HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` These highlights do not include all the information needed to use VFEND
`
`
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` safely and effectively. See full prescribing information for VFEND.
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`
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` VFEND® (voriconazole) tablets, for oral use
`
`
`
` VFEND® (voriconazole) for oral suspension
`
`
`
` VFEND® (voriconazole) for injection, for intravenous use
`
`
`
` Initial U.S. Approval: 2002
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`
`
`
`
`
`
`---------------------------RECENT MAJOR CHANGES --------------------------­
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`
`
`9/2021
`Contraindications (4)
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`
`
`Warnings and Precautions, Severe Cutaneous Adverse Reactions (5.5) 9/2020
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`
`
`
`Warnings and Precautions, Adrenal Dysfunction (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)
`
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`• Serious fungal infections caused by Scedosporium apiospermum and
`
`
`
`
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`Fusarium species including Fusarium solani, in patients intolerant of, or
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`
`
`refractory to, other therapy (1.4)
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`
`
`-----------------------DOSAGE AND ADMINISTRATION ----------------------­
`
`
`• Dosage in Adults (2.3)
`
`
`
`
`Loading dose
`
`
` Intravenous
`infusion
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` 6 mg/kg every
`
`
`
` 12 hours for
` the first
`
`24 hours
`
`
`
`
`
`Maintenance Dose
`
`Oral
`
`
` Intravenous
`infusion
`
`
` 4 mg/kg
`
` every
`
`
` 12 hours
`
`
` 3-4 mg/kg
` every
`
` 12 hours
`
`
`
` 200 mg
` every
`
`
`
` 12 hours
`
` 200 mg
`
` every
` 12 hours
`
`
`
`
`
`
`
`
`Infection
`
`
`Invasive Aspergillosis
`
`
`
`
` Candidemia in
`
` nonneutropenics and
` other deep tissue
`
`Candida infections
`
`
` Scedosporiosis and
`
`Fusariosis
`
`
`
` Esophageal
`Candidiasis
`
`
`
`
` Not Evaluated
`
`
`
`
`
` 4 mg/kg
`
`
` every
` 12 hours
`
`
` Not
` Evaluated
`
`
`
`
` 200 mg
` every
`
`
`
` 12 hours
`
` 200 mg
` every
`
`
`
` 12 hours
` o Adult patients weighing less than 40 kg: oral maintenance dose 100 mg or
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`
`
` 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)
`
`
`
`
`
` Invasive
`
`Aspergillosis
`
` Candidemia in
`
` nonneutropenics
`
`
`
` and other deep
` tissue Candida
`
`
`infections
`
`
` Scedosporiosis
`and Fusariosis
`
`
`Infection
`
`
`• Dosage in Pediatric Patients 2 years of age and older (2.4)
`
`
`
`
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`o For pediatric patients 2 to less than 12 years of age and 12 to 14 years of
`
`
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`
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`age weighing less than 50 kg see Table below.
`
`Maintenance Dose
`Loading Dose
`
`
`
`Oral
`
`
`
` Intravenous
` Intravenous
`infusion
`infusion
`
`
`
`
` 8 mg/kg every
`
` 9 mg/kg
`
`
` 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
`
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`
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`
`
`
`
` to 50 kg and those aged 15 years and older regardless of body weight use
`
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` adult dosage. (2.4)
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` o Dosage adjustment of VFEND in pediatric patients with renal or hepatic
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` impairment has not been established (2.5, 2.6)
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` • 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---------------------­
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`• Tablets: 50 mg, 200 mg (3)
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`• For Oral Suspension: 40 mg/mL (200 mg/5 mL) when reconstituted (3)
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`• For Injection: Lyophilized powder containing 200 mg of voriconazole
`
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`and 3,200 mg of sulfobutyl ether beta-cyclodextrin sodium (SBECD);
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`
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`after reconstitution 10 mg/mL of voriconazole and 160 mg/mL of
`
`
`SBECD (3)
`
`
`
`
`------------------------------ CONTRAINDICATIONS -----------------------------­
`
`
`
`• Hypersensitivity to voriconazole or its excipients (4)
`
`
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`• Coadministration with cisapride, pimozide, quinidine, sirolimus or
`
`
`
`
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`ivabradine due to risk of serious adverse reactions (4, 7)
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`• Coadministration with rifampin, carbamazepine, long-acting barbiturates,
`
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`
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`efavirenz, ritonavir, rifabutin, ergot alkaloids, and St. John’s Wort due to
`
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`
`
`
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`risk of loss of efficacy (4, 7)
`
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`• Coadministration with naloxegol, tolvaptan, and lurasidone due to risk of
`
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`
`
`
`
`
`adverse reactions (4, 7)
`
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`• Coadministration of voriconazole with venetoclax at initiation and during
`
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`
`
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`
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`the ramp-up phase in patients with chronic lymphocytic leukemia (CLL)
`
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`
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`or small lymphocytic lymphoma (SLL) due to increased risk of adverse
`
`
`reactions (4, 7)
`
`
`
`
`
`•
`
`
`•
`
`----------------------- WARNINGS AND PRECAUTIONS ----------------------­
`
`
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`• Hepatic Toxicity: Serious hepatic reactions reported. Evaluate liver
`
`
`
`
`
`function tests at start of and during VFEND therapy (5.1)
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`• Arrhythmias and QT Prolongation: Correct potassium, magnesium and
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`
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`calcium prior to use; caution patients with proarrhythmic conditions (5.2)
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`Infusion Related Reactions (including anaphylaxis): Stop the infusion
`
`(5.3)
`
`• Visual Disturbances (including optic neuritis and papilledema): Monitor
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`visual function if treatment continues beyond 28 days (5.4)
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`
`
`Severe Cutaneous Adverse Reactions: Discontinue for exfoliative
`
`
`
`
`
`cutaneous reactions (5.5)
`
`• Photosensitivity: Avoid sunlight due to risk of photosensitivity (5.6)
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`
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`• Adrenal Dysfunction: Carefully monitor patients receiving VFEND and
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`
`
`
`
`corticosteroids (via all routes of administration) for adrenal dysfunction
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`both during and after VFEND treatment. Instruct patients to seek
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`
`
`immediate medical care if they develop signs and symptoms of Cushing’s
`
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`syndrome or adrenal insufficiency (5.8)
`
`
`• Embryo-Fetal Toxicity: Voriconazole can cause fetal harm when
`
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`
`
`
`administered to a pregnant woman. Inform pregnant patients of the
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`
`
`
`potential hazard to the fetus. Advise females of reproductive potential to
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`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)
`
`
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`• 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.
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`
` 1
`
`Reference ID: 4871269
`
`

`

`
` ------------------------------ 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
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`
`
`
` oral and intravenous dosage of VFEND (2.3, 2.7, 7)
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`
`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
`
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`
`
` 2.4 Recommended Dosing Regimen in Pediatric Patients
`
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`
`
`
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` 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
`
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` 5.13Clinically Significant Drug Interactions
`
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` 5.14Galactose Intolerance
`
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`
`
`Reference ID: 4871269
`
` ----------------------- 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: 10/2021
`
`
`
`
`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
`
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`8.4 Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
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`
`12.2 Pharmacodynamics
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`12.3 Pharmacokinetics
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`12.4 Microbiology
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`12.5 Pharmacogenomics
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`13 NONCLINICAL TOXICOLOGY
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`13.1Carcinogenesis, Mutagenesis, Impairment of Fertility
`
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`
`
`14 CLINICAL STUDIES
`
`
`
`14.1Invasive Aspergillosis (IA)
`
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`
`
`14.2Candidemia in Non-neutropenic Patients and Other Deep
`
`
`
`Tissue Candida Infections
`
`
`
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`14.3 Esophageal Candidiasis (EC)
`
`
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`14.4 Other Serious Fungal Pathogens
`
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`14.5 Pediatric Studies
`
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`
`16 HOW SUPPLIED/STORAGE AND HANDLING
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`
`16.1 How Supplied
`
`
`
`16.2 Storage
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
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`
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`*Sections or subsections omitted from the full prescribing
`
`
`
` information are not listed.
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`
` 2
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
` 1 INDICATIONS AND USAGE
`
`
`
`
` 1.1 Invasive Aspergillosis
`
`
`
`
`
`
`
`
`
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` VFEND is indicated in adults and pediatric patients (2 years of age and older) for the treatment of invasive aspergillosis (IA). In
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`clinical trials, the majority of isolates recovered were Aspergillus fumigatus. There was a small number of cases of culture-proven
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`disease due to species of Aspergillus other than A. fumigatus [see Clinical Studies (14.1, 14.5) and Microbiology (12.4)].
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` 1.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue Candida Infections
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` VFEND is indicated in adults and pediatric patients (2 years of age and older) for the treatment of candidemia in non-neutropenic
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`patients and the following Candida infections: disseminated infections in skin and infections in abdomen, kidney, bladder wall, and
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`wounds [see Clinical Studies (14.2, 14.5) and Microbiology (12.4)].
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` 1.3 Esophageal Candidiasis
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` VFEND is indicated in adults and pediatric patients (2 years of age and older) for the treatment of esophageal candidiasis (EC) in
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`adults and pediatric patients 2 years of age and older [see Clinical Studies (14.3, 14.5) and Microbiology (12.4)].
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` 1.4 Scedosporiosis and Fusariosis
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` VFEND is indicated for the treatment of serious fungal infections caused by Scedosporium apiospermum (asexual form of
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`Pseudallescheria boydii) and Fusarium spp. including Fusarium solani, in adults and pediatric patients (2 years of age and older)
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`intolerant of, or refractory to, other therapy [see Clinical Studies (14.4) and Microbiology (12.4)].
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` 1.5 Usage
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` Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to
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`isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are
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`known. However, once these results become available, antifungal therapy should be adjusted accordingly.
` 2 DOSAGE AND ADMINISTRATION
`
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` 2.1
` Important Administration Instructions for Use in All Patients
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` Administer VFEND Tablets or Oral Suspension at least one hour before or after a meal.
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` VFEND I.V. for Injection requires reconstitution to 10 mg/mL and subsequent dilution to 5 mg/mL or less prior to administration as
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`an infusion, at a maximum rate of 3 mg/kg per hour over 1 to 3 hours.
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`Administer diluted VFEND I.V. by intravenous infusion over 1 to 3 hours only. Do not administer as an IV bolus injection.
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` 2.2 Use of VFEND I.V. With Other Parenteral Drug Products
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` Blood products and concentrated electrolytes
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`VFEND I.V. must not be infused concomitantly with any blood product or short-term infusion of concentrated electrolytes,
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`even if the two infusions are running in separate intravenous lines (or cannulas). Electrolyte disturbances such as hypokalemia,
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`hypomagnesemia and hypocalcemia should be corrected prior to initiation of and during VFEND therapy [see Warnings and
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`Precautions (5.10)].
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`Intravenous solutions containing (non-concentrated) electrolytes
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`VFEND I.V. can be infused at the same time as other intravenous solutions containing (non-concentrated) electrolytes, but must be
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`infused through a separate line.
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`Total parenteral nutrition (TPN)
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`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
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`multiple-lumen catheter, TPN needs to be administered using a different port from the one used for VFEND I.V.
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`Reference ID: 4871269
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` 3
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`

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` 2.3 Recommended Dosing Regimen in Adults
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` Invasive aspergillosis and serious fungal infections due to Fusarium spp. and Scedosporium apiospermum
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`See Table 1. Therapy must be initiated with the specified loading dose regimen of intravenous VFEND on Day 1 followed by the
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`recommended maintenance dose (RMD) regimen. Intravenous treatment should be continued for at least 7 days. Once the patient has
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`clinically improved and can tolerate medication given by mouth, the oral tablet form or oral suspension form of VFEND may be
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`utilized. The recommended oral maintenance dose of 200 mg achieves a voriconazole exposure similar to 3 mg/kg intravenously; a
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`300 mg oral dose achieves an exposure similar to 4 mg/kg intravenously. Switching between the intravenous and oral formulations is
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`appropriate because of the high bioavailability of the oral formulation in adults [see Clinical Pharmacology (12)].
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`Candidemia in non-neutropenic patients and other deep tissue Candida infections
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`See Table 1. Patients should be treated for at least 14 days following resolution of symptoms or following last positive culture,
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`whichever is longer.
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`Esophageal Candidiasis
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`See Table 1. Patients should be treated for a minimum of 14 days and for at least 7 days following resolution of symptoms.
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`Table 1:
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`Recommended Dosing Regimen (Adults)
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`Loading Dose
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`Intravenous infusion
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` Maintenance Dosea,b
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`Intravenous infusion
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`Oralc
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`Infection
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`Invasive Aspergillosisd
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` Candidemia in nonneutropenic
` patients and other deep tissue Candida
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`infections
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`Esophageal Candidiasis
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` Scedosporiosis and Fusariosis
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` e
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` 6 mg/kg every 12 hours for the first
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` 24 hours
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` 6 mg/kg every 12 hours for the first
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` 24 hours
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`Not Evaluatedf
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` 4 mg/kg every 12 hours
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` 3-4 mg/kg every 12 hourse
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`Not Evaluatedf
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` 4 mg/kg every 12 hours
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` 200 mg every 12 hours
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` 200 mg every 12 hours
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` 200 mg every 12 hours
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` 200 mg every 12 hours
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` 6 mg/kg every 12 hours for the first
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` 24 hours
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` Increase dose when VFEND is co-administered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment (2.5)
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` 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
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` 300 mg oral every 12 hours dose provided an exposure (AUCτ) similar to a 4 mg/kg intravenous infusion every 12 hours dose (12).
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`Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose.
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` 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
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` days (range 2 to 232 days) (14.1).
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` 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
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` infections received 4 mg/kg every 12 hours as salvage therapy. Appropriate dose should be based on the severity and nature of the infection.
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` f Not evaluated in patients with EC.
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` Method for Adjusting the Dosing Regimen in Adults
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`If patient’s response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours (similar to 3 mg/kg
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`intravenously every 12 hours) to 300 mg every 12 hours (similar to 4 mg/kg intravenously every 12 hours). For adult patients
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`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
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`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
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`every 12 hours (or to 100 mg every 12 hours for adult patients weighing less than 40 kg).
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`If patient is unable to tolerate 4 mg/kg intravenously every 12 hours, reduce the intravenous maintenance dose to 3 mg/kg every 12
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`hours.
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` 2.4 Recommended Dosing Regimen in Pediatric Patients
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` 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
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`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
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`15 years of age and above regardless of body weight, administer the adult dosing regimen of VFEND [see Dosage and Administration
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`(2.3)].
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`Reference ID: 4871269
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` 4
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`

`

`
`Table 2:
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`Recommended Dosing Regimen for Pediatric Patients 2 to less than 12 years of age and
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`12 to 14 years of age with body weight less than 50 kg^
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`Invasive Aspergillosis*
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` Candidemia in nonneutropenics
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` and other deep tissue Candida
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`infections†
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` Scedosporiosis and Fusariosis
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`Loading Dose
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`Intravenous infusion
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` 9 mg/kg every 12 hours for the
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` first 24 hours
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`Intravenous infusion
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` 8 mg/kg every 12 hours after the
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` first 24 hours
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` Maintenance Dose
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`Oral
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` 9 mg/kg every 12 hours (maximum
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` dose of 350 mg every 12 hours)
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` 9 mg/kg every 12 hours
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`Esophageal Candidiasis†
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` Not Evaluated
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` 4 mg/kg every 12 hours
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`(maximum dose of 350 mg every
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` 12 hours)
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` ^ Based on a population pharmacokinetic analysis in 112 immunocompromised pediatric patients aged 2 to less than 12 years of age and 26 immunocompromised
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` pediatric patients aged 12 to less than 17 years of age.
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` * 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
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` treatment for at least the first 7 days of therapy and then could be switched to oral VFEND therapy.
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` † 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
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` 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
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` 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
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` resolution of clinical signs and symptoms. A maximum of 42 days of treatment was permitted.
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` Initiate therapy with an intravenous infusion regimen. Consider an oral regimen only after there is a significant clinical improvement.
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`Note that an 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.
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`The oral dose recommendation for children is based on studies in which VFEND was administered as the powder for oral suspension
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`formulation. Bioequivalence between the VFEND powder for oral suspension and VFEND tablets has not been investigated in a
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`pediatric population.
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`Oral bioavailability may be limited in pediatric patients 2 to 12 years with malabsorption and very low body weight for age. In that
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`case, intravenous VFEND administration is recommended.
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`Method for Adjusting the Dosing Regimen in Pediatric Patients
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`Pediatric Patients 2 to less than 12 years of age and 12 to 14 years of age with body weight less than 50 kg
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`If patient response is inadequate and the patient is able to tolerate the initial intravenous maintenance dose, the maintenance dose may
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`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
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`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
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`intravenous maintenance dose, reduce the dose by 1 mg/kg steps. If patients are unable to tolerate the oral maintenance dose, reduce the
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`dose by 1 mg/kg or 50 mg steps.
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`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
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`weight:
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`Use the optimal method for titrating dosage recommended for adults [see Dosage and Administration (2.3)].
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` 2.5 Dosage Modifications in Patients With Hepatic Impairment
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` Adults
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`The maintenance dose of VFEND should be reduced in adult patients with mild to moderate hepatic impairment, Child-Pugh Class A
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`and B. There are no PK data to allow for dosage adjustment recommendations in patients with severe hepatic impairment (Child-Pugh
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`Class C).
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`Duration of therapy should be based on the severity of the patient’s underlying disease, recovery from immunosuppression, and
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`clinical response.
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`Adult patients with baseline liver function tests (ALT, AST) of up to 5 times the upper limit of normal (ULN) were included in the
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`clinical program. Dose adjustments are not necessary for adult patients with this degree of abnormal liver function, but continued
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`monitoring of liver function tests for further elevations is recommended [see Warnings and Precautions (5.1)].
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`Reference ID: 4871269
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` 5
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`

`

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` It is recommended that the recommended VFEND loading dose regimens be used, but that the maintenance dose be halved in adult
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`patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) [see Clinical Pharmacology (12.3)].
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`VFEND has not been studied in adult patients with severe hepatic cirrhosis (Child-Pugh Class C) or in patients with chronic hepatitis
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`B or chronic hepatitis C disease. VFEND has been associated with elevations in liver function tests and with clinical signs of liver
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`damage, such as jaundice. VFEND should only be used in patients with severe hepatic impairment if the benefit outweighs the
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`potential risk. Patients with hepatic impairment must be carefully monitored for drug toxicity.
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`Pediatric Patients
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`Dosage adjustment of VFEND in pediatric patients with hepatic impairment has not been established [see Use in Specific
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`Populations (8.4)].
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` 2.6 Dosage Modifications in Patients With Renal Impairment
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` Adult Patients
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`The pharmacokinetics of orally administered VFEND are not significantly affected by renal impairment. Therefore, no adjustment is
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`necessary for oral dosing in patients with mild to severe renal impairment [see Clinical Pharmacology (12.3)].
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`In patients with moderate or severe renal impairment (creatinine clearance <50 mL/min) who are receiving an intravenous infusion of
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`VFEND, accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless
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`an assessment of the benefit/risk to the patient justifies the use of intravenous VFEND. Serum creatinine levels should be closely
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`monitored in these patients, and, if increases occur, consideration should be given to changing to oral VFEND therapy [see Warnings
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`and Precautions (5.7)].
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`Voriconazole and the intravenous vehicle, SBECD, are dialyzable. A 4-hour hemodialysis session does not remove a sufficient
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`amount of voriconazole to warrant dose adjustment [see Clinical Pharmacology (12.3)].
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`Pediatric Patients
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`Dosage adjustment of VFEND in pediatric patients with renal impairment has not been established [see Use in Specific Populations
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`(8.4)].
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` 2.7 Dosage Adjustment When Co-Administered With Phenytoin or Efavirenz
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` The maintenance dose of voriconazole should be increased when co-administered with phenytoin or efavirenz. Use the optimal
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`method for titrating dosage [see Drug Interactions (7) and Dosage and Administration (2.3)].
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` 2.8 Preparation and Intravenous Administration of VFEND for Injection
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` Reconstitution
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`The powder is reconstituted with 19 mL of Water For Injection to obtain an extractable volume of 20 mL of clear concentrate
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`containing 10 mg/mL of voriconazole. It is recommended that a standard 20 mL (non-automated) syringe be used to ensure that the
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`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
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`the vial until all the powder is dissolved.
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`Dilution
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`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
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`VFEND concentrate should be further diluted as follows (appropriate diluents listed below):
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` 1. Calculate the volume of 10 mg/mL VFEND concentrate required based on the patient’s weight (see Table 3).
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` 2.
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` In order to allow the required volume of VFEND concentrate to be added, withdraw and discard at least an equal volume of
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`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
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`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
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`number of vials and add to the infusion bag or bottle. Discard Partially Used Vials.
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`The final VFEND solution must be infu