`
` 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 --------------------------­
`
`
`Contraindications (4)
`1/2021
`
`
`
`Warnings and Precautions (5.5)
`9/2020
`
`
`
`Warnings and Precautions (5.8)
`1/2021
`
`
`
`
`
`--------------------------- 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
`
`
`
`
` 4 mg/kg
`
` every
` 12 hours
`
`
` Not
`
` Evaluated
`
`
`
`
` Not Evaluated
`
`
`
`
`
`
`
`
`Infection
`
`
`
` Invasive Aspergillosis
`
`Candidemia in
`nonneutropenics and
`other deep tissue
`
`
` Candida infections
`
`Scedosporiosis and
`
` Fusariosis
`
`
` Esophageal
`
` Candidiasis
`
`
`
` Infection
`
` Invasive
`
`
` Aspergillosis
`Candidemia in
`
` nonneutropenics
`
` and other deep
` tissue Candida
`
`
` infections
`
`Scedosporiosis
`
` and Fusariosis
`
`
` 200 mg
`
` every
`
` 12 hours
`
`
` 200 mg
`
` every
`
` 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
`
`
` Oral
`
` Intravenous
`
` Intravenous
`
` infusion
`
`
` infusion
`
`
` 9 mg/kg
` 8 mg/kg every
`
` 12 hours after
` every12 hours
`
` for the first
`
`
` the first
`
`
`
` 24 hours
`
` 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)
`
`
` 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)
`
`
`
`
`Reference ID: 4731433
`
`
`
` 1
`
` • See full prescribing information for instructions on reconstitution of
`
`
`
`
`
`
`
`
`
`
` 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: 40 mg/mL (200 mg/5 mL) when reconstituted ((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)
`
`
`
`• Coadministration with naloxegol due to risk of adverse reactions (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)
`
`
`
`
`Severe Cutaneous Adverse Reactions: Discontinue for exfoliative
`
`
`
`
`cutaneous reactions (5.5)
`
`• Photosensitivity: Avoid sunlight due to risk of photosensitivity (5.6)
`
`
`
`
`
`
`• Adrenal Dysfunction: Carefully monitor patients receiving VFEND and
`
`
`
`
`corticosteroids (via all routes of administration) for adrenal dysfunction
`
`
`
`
`both during and after VFEND treatment. Instruct patients to seek
`
`
`
`
`immediate medical care if they develop signs and symptoms of Cushing’s
`
`
`
`
`
`syndrome or adrenal insufficiency (5.8)
`
`
`• 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 (5.9, 8.1, 8.3)
`
`
`
`
`Skeletal Adverse Reactions: Fluorosis and periostitis with long-term
`
`voriconazole therapy. Discontinue if these adverse reactions occur (5.12)
`
`
`• Clinically Significant Drug Interactions: Review patient’s concomitant
`
`
`
`
`medications (5.13, 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 (5.14)
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`------------------------------ 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: 01/2021
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
` 12.5 Pharmacogenomics
`
` 13 NONCLINICAL TOXICOLOGY
`
`
`
`
` 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility
`
` 14 CLINICAL STUDIES
`
`
`
`
` 14.1 Invasive Aspergillosis (IA)
`
`
` 14.2Candidemia 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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 Severe Cutaneous Adverse Reactions
`
`
`
`
` 5.6 Photosensitivity
`
`
`
` 5.7 Renal Toxicity
`
`
`
`
` 5.8 Adrenal Dysfunction
`
`
` 5.9 Embryo-Fetal Toxicity
`
` 5.10Laboratory Tests
`
`
`
`
` 5.11Pancreatitis
`
`
`
`
` 5.12Skeletal Adverse Reactions
`
`
` 5.13Clinically Significant Drug Interactions
`
`
`
` 5.14Galactose Intolerance
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4731433
`
`
`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 (5.10)].
`
`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.
`
`
`
`
`
`Reference ID: 4731433
`
`
`
` 3
`
`

`

`
` Infection
`
`
` Invasive Aspergillosisd
`
`
`
`
`
`
`
` Maintenance Dosea,b
`
` Intravenous infusion
`
` 4 mg/kg every 12 hours
`
`
` Oralc
`
` 200 mg every 12 hours
`
`
`
`
`
`
`
`
`
` 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)].
`
`
`
`
`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
`
`
`
`
` 6 mg/kg every 12 hours for the first
` 24 hours
`
`
`
` 6 mg/kg every 12 hours for the first
` 24 hours
`
`
`
`
`
` 3-4 mg/kg every 12 hourse
`
`
`
`
`
`
`
`
` 200 mg every 12 hours
`
`
`
`
`
`
`
` Candidemia in nonneutropenic
` patients and other deep tissue Candida
`
`
` infections
`
`
` Esophageal Candidiasis
`
` Scedosporiosis and Fusariosis
`
`
`
`
`
`
`
`
`
`
` Not Evaluatedf
`
` 4 mg/kg every 12 hours
`
`
`
`
`
`
`
`
`
` 200 mg every 12 hours
`
` 200 mg every 12 hours
`
`
`
`
`
`
`
`
`
` Not Evaluatedf
`
`
` 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)
`
`
`
`a
`
`
`
`
`
`
`
`
`
`
`
`
`b 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).
`
`
`
`
`
`
`
`
`Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose.
`c
` d 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
`
`
`
`
`
`
`
`
`
`
`
` 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)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`e
`
`Reference ID: 4731433
`
`
`
` 4
`
`

`

` 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)
`
`
`
` 9 mg/kg every 12 hours
`
`Esophageal Candidiasis†
`
`
`
`
` Not Evaluated
`
`
`
` 4 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 than 12 years of age and 26 immunocompromised
`
` pediatric patients aged 12 to less than 17 years of age.
`
`
`
`
`
`* 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)].
`
`
`
`
`
`
`
`Reference ID: 4731433
`
`
`
` 5
`
`

`

`
`
`
`
`
`
`
` 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)].
`
`
`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:
`
`
`
` 8 mg/kg dose
` 4 mg/kg dose
` 6 mg/kg dose
` (number of vials)
` (number of vials)
`
` (number of
`
`
`
` vials)
` 8 mL (1)
`
`
`
`Body
`Weight
`
`
` (kg)
`
` 10
`
`Reference ID: 4731433
`
`
` 3 mg/kg dose
`
` (number of
`
` vials)
`
`-
`
`
`
`
`
`
`
` 4 mL (1)
`
`-
`
`
`
`
`
` 6
`
`
` 9 mg/kg dose
`
` (number of
`
` vials)
` 9 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)
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
` 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
`
`
`
`
`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.
`
`
` 15
`
` 20
`
` 25
`
` 30
`
` 35
`
` 40
`
` 45
`
` 50
`
` 55
`
` 60
`
` 65
`
` 70
`
` 75
`
` 80
`
` 85
`
` 90
`
` 95
` 100
`
`
`-
`
`-
`
`-
`
`
` 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)
`
`
` 6 mL (1)
`
` 8 mL (1)
`
` 10 mL (1)
`
` 12 mL