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
`---------------------------RECENT MAJOR CHANGES ---------------------------
`Indications and Usage (1)
`1/2019
`Dosage and Administration (2)
`1/2019
`Contraindications (4)
`1/2019
`Warnings and Precautions (5)
`1/2019
`--------------------------- INDICATIONS AND USAGE----------------------------
`VFEND is an azole antifungal indicated for the treatment of adults and
`pediatric patients 2 years of age and older with:
`Invasive aspergillosis (1.1)
`
` Candidemia in non-neutropenics and other deep tissue Candida infections
`(1.2)
`Esophageal candidiasis (1.3)
`Serious fungal infections caused by Scedosporium apiospermum and
`Fusarium species including Fusarium solani, in patients intolerant of, or
`refractory to, other therapy (1.4)
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
` Dosage in Adults (2.3)
`
`
`
`
`Loading dose
`Intravenous
`infusion
`6 mg/kg every
`12 hours for
`the first
`24 hours
`
`Maintenance Dose
`Intravenous
`Oral
`infusion
`4 mg/kg
`every
`12 hours
`3-4 mg/kg
`every
`12 hours
`
`200 mg
`every
`12 hours
`200 mg
`every
`12 hours
`
`9 mg/kg every
`12 hours
`(maximum dose
`of 350 mg every
`12 hours)
`o For pediatric patients aged 12 to 14 years weighing greater than or equal
`to 50 kg and those aged 15 years and older regardless of body weight use
`adult dosage. (2.4)
`o Dosage adjustment of VFEND in pediatric patients with renal or hepatic
`impairment has not been established (2.5, 2.6)
`See full prescribing information for instructions on reconstitution of
`
`Esophageal
`Candidiasis
`
`Not Evaluated
`
`4 mg/kg every
`12 hours
`
`
`
`Reference ID: 4383042
`
`Infection
`
`Invasive Aspergillosis
`
`Candidemia in
`nonneutropenics and
`other deep tissue
`Candida infections
`Scedosporiosis and
`Fusariosis
`
`Infection
`
`200 mg
`4 mg/kg
`every
`every
`12 hours
`12 hours
`Esophageal
`200 mg
`Not
`Candidiasis
`every
`Evaluated
`12 hours
`o Adult patients weighing less than 40 kg: oral maintenance dose 100 mg or
`150 mg every 12 hours
`o Hepatic Impairment: Use half the maintenance dose in adult patients with
`mild to moderate hepatic impairment (Child-Pugh Class A and B) (2.5)
`o Renal Impairment: Avoid intravenous administration in adult patients
`with moderate to severe renal impairment (creatinine clearance
`<50 mL/min) (2.6)
` Dosage in Pediatric Patients 2 years of age and older (2.4)
`o For pediatric patients 2 to less than 12 years of age and 12 to 14 years of
`age weighing less than 50 kg see Table below.
`Loading Dose
`Maintenance Dose
`Intravenous
`Intravenous
`Oral
`infusion
`infusion
`9 mg/kg
`8 mg/kg every
`every12 hours
`12 hours after
`for the first
`the first
`24 hours
`24 hours
`
`Not Evaluated
`
`9 mg/kg every
`12 hours
`(maximum dose
`of 350 mg every
`12 hours)
`
`Invasive
`Aspergillosis
`Candidemia in
`nonneutropenics
`and other deep
`tissue Candida
`infections
`Scedosporiosis
`and Fusariosis
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`VFEND lyophilized powder for intravenous use and reconstitution of
`VFEND oral suspension and important administration instructions (2.1,
`2.6, 2.7)
`--------------------- 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 of voriconazole
`and 3,200 mg of sulfobutyl ether beta-cyclodextrin sodium (SBECD);
`after reconstitution 10 mg/mL of voriconazole and 160 mg/mL of
`SBECD (3)
`------------------------------ CONTRAINDICATIONS ------------------------------
` Hypersensitivity to voriconazole or its excipients (4)
` Coadministration with 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 -----------------------
` Hepatic Toxicity: Serious hepatic reactions reported. Evaluate liver
`function tests at start of and during VFEND therapy (5.1)
`Arrhythmias and QT Prolongation: Correct potassium, magnesium and
`calcium prior to use; caution patients with proarrhythmic conditions (5.2)
`Infusion Related Reactions (including anaphylaxis): Stop the infusion
`(5.3)
`Visual Disturbances (including optic neuritis and papilledema): Monitor
`visual function if treatment continues beyond 28 days (5.4)
`Serious Exfoliative Cutaneous Reactions: Discontinue for exfoliative
`cutaneous reactions (5.5)
`Photosensitivity: Avoid sunlight due to risk of photosensitivity (5.6)
`Embryo-Fetal Toxicity: Voriconazole can cause fetal harm when
`administered to a pregnant woman. Inform pregnant patients of the
`potential hazard to the fetus. Advise females of reproductive potential to
`use effective contraception during treatment with VFEND (5.8, 8.1, 8.3)
`Skeletal Adverse Reactions: Fluorosis and periostitis with long-term
`voriconazole therapy. Discontinue if these adverse reactions occur (5.11)
` Clinically Significant Drug Interactions: Review patient’s concomitant
`medications (5.12, 7)
`Patients with Hereditary Galactose Intolerance, Lapp Lactase Deficiency
`or Glucose-Galactose Malabsorption: VFEND tablets should not be
`given to these patients because it contains lactose (5.13)
`------------------------------ ADVERSE REACTIONS ------------------------------
`Adult Patients: The most common adverse reactions (incidence ≥2%)
`
`were visual disturbances, fever, nausea, rash, vomiting, chills, headache,
`liver function test abnormal, tachycardia, hallucinations (6)
`Pediatric Patients: The most common adverse reactions (incidence ≥5%)
`were visual disturbances, pyrexia, vomiting, epistaxis, nausea, rash,
`abdominal pain, diarrhea, hypertension, hypokalemia, cough, headache,
`thrombocytopenia, ALT abnormal, hypotension, peripheral edema,
`hyperglycemia, tachycardia, dyspnea, hypocalcemia, hypophosphatemia,
`LFT abnormal, mucosal inflammation, photophobia, abdominal
`distention, constipation, dizziness, hallucinations, hemoptysis,
`hypoalbuminemia, hypomagnesemia, renal impairment, upper respiratory
`tract infection (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, 2.7, 7)
`----------------------- USE IN SPECIFIC POPULATIONS -----------------------
`Pediatrics: Safety and effectiveness in patients younger than 2 years has
`
`not been established (8.4)
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA-approved patient labeling.
`
`
`
`Revised: 1/2019
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1 Invasive Aspergillosis
`1.2 Candidemia in Non-neutropenic Patients and Other Deep
`Tissue Candida Infections
`1.3 Esophageal Candidiasis
`1.4 Scedosporiosis and Fusariosis
`1.5 Usage
`2 DOSAGE AND ADMINISTRATION
`2.1 Important Administration Instructions for Use in All Patients
`2.2 Use of VFEND I.V. With Other Parenteral Drug Products
`2.3 Recommended Dosing Regimen in Adults
`2.4 Recommended Dosing Regimen in Pediatric Patients
`2.5 Dosage Modifications in Patients With Hepatic Impairment
`2.6 Dosage Modifications in Patients With Renal Impairment
`2.7 Dosage Adjustment When Co-Administered With Phenytoin
`or Efavirenz
`2.8 Preparation and Intravenous Administration of VFEND for
`Injection
`2.9 Preparation and Administration of VFEND Oral Suspension
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Hepatic Toxicity
`5.2 Arrhythmias and QT Prolongation
`5.3 Infusion Related Reactions
`5.4 Visual Disturbances
`5.5 Serious Exfoliative Cutaneous Reactions
`5.6 Photosensitivity
`5.7 Renal Toxicity
`5.8 Embryo-Fetal Toxicity
`5.9 Laboratory Tests
`5.10 Pancreatitis
`5.11 Skeletal Adverse Reactions
`5.12 Clinically Significant Drug Interactions
`5.13 Galactose Intolerance
`
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience in Adult and Pediatric Patients
`7 DRUG INTERACTIONS
`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
`12.5Pharmacogenomics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Invasive Aspergillosis (IA)
`14.2 Candidemia in Non-neutropenic Patients and Other Deep
`Tissue Candida Infections
`14.3 Esophageal Candidiasis (EC)
`14.4 Other Serious Fungal Pathogens
`14.5 Pediatric Studies
`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.
`
`Reference ID: 4383042
`
`2
`
`

`

`FULL PRESCRIBING INFORMATION
`1 INDICATIONS AND USAGE
`1.1 Invasive Aspergillosis
`VFEND is indicated in adults and pediatric patients (2 years of age and older) for the treatment of invasive apergillosis (IA). 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, 14.5) and Microbiology (12.4)].
`1.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue Candida Infections
`VFEND is indicated in adults and pediatric patients (2 years of age and older) for the treatment of 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, 14.5) and Microbiology (12.4)].
`1.3 Esophageal Candidiasis
`VFEND is indicated in adults and pediatric patients (2 years of age and older) for the treatment of esophageal candidiasis (EC) in
`adults and pediatric patients 2 years of age and older [see Clinical Studies (14.3, 14.5) and Microbiology (12.4)].
`1.4 Scedosporiosis and Fusariosis
`VFEND is indicated for the treatment of serious fungal infections caused by Scedosporium apiospermum (asexual form of
`Pseudallescheria boydii) and Fusarium spp. including Fusarium solani, in adults and pediatric patients (2 years of age and older)
`intolerant of, or refractory to, other therapy [see Clinical Studies (14.4) and Microbiology (12.4)].
`1.5 Usage
`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
`Important Administration Instructions for Use in All Patients
`Administer VFEND Tablets or Oral Suspension 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.
`Administer diluted VFEND I.V. by intravenous infusion over 1 to 2 hours only. 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 (5.9)].
`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 Regimen 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 intravenously; a
`300 mg oral dose achieves an exposure similar to 4 mg/kg intravenously. Switching between the intravenous and oral formulations is
`appropriate because of the high bioavailability of the oral formulation in adults [see Clinical Pharmacology (12)].
`3
`
`Reference ID: 4383042
`
`

`

`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 (Adults)
`Loading Dose
`Intravenous infusion
`
`Maintenance Dosea,b
`Intravenous infusion
`
`Oralc
`
`Infection
`
`Invasive Aspergillosisd
`
`Candidemia in nonneutropenic
`patients and other deep tissue Candida
`infections
`
`6 mg/kg every 12 hours for the first
`24 hours
`
`6 mg/kg every 12 hours for the first
`24 hours
`
`4 mg/kg every 12 hours
`
`200 mg every 12 hours
`
`3-4 mg/kg every 12 hourse
`
`200 mg every 12 hours
`
`Esophageal Candidiasis
`
`Not Evaluatedf
`
`Not Evaluatedf
`
`200 mg every 12 hours
`
`a
`b
`
`e
`
`Scedosporiosis and Fusariosis
`
`4 mg/kg every 12 hours
`
`200 mg every 12 hours
`
`6 mg/kg every 12 hours for the first
`24 hours
`Increase dose when VFEND is co-administered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment (2.5)
`In healthy volunteer studies, the 200 mg oral every 12 hours dose provided an exposure (AUCτ) similar to a 3 mg/kg intravenous infusion every 12 hours dose; the
`300 mg oral every 12 hours dose provided an exposure (AUCτ) similar to a 4 mg/kg intravenous infusion every 12 hours dose (12).
`c Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose.
`In a clinical study of IA, the median duration of intravenous VFEND therapy was 10 days (range 2 to 85 days). The median duration of oral VFEND therapy was 76
`d
`days (range 2 to 232 days) (14.1).
`In clinical trials, patients with candidemia received 3 mg/kg intravenous infusion every 12 hours as primary therapy, while patients with other deep tissue Candida
`infections received 4 mg/kg every 12 hours as salvage therapy. Appropriate dose should be based on the severity and nature of the infection.
`f Not evaluated in patients with EC.
`Method for Adjusting the Dosing Regimen in Adults
`If patient’s response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours (similar to 3 mg/kg
`intravenously every 12 hours) to 300 mg every 12 hours (similar to 4 mg/kg intravenously every 12 hours). For adult patients
`weighing less than 40 kg, the oral maintenance dose may be increased from 100 mg every 12 hours to 150 mg every 12 hours. If
`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 intravenously every 12 hours, reduce the intravenous maintenance dose to 3 mg/kg every 12
`hours.
`2.4 Recommended Dosing Regimen in Pediatric Patients
`The recommended dosing regimen for pediatric patients 2 to less than 12 years of age and 12 to 14 years of age with body weight less
`than 50 kg is shown in Table 2. For pediatric patients 12 to 14 years of age with a body weight greater than or equal to 50 kg and those
`15 years of age and above regardless of body weight, administer the adult dosing regimen of VFEND [see Dosage and Administration
`(2.3)].
`
`Table 2:
`Recommended Dosing Regimen for Pediatric Patients 2 to less than 12 years of age and
`12 to 14 years of age with body weight less than 50 kg^
`Loading Dose
`Maintenance Dose
`Intravenous infusion
`Intravenous infusion
`
`Oral
`
`Invasive Aspergillosis*
`Candidemia in nonneutropenics
`and other deep tissue Candida
`infections†
`Scedosporiosis and Fusariosis
`
`9 mg/kg every 12 hours for the
`first 24 hours
`
`8 mg/kg every 12 hours after the
`first 24 hours
`
`9 mg/kg every 12 hours (maximum
`dose of 350 mg every 12 hours)
`
`Esophageal Candidiasis†
`
`Not Evaluated
`
`4 mg/kg every 12 hours
`
`9 mg/kg every 12 hours
`(maximum dose of 350 mg every
`12 hours)
`^ Based on a population pharmacokinetic analysis in 112 immunocompromised pediatric patients aged 2 to less than12 years of age and 26 immunocompromised
`pediatric patients aged 12 to less than 17 years of age.
`
`4
`
`Reference ID: 4383042
`
`

`

`* In the Phase 3 clinical trials, patients with IA received intravenous (IV) treatment for at least 6 weeks and up to a maximum of 12 weeks. Patients received IV
`treatment for at least the first 7 days of therapy and then could be switched to oral VFEND therapy.
`† Study treatment for primary or salvage invasive candidiasis and candidemia (ICC) or EC consisted of intravenous VFEND, with an option to switch to oral therapy
`after at least 5 days of IV therapy, based on subjects meeting switch criteria. For subjects with primary or salvage ICC, VFEND was administered for at least 14 days
`after the last positive culture. A maximum of 42 days of treatment was permitted. Patients with primary or salvage EC were treated for at least 7 days after the
`resolution of clinical signs and symptoms. A maximum of 42 days of treatment was permitted.
`Initiate therapy with an intravenous infusion regimen. Consider an oral regimen only after there is a significant clinical improvement.
`Note that an 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.
`The oral dose recommendation for children is based on studies in which VFEND was administered as the powder for oral suspension
`formulation. Bioequivalence between the VFEND powder for oral suspension and VFEND tablets has not been investigated in a
`pediatric population.
`Oral bioavailability may be limited in pediatric patients 2 to 12 years with malabsorption and very low body weight for age. In that
`case, intravenous VFEND administration is recommended.
`Method for Adjusting the Dosing Regimen in Pediatric Patients
`Pediatric Patients 2 to less than 12 years of age and 12 to 14 years of age with body weight less than 50 kg
`If patient response is inadequate and the patient is able to tolerate the initial intravenous maintenance dose, the maintenance dose may
`be increased by 1 mg/kg steps. If patient response is inadequate and the patient is able to tolerate the oral maintenance dose, the dose
`may be increased by 1 mg/kg steps or 50 mg steps to a maximum of 350 mg every 12 hours. If patients are unable to tolerate the initial
`intravenous maintenance dose, reduce the dose by 1 mg/kg steps. If patients are unable to tolerate the oral maintenance dose, reduce
`the dose by 1 mg/kg or 50 mg steps.
`Pediatric patients 12 to 14 years of age weighing greater than or equal to 50 kg and 15 years of age and older regardless of body
`weight:
`Use the optimal method for titrating dosage recommended for adults [see Dosage and Administration (2.3)].
`2.5 Dosage Modifications in Patients With Hepatic Impairment
`Adults
`The maintenance dose of VFEND should be reduced in adult patients with mild to moderate hepatic impairment, Child-Pugh Class A
`and B. 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.
`Adult patients with baseline liver function tests (ALT, AST) of up to 5 times the upper limit of normal (ULN) were included in the
`clinical program. Dose adjustments are not necessary for adult patients with this degree of abnormal liver function, but continued
`monitoring of liver function tests for further elevations is recommended [see Warnings and Precautions (5.1)].
`It is recommended that the recommended VFEND loading dose regimens be used, but that the maintenance dose be halved in adult
`patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) [see Clinical Pharmacology (12.3)].
`VFEND has not been studied in adult 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 with clinical signs of liver
`damage, such as jaundice. VFEND 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.
`Pediatric Patients
`Dosage adjustment of VFEND in pediatric patients with hepatic impairment has not been established [see Use in Specific Populations
`(8.4)].
`2.6 Dosage Modifications in Patients With Renal Impairment
`Adult Patients
`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) who are receiving an intravenous infusion of
`VFEND, 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 VFEND. Serum creatinine levels should be closely
`monitored in these patients, and, if increases occur, consideration should be given to changing to oral VFEND therapy [see Warnings
`and Precautions (5.7)].
`
`5
`
`Reference ID: 4383042
`
`

`

`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.
`Pediatric Patients
`Dosage adjustment of VFEND in pediatric patients with renal impairment has not been established [see Use in Specific Populations
`(8.4)].
`2.7 Dosage Adjustment When Co-Administered With Phenytoin or Efavirenz
`The maintenance dose of voriconazole should be increased when co-administered with phenytoin or efavirenz. Use the optimal
`method for titrating dosage [see Drug Interactions (7) and Dosage and Administration (2.3)].
`2.8 Preparation and Intravenous Administration of VFEND for Injection
`Reconstitution
`The powder is reconstituted with 19 mL of Water For Injection to obtain an extractable volume of 20 mL of clear concentrate
`containing 10 mg/mL of voriconazole. It is recommended that a standard 20 mL (non-automated) syringe be used to ensure that the
`exact amount (19.0 mL) of Water for Injection is dispensed. Discard the vial if a vacuum does not pull the diluent into the vial. Shake
`the vial until all the powder is dissolved.
`Dilution
`VFEND must be infused over 1 to 3 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 3).
`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 to 3 hours at a maximum rate of 3 mg/kg per hour.
`Table 3:
`Required Volumes of 10 mg/mL VFEND Concentrate
`Volume of VFEND Concentrate (10 mg/mL) required for:
`4 mg/kg dose
`6 mg/kg dose
`8 mg/kg dose
`(number of vials)
`(number of vials)
`(number of
`vials)
`8 mL (1)
`12 mL (1)
`16 mL (1)
`20 mL (1)
`24 mL (2)
`28 mL (2)
`32 mL (2)
`36 mL (2)
`40 mL (2)
`44 mL (3)
`48 mL (3)
`52 mL (3)
`-
`-
`-
`-
`-
`-
`-
`
`Body
`Weight
`(kg)
`10
`15
`20
`25
`30
`35
`40
`45
`50
`55
`60
`65
`70
`75
`80
`85
`90
`95
`100
`
`3 mg/kg dose
`(number of
`vials)
`-
`-
`-
`-
`9 mL (1)
`10.5 mL (1)
`12 mL (1)
`13.5 mL (1)
`15 mL (1)
`16.5 mL (1)
`18 mL (1)
`19.5 mL (1)
`21 mL (2)
`22.5 mL (2)
`24 mL (2)
`25.5 mL (2)
`27 mL (2)
`28.5 mL (2)
`30 mL (2)
`
`4 mL (1)
`6 mL (1)
`8 mL (1)
`10 mL (1)
`12 mL (1)
`14 mL (1)
`16 mL (1)
`18 mL (1)
`20 mL (1)
`22 mL (2)
`24 mL (2)
`26 mL (2)
`28 mL (2)
`30 mL (2)
`32 mL (2)
`34 mL (2)
`36 mL (2)
`38 mL (2)
`40 mL (2)
`
`-
`-
`-
`-
`18 mL (1)
`21 mL (2)
`24 mL (2)
`27 mL (2)
`30 mL (2)
`33 mL (2)
`36 mL (2)
`39 mL (2)
`42 mL (3)
`45 mL (3)
`48 mL (3)
`51 mL (3)
`54 mL (3)
`57 mL (3)
`60 mL (3)
`
`9 mg/kg dose
`(number of
`vials)
`9 mL (1)
`13.5 mL (1)
`18 mL (1)
`22.5 mL (2)
`27 mL (2)
`31.5 mL (2)
`36 mL (2)
`40.5 mL (3)
`45 mL (3)
`49.5 mL (3)
`54 mL (3)
`58.5 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
`
`Reference ID: 4383042
`
`6
`
`

`

`the responsibility of the user and should not be longer than 24 hours at 2C to 8C (36F 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:
`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.
`2.9 Preparation and Administration of VFEND 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°C to 30°C
`[59°F to 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.
`3 DOSAGE FORMS AND STRENGTHS
`Powder for Solution for Injection
`VFEND I.V. for Injection is supplied in a single-dose vial as a sterile lyophilized powder equivalent to 200 mg voriconazole and 3,200
`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 grams 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.
`
`Reference ID: 4383042
`
`7
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Coadministration of 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 every 24 hours 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 every 12 hours) is contraindicated because ritonavir (400 mg
`every 12 hours) significantly decreases plasma voriconazole concentrations. Coadministration of voriconazole and low-dose
`ritonavir (100 mg every 12 hours) 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)].
`Coadministration of VFEND with St. John’s Wort i