------------
`• Hypersensitivity to voriconazole or its excipients.
`
`• To reduce risk of serious adverse events, do not use VFEND with
`
`terfenadine, astemizole, cisapride, pimozide or quinidine, sirolimus
`
`(4, 7)
`________________________________________________________________________________________________________________________
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`
`Reference ID: 3045001
`
`

`

`
`
`
`USE IN SPECIFIC POPULATIONS
`
` 8.1 Pregnancy
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Women of Childbearing Potential
`
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`
`12.3 Pharmacokinetics
`
`
`
`12.4 Microbiology
`
`
`13 NONCLINICAL TOXICOLOGY
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`13.2 Teratogenic Effects
`
`
`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
`
`
`2.1 Instructions for Use in All Patients
`
`
`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 Pregnancy Category D
`
`
`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
`
`8
`
`Reference ID: 3045001
`
`
`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 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 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.
`
`3
`
`
`Reference ID: 3045001
`
`

`

`
`
`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.
`
`IV
`
`4 mg/kg q12h
`
` Maintenance Dosea,b
`
`
` Oralc
`
`200 mg q12h
`
`
`Table 1:
`
`Recommended Dosing Regimen
`
`Loading dose
`IV
`
`6 mg/kg q12h for the first 24
`hours
`
`6 mg/kg q12h for the first 24
`hours
`
`
` 3-4 mg/kg q12he
`
`
`
`
`f
`
`
`4 mg/kg q12h
`
`
`200 mg q12h
`
`
`200 mg q12h
`
`200 mg q12h
`
`
`
` Infection
`
`
` Invasive Aspergillosisd
`
`
`
`
` Candidemia in nonneutropenic
`
`patients and other deep tissue
`
` Candida infections
`
`Esophageal Candidiasis
`
`Scedosporiosis and Fusariosis
`
`e
`
`
`
`4
`
`Reference ID: 3045001
`
`
`f
`
`
`6 mg/kg q12h for the first 24
`hours
`a
`Increase dose when VFEND is co-administered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment (2.7)
`
`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 2-90 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.
`
`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):
`
`
`1. Calculate the volume of 10 mg/mL VFEND concentrate required based on the patient’s weight (see Table 2).
`
`
`
`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.
`
`
`
`
`
`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% Dextrose and 0.9% Sodium Chloride USP
`
`
`
`
`5
`
`
`Reference ID: 3045001
`
`

`

`
`
`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 insufficiency 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: 3045001
`
`

`

`
`
`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 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), Clinical Pharmacology (12.3)].
`
`
`
`• 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)].
`
`
`
`7
`
`
`Reference ID: 3045001
`
`

`

`
`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)].
`
`
`
`
`
`
`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 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 Pregnancy Category D
`
`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 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 these potentially proarrhythmic conditions.
`
`Rigorous attempts to correct potassium, magnesium and calcium should be made before starting voriconazole [see
`
`Clinical Pharmacology (12.3)].
`
`
`
`8
`
`
`Reference ID: 3045001
`
`

`

`
`Infusion Related Reactions
`5.7
`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 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 insufficiency if the benefit outweighs the potential risk. Patients with hepatic
`
`
`insufficiency 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 decreas