`
`-----------------------WARNINGS AND PRECAUTIONS-------------­
` • Clinically Significant Drug Interactions: Review patient’s
`
`
`
` concomitant medications (5.1, 7)
`
`
`
` • Hepatic Toxicity: Serious hepatic reactions reported. Evaluate liver
`
`
`
`
`
`
`function tests at start of and during voriconazole therapy (5.2)
` • Visual Disturbances (including optic neuritis and papilledema):
`
`
` Monitor visual function if treatment continues beyond 28 days (5.3)
`
`
`
` • Embryo-Fetal Toxicity: Do not administer to pregnant women
`
` unless the benefit to the mother outweighs the risk to the fetus.
`
` Inform pregnant patient of hazard (5.4, 8.1)
`
`
` • Patients with Hereditary Galactose Intolerance Lapp Lactase
`
`
`
`
` Deficiency or Glucose-Galactose Malabsorption: Do not use (5.5)
`
`
`
`
` • Arrhythmias and QT Prolongation: Correct potassium, magnesium
`
`
`
` and calcium prior to use; caution patients with proarrhythmic
`
`
`
`
`
` conditions (5.6)
`
` • Infusion Related Reactions (including anaphylaxis): Stop the
`
`
`
` infusion (5.7)
` • Dermatological Reactions: Discontinue for exfoliative cutaneous
`
`
`
`
`
` reactions or phototoxicity. Avoid sunlight due to risk of
` photosensitivity (5.13)
`
`
` • Skeletal Events: Fluorosis and periostitis with long-term
`
`
` voriconazole therapy. Discontinue if these events occur (5.14)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` ------------------------------ADVERSE REACTIONS--------------------­
`Most common adverse reactions (incidence ≥2%): visual
`
`
`
`disturbances, fever, nausea, rash, vomiting, chills, headache, liver
`
`
`
`
`
`function test abnormal, tachycardia, hallucinations (6)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer
`
`Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or
`
`
`www.fda.gov/medwatch
`
`
`------------------------------DRUG INTERACTIONS--------------------­
` • CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers: Adjust
`
`
`
` VFEND dosage and monitor for adverse reactions or lack of
`
`
`
`
` efficacy (4, 7)
` • VFEND may increase the concentrations and activity of drugs that
`
`
`are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce dosage of
`
` these other drugs and monitor for adverse reactions (4, 7)
`
`
`
`
`• Phenytoin or Efavirenz: with co-administration, increase
`
` maintenance oral and intravenous dosage of VFEND (2.3, 7)
`
`
`-----------------------USE IN SPECIFIC POPULATIONS------------­
`
`
` • Pregnant women: Do not administer to pregnant women unless the
`
`
` benefit to the mother outweighs the risk to the fetus. Inform
`
`
` pregnant woman of risk (8.1)
` • Nursing women: Discontinue VFEND or discontinue nursing (8.3)
`
`
`
`
` • Pediatrics: Safety/effectiveness in patients <12 years has not been
`
`
`
`
`
`
` established (8.4)
` • Hepatic impairment: Use half the maintenance dose in patients with
`
`
`
` mild to moderate hepatic impairment (Child-Pugh Class A and B)
`
` (2.7)
` • Renal impairment: Avoid intravenous administration in patients
`
`
`with moderate to severe renal impairment (creatinine clearance
`
`
`<50 mL/min) (2.8)
`
` 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
`
`
`
`
`
` Infection
`
` Invasive Aspergillosis
`
`
`
`
`----------------------------RECENT MAJOR CHANGES-----------------
`
`2/2014
`Contraindications, Efavirenz 400 mg q24h or higher (4)
`
`
`
`
`
`
`Warnings and Precautions, Hepatic Toxicity (5.2)
`2/2015
`
`
`
`
`
`
`Warnings and Precautions, Arrhythmias/QT Prolongation (5.6) 2/2015
`
`
`
`Warnings and Precautions, Dermatological Reactions (5.13)
`2/2015
`
`
`
`
`
`
`----------------------------INDICATIONS AND USAGE----------------­
`
`
`
`
`VFEND is an azole antifungal drug indicated for use in the treatment of:
`
`• Invasive aspergillosis (1.1)
`
`
`
`
`
`• Candidemia (nonneutropenics) and disseminated candidiasis in skin,
`
`
`
`abdomen, kidney, bladder wall, and wounds (1.2)
`
`
`• Esophageal candidiasis (1.3)
`
`• Serious infections caused by Scedosporium apiospermum and
`
`
`
`
`
`Fusarium species including Fusarium solani, in patients intolerant of,
`
`
`
`
`
`or refractory to, other therapy (1.4)
`
`
`----------------------DOSAGE AND ADMINISTRATION-------------­
`
` Recommended Dosage (2.3)
`
` Maintenance Dose
`
` Loading dose
`
` Oral
`
`
` IV
` IV
`
` 4 mg/kg
`200 mg
`
`
` 6 mg/kg q12h
`
`
`
` for the first 24
`
` q12h
` q12h
`
` hours
`
` 3-4 mg/kg
`200 mg
`
`
`
` q12h
` q12h
`
`
`
` Not Evaluated
`
`
`
`Candidemia in
`nonneutropenics and
`other deep tissue
`
` Candida infections
`
`
`Scedosporiosis and
`
` 4 mg/kg
`200 mg
`
` Fusariosis
`
` q12h
`
` q12h
`
` Esophageal
`
` not
`200 mg
`
` Candidiasis
` evaluated
`
`
` q12h
`
` • Adult patients weighing less than 40 kg: oral maintenance dose 100 or 150
`
`
`
`
`
`
` mg q12 hours
` • See full prescribing information for instructions on reconstitution of
`
`
`
` lyophilized powder for intravenous use and reconstitution of oral suspension
`
`
`
` and important administration instructions (2.5, 2.6)
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3696601
`
`
`---------------------DOSAGE FORMS AND STRENGTHS-----------­
` • Tablets: 50 mg, 200 mg (3)
`
`
`
` • For Oral Suspension: 45 grams of powder; after reconstitution 40
`
`
` mg/mL (3)
`
` • For Injection: lyophilized powder containing 200 mg voriconazole
`
`
`
` and 3200 mg of sulfobutyl ether beta-cyclodextrin sodium (SBECD);
`
` after reconstitution 10 mg/mL of voriconazole and 160 mg/mL of
`
`
`
`
` SBECD (3)
`
`-------------------------------CONTRAINDICATIONS------------------­
` • Hypersensitivity to voriconazole or its excipients (4)
`
`
`
`
` • Coadministration with terfenadine, astemizole, cisapride, pimozide or
`
`
`
` quinidine, sirolimus due to risk of serious adverse reactions (4, 7)
`
`
`
` • Coadministration with rifampin, carbamazepine, long-acting
`
`
`
`
` barbiturates, efavirenz, ritonavir, rifabutin, ergot alkaloids, and St.
`
`
`
` John’s Wort due to risk of loss of efficacy (4, 7)
`
`
`
`________________________________________________________________________________________________________________________
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`
`
`FDA-approved patient labeling.
`
`
`
`
`
`
`
`
`
`Revised: 02/2015
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2025, Page 1
`
`

`

`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`8.3 Nursing Mothers
`
`
`
`8.4 Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`8.6 Women of Childbearing Potential
`
`
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`
`12.3 Phrmacokinetics
`
`
`
`12.4 Microbiology
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`13.2 Teratogenic Effects
`
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Invasive Aspergillosis
`
`
`
`14.2 Candidemia in Non-neutropenic Patients and Other Deep
`
`
`
`
`
`
`Tissue Candida Infections
`
`
`
`14.3 Esophageal Candidiasis
`
`
`
`14.4 Other Serious Fungal Pathogens
`
`
`
`
`15 REFERENCES
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`16.1 How Supplied
`
`
`
`16.2 Storage
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`*Sections or subsections omitted from the full prescribing
`
`
`
`information are not listed.
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
` 1 INDICATIONS AND USAGE
`
`
`
` 1.1 Invasive Aspergillosis
`
`
`
`
` 1.2 Candidemia in Non-neutropenic Patients and the Following
`
`
`
`
`Candida Infections: Disseminated Infections in Skin and
`
`
`Infections in Abdomen, Kidney, Bladder Wall, and Wounds
`
`
`1.3 Esophageal Candidiasis
`
`
`
`
`1.4 Serious Fungal Infections Caused by Scedosporium
`
`
`
`
`
`
`
`apiospermum (Asexual Form of Pseudallescheria boydii)
`
`
`
`
`and Fusarium spp, Including Fusarium solani, in Patients
`
`
`
`
`
`Intolerant of, or Refractory to, Other Therapy
`
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Instructions for Use in All Patients
`
`
`
`2.2 Use of VFEND I.V. With Other Parenteral Drug Products
`
`
`
`
`
`
`
`2.3 Recommended Dosing in Adults
`
`
`
`2.4 Dosage Adjustment
`
`
`
`2.5 Intravenous Administration
`
`
`
`2.6 Oral Suspension
`
`
`
`2.7 Use in Patients With Hepatic Impairment
`
`
`
`
`
`2.8 Use in Patients With Renal Impairment
`
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Drug Interactions
`
`
`
`5.2 Hepatic Toxicity
`
`
`
`5.3 Visual Disturbances
`
`
`
`5.4 Embryo-Fetal Toxicity
`
`
`
`5.5 Galactose Intolerance
`
`
`
`5.6 Arrhythmias and QT Prolongation
`
`
`
`5.7 Infusion Related Reactions
`
`
`
`5.8 Laboratory Tests
`
`
`
`5.9 Patients With Hepatic Impairment
`
`
`
`
`5.10 Patients With Renal Impairment
`
`
`
`
`5.11 Monitoring Renal Function
`
`
`
`5.12 Monitoring Pancreatic Function
`
`
`
`5.13 Dermatological Reactions
`
`
`
`
`5.14 Skeletal Adverse Events
`
`
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Overview
`
`
`
`6.2 Clinical Trial Experience in Adults
`
`
`
`6.3 Clinical Laboratory Values
`
`
`
`6.4 Postmarketing Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`
`Reference ID: 3696601
`
`
`
` 2
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2025, Page 2
`
`

`

`
`
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
` 1 INDICATIONS AND USAGE
` VFEND is indicated for use in patients 12 years of age and older in the treatment of the following fungal infections:
`
`
` 1.1 Invasive Aspergillosis
`
`
` In clinical trials, the majority of isolates recovered were Aspergillus fumigatus. There was a small number of cases
`
`
`
` of culture-proven disease due to species of Aspergillus other than A. fumigatus [see Clinical Studies (14.1) and
`
`
`
`
`
`
` Clinical Pharmacology (12.4)].
` 1.2 Candidemia in Non-neutropenic Patients and the Following Candida Infections: Disseminated Infections
`
`
` in Skin and Infections in Abdomen, Kidney, Bladder Wall, and Wounds
`
`
`
`
`
`
`
` [see Clinical Studies (14.2) and Clinical Pharmacology (12.4)]
`
` 1.3 Esophageal Candidiasis
`
`
`
`
` [see Clinical Studies (14.3) and Clinical Pharmacology (12.4)]
`
`
`
` 1.4 Serious Fungal Infections Caused by Scedosporium apiospermum (Asexual Form of Pseudallescheria
`
`
`
`
`
`
`
`
`
` boydii) and Fusarium spp. Including Fusarium solani, in Patients Intolerant of, or Refractory to, Other
`
`
`
`
`
`
`
` Therapy
`
`
`
`
` [see Clinical Studies (14.4) and Clinical Pharmacology (12.4)]
` Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained
`
`
`
`
`
`
` prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the
` cultures and other laboratory studies are known. However, once these results become available, antifungal therapy
`
`
` should be adjusted accordingly.
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
` Instructions for Use in All Patients
` 2.1
`
` VFEND Tablets or Oral Suspension should be taken at least one hour before or after a meal.
`
`
`
`
`VFEND I.V. for Injection requires reconstitution to 10 mg/mL and subsequent dilution to 5 mg/mL or less prior to
`
`
`
`
`
` administration as an infusion, at a maximum rate of 3 mg/kg per hour over 1 to 2 hours.
` Do not administer as an IV bolus injection.
`
`
`2.2 Use of VFEND I.V. With Other Parenteral Drug Products
`
`
`
`Blood products and concentrated electrolytes
`
`
`VFEND I.V. must not be infused concomitantly with any blood product or short-term infusion of
`
`
`concentrated electrolytes, even if the two infusions are running in separate intravenous lines (or cannulas).
`
`Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to
`
`
`initiation of and during VFEND therapy [see Warnings and Precautions (5.8)].
`
`
`
`
`Intravenous solutions containing (non-concentrated) electrolytes
`
`
`
`
`
`VFEND I.V. can be infused at the same time as other intravenous solutions containing (non-concentrated)
`
`
`electrolytes, but must be infused through a separate line.
`
`Total parenteral nutrition (TPN)
`
`
`VFEND I.V. can be infused at the same time as total parenteral nutrition, but must be infused in a separate line. If
`
`
`infused through a multiple-lumen catheter, TPN needs to be administered using a different port from the one used
`
`for VFEND I.V.
`
`2.3 Recommended Dosing in Adults
`
`Invasive aspergillosis and serious fungal infections due to Fusarium spp. and Scedosporium apiospermum
`
`
`
`
`
`
`See Table 1. Therapy must be initiated with the specified loading dose regimen of intravenous VFEND on Day 1
`
`
`followed by the recommended maintenance dose regimen. Intravenous treatment should be continued for at least 7
`
`
`
`
`
`days. Once the patient has clinically improved and can tolerate medication given by mouth, the oral tablet form or
`
`
`
`oral suspension form of VFEND may be utilized. The recommended oral maintenance dose of 200 mg achieves a
`voriconazole exposure similar to 3 mg/kg IV; a 300 mg oral dose achieves an exposure similar to 4 mg/kg IV.
`
` 3
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3696601
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2025, Page 3
`
`

`

`
`
`
` Switching between the intravenous and oral formulations is appropriate because of the high bioavailability of the
` oral formulation in adults [see Clinical Pharmacology (12)].
`
`
`
` Candidemia in non-neutropenic patients and other deep tissue Candida infections
`
`
`
`See Table 1. Patients should be treated for at least 14 days following resolution of symptoms or following last
`
`
`
`positive culture, whichever is longer.
`
`Esophageal Candidiasis
`
`
`
`See Table 1. Patients should be treated for a minimum of 14 days and for at least 7 days following resolution of
`
`symptoms.
`
`
`
`
`
` Infection
`
`
` Invasive Aspergillosisd
`
`
`
`
`
`
` IV
`
` 4 mg/kg q12h
`
`
`
` Maintenance Dosea,b
`
`
` Oralc
`
` 200 mg q12h
`
`
`Table 1:
`
`
`Recommended Dosing Regimen
`
`
` Loading dose
`
` IV
`
` 6 mg/kg q12h for the first 24
`
` hours
`
` 6 mg/kg q12h for the first 24
`
` hours
`
`
`
`
` 200 mg q12h
`
`
`
`
`
`
`
`
` 3-4 mg/kg q12he
`
`
`
`
` Candidemia in nonneutropenic
`
`
`
` patients and other deep tissue
` Candida infections
`
`
`
` Esophageal Candidiasis
`
` Scedosporiosis and Fusariosis
`
`
`
`
`
`
`
`
`f
`
`
` 4 mg/kg q12h
`
`
`
`
`
` 200 mg q12h
`
` 200 mg q12h
`
`
`
`
`f
`
`
` 6 mg/kg q12h for the first 24
`
` hours
`a
` Increase dose when VFEND is co-administered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment (2.7)
`
`
`
`
`b In healthy volunteer studies, the 200 mg oral q12h dose provided an exposure (AUCτ) similar to a 3 mg/kg IV q12h dose; the 300 mg oral
`
`
`
`
`
`
`
`
`q12h dose provided an exposure (AUCτ) similar to a 4 mg/kg IV q12h dose [see Clinical Pharmacology (12)].
`
`
`
`
`
`
`c Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose.
`
`
`
`
` d In a clinical study of invasive aspergillosis, the median duration of IV VFEND therapy was 10 days (range 2-85 days). The median duration of
`
`
`
` oral VFEND therapy was 76 days (range 2-232 days) [see Clinical Studies (14.1)].
`
`
`
` In clinical trials, patients with candidemia received 3 mg/kg IV q12h as primary therapy, while patients with other deep tissue Candida
`
`
`
`
` infections received 4 mg/kg q12h as salvage therapy. Appropriate dose should be based on the severity and nature of the infection.
`
`
`
`
`
`
`
` f Not evaluated in patients with esophageal candidiasis.
`
`
`2.4 Dosage Adjustment
`
`
`
`
`
`If patient response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours (similar
`
`
`
`
`to 3 mg/kg IV q12h) to 300 mg every 12 hours (similar to 4 mg/kg IV q12h). For adult patients weighing less than
`
`
`
`40 kg, the oral maintenance dose may be increased from 100 mg every 12 hours to 150 mg every 12 hours. If patient
`
`
`
`
`is unable to tolerate 300 mg orally every 12 hours, reduce the oral maintenance dose by 50 mg steps to a minimum
`
`
`
`
`of 200 mg every 12 hours (or to 100 mg every 12 hours for adult patients weighing less than 40 kg).
`
`
`
`
`
`If patient is unable to tolerate 4 mg/kg IV q12h, reduce the intravenous maintenance dose to 3 mg/kg q12h.
`The maintenance dose of voriconazole should be increased when co-administered with phenytoin or efavirenz [see
`
`Drug Interactions (7)].
`
`
`
`
`The maintenance dose of voriconazole should be reduced in patients with mild to moderate hepatic impairment,
`
`Child-Pugh Class A and B [see Dosage and Administration (2.7)]. There are no PK data to allow for dosage
`
`
`
`
`
`adjustment recommendations in patients with severe hepatic impairment (Child-Pugh Class C).
`
`
`
`Duration of therapy should be based on the severity of the patient’s underlying disease, recovery from
`
`
`immunosuppression, and clinical response.
`
`
`
`e
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 4
`
`Reference ID: 3696601
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2025, Page 4
`
`

`

`
`
` Intravenous Administration
` 2.5
`
`
` Reconstitution
`
`
`
`
`The powder is reconstituted with 19 mL of Water For Injection to obtain an extractable volume of 20 mL of clear
`
`
`concentrate containing 10 mg/mL of voriconazole. It is recommended that a standard 20 mL (non-automated)
`
`syringe be used to ensure that the exact amount (19.0 mL) of Water for Injection is dispensed. Discard the vial if a
`
`vacuum does not pull the diluent into the vial. Shake the vial until all the powder is dissolved.
`
`Dilution
`
`
`
`VFEND must be infused over 1-2 hours, at a concentration of 5 mg/mL or less. Therefore, the required volume of
`
`
`
`the 10 mg/mL VFEND concentrate should be further diluted as follows (appropriate diluents listed below):
`
`
`
`
`
`
`1. Calculate the volume of 10 mg/mL VFEND concentrate required based on the patient’s weight (see Table 2).
`
`
`
`2.
`In order to allow the required volume of VFEND concentrate to be added, withdraw and discard at least an
`
`
`equal volume of diluent from the infusion bag or bottle to be used. The volume of diluent remaining in the bag
`
`
`
`
`or bottle should be such that when the 10 mg/mL VFEND concentrate is added, the final concentration is not
`
`
`
`
`less than 0.5 mg/mL nor greater than 5 mg/mL.
`
`
`
`3. Using a suitable size syringe and aseptic technique, withdraw the required volume of VFEND concentrate from
`
`the appropriate number of vials and add to the infusion bag or bottle. Discard Partially Used Vials.
`
`
`
`The final VFEND solution must be infused over 1-2 hours at a maximum rate of 3 mg/kg per hour.
`
`Table 2:
`
`
`Required Volumes of 10 mg/mL VFEND Concentrate
`
` Volume of VFEND Concentrate (10 mg/mL) required for:
`
`
`
`
` 6 mg/kg dose
` 3 mg/kg dose
` 4 mg/kg dose
`
`
` (number of vials)
` (number of vials)
`
`
` (number of vials)
`
`
` 9.0 mL (1)
` 12 mL (1)
`
` 18 mL (1)
` 10.5 mL (1)
`
` 14 mL (1)
`
`
` 21 mL (2)
`
` 12.0 mL (1)
`
` 16 mL (1)
`
` 24 mL (2)
`
` 13.5 mL (1)
`
` 18 mL (1)
`
` 27 mL (2)
`
` 15.0 mL (1)
`
` 20 mL (1)
`
` 30 mL (2)
`
` 16.5 mL (1)
`
` 22 mL (2)
`
` 33 mL (2)
`
` 18.0 mL (1)
`
` 24 mL (2)
`
` 36 mL (2)
`
` 19.5 mL (1)
`
` 26 mL (2)
`
` 39 mL (2)
`
` 21.0 mL (2)
`
` 28 mL (2)
`
` 42 mL (3)
`
` 22.5 mL (2)
`
` 30 mL (2)
`
` 45 mL (3)
`
` 24.0 mL (2)
`
` 32 mL (2)
`
` 48 mL (3)
`
` 25.5 mL (2)
`
` 34 mL (2)
`
` 51 mL (3)
`
` 27.0 mL (2)
`
` 36 mL (2)
`
` 54 mL (3)
`
` 28.5 mL (2)
`
` 38 mL (2)
`
` 57 mL (3)
`
` 30.0 mL (2)
`
` 40 mL (2)
`
` 60 mL (3)
`
`
`
` Body Weight
`
` (kg)
`
` 30
`
` 35
`
` 40
`
` 45
`
` 50
`
` 55
`
` 60
`
` 65
`
` 70
`
` 75
`
` 80
`
` 85
`
` 90
`
` 95
`
` 100
`
`
`VFEND I.V. for Injection is a single dose unpreserved sterile lyophile. Therefore, from a microbiological point of
`
`view, once reconstituted, the product should be used immediately. If not used immediately, in-use storage times and
`
`
`conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2° to 8°C (36° to
`
`
`
`
`46°F). This medicinal product is for single use only and any unused solution should be discarded. Only clear
`
`
`
`
`
`solutions without particles should be used.
`
`
`The reconstituted solution can be diluted with:
`
`
`9 mg/mL (0.9%) Sodium Chloride USP
`
`
`Lactated Ringers USP
`
`5% Dextrose and Lactated Ringers USP
`
`
`5% Dextrose and 0.45% Sodium Chloride USP
`
`
`5% Dextrose USP
`
`5% Dextrose and 20 mEq Potassium Chloride USP
`
`
`0.45% Sodium Chloride USP
`
`
`
`
`
` 5
`
`Reference ID: 3696601
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2025, Page 5
`
`

`

`
`
`
`
`
`
`
`
`
`
` 5% Dextrose and 0.9% Sodium Chloride USP
`
` The compatibility of VFEND I.V. with diluents other than those described above is unknown (see Incompatibilities
`
` below).
` Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration,
`
` whenever solution and container permit.
`
` Incompatibilities
`
`
`
`
`VFEND I.V. must not be diluted with 4.2% Sodium Bicarbonate Infusion. The mildly alkaline nature of this diluent
`
`
`
`
`caused slight degradation of VFEND after 24 hours storage at room temperature. Although refrigerated storage is
`
`
`
`
`recommended following reconstitution, use of this diluent is not recommended as a precautionary measure.
`
`
`
`Compatibility with other concentrations is unknown.
`
`2.6 Oral Suspension
`
`
`Reconstitution
`
`
`
`Tap the bottle to release the powder. Add 46 mL of water to the bottle. Shake the closed bottle vigorously for about
`1 minute. Remove child-resistant cap and push bottle adaptor into the neck of the bottle. Replace the cap. Write the
`
`date of expiration of the reconstituted suspension on the bottle label (the shelf-life of the reconstituted suspension is
`
`14 days at controlled room temperature 15-30°C [59-86°F]).
`
`Instructions for use
`
`Shake the closed bottle of reconstituted suspension for approximately 10 seconds before each use. The reconstituted
`
`
`oral suspension should only be administered using the oral dispenser supplied with each pack.
`
`Incompatibilities
`
`
`VFEND for Oral Suspension and the 40 mg/mL reconstituted oral suspension should not be mixed with any other
`
`
`
`
`medication or additional flavoring agent. It is not intended that the suspension be further diluted with water or other
`
`vehicles.
`
`
`
`2.7 Use in Patients With Hepatic Impairment
`
`
`
`
`In the clinical program, patients were included who had baseline liver function tests (ALT, AST) up to 5 times the
`
`
`
`
`upper limit of normal. No dose adjustment is necessary in patients with this degree of abnormal liver function, but
`
`
`continued monitoring of liver function tests for further elevations is recommended [see Warnings and Precautions
`
`
`
`(5.9)].
`
`
`It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in
`patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) [see Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`
`
`
`
`VFEND has not been studied in patients with severe hepatic cirrhosis (Child-Pugh Class C) or in patients with
`
`
`
`
`chronic hepatitis B or chronic hepatitis C disease. VFEND has been associated with elevations in liver function tests
`
`
`and clinical signs of liver damage, such as jaundice, and should only be used in patients with severe hepatic
`
`
`
`
`impairment if the benefit outweighs the potential risk. Patients with hepatic insufficiency must be carefully
`
`monitored for drug toxicity.
`
`
`
`
`2.8 Use in Patients With Renal Impairment
`
`The pharmacokinetics of orally administered VFEND are not significantly affected by renal impairment. Therefore,
`
`no adjustment is necessary for oral dosing in patients with mild to severe renal impairment [see Clinical
`
`
`
`
`
`
`Pharmacology (12.3)].
`
`
`
`
`
`
`In patients with moderate or severe renal impairment (creatinine clearance <50 mL/min), accumulation of the
`
`intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an
`
`
`
`assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels
`
`
`
`should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to
`
`
`oral voriconazole therapy [see Warnings and Precautions (5.10)].
`
`
`
`
`
`
`
`
`
`
`
` 6
`
`Reference ID: 3696601
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2025, Page 6
`
`

`

`
`
`
`
` Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed
` with clearance of 55 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to
`
`
`
`
` warrant dose adjustment.
`
` 3 DOSAGE FORMS AND STRENGTHS
`
` Powder for Solution for Injection
`
`
`VFEND I.V. for Injection is supplied in a single use vial as a sterile lyophilized powder equivalent to 200 mg
`
`
`
`
`
`VFEND and 3200 mg sulfobutyl ether beta-cyclodextrin sodium (SBECD).
`
`
`Tablets
`
`VFEND 50 mg tablets; white, film-coated, round, debossed with “Pfizer” on one side and “VOR50” on the reverse.
`
`
`
`
`VFEND 200 mg tablets; white, film-coated, capsule shaped, debossed with “Pfizer” on one side and “VOR200” on
`
`
`
`the reverse.
`Powder for Oral Suspension
`
`
`VFEND for Oral Suspension is supplied in 100 mL high density polyethylene (HDPE) bottles. Each bottle contains
`
`
`
`45 g of powder for oral suspension. Following reconstitution, the volume of the suspension is 75 mL, providing a
`
`
`
`usable volume of 70 mL (40 mg voriconazole/mL). A 5 mL oral dispenser and a press-in bottle adaptor are also
`
`provided.
`
`
`4 CONTRAINDICATIONS
`
`
`
`
`
`• VFEND is contraindicated in patients with known hypersensitivity to voriconazole or its excipients. There
`
`
`is no information regarding cross-sensitivity between VFEND (voriconazole) and other azole antifungal
`
`
`
`
`
`agents. Caution should be used when prescribing VFEND to patients with hypersensitivity to other azoles.
`
`
`
`• Coadministration of terfenadine, astemizole, cisapride, pimozide or quinidine with VFEND is
`
`
`
`contraindicated because increased plasma concentrations of these drugs can lead to QT prolongation and
`
`
`
`
`rare occurrences of torsade de pointes [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
`
`
`
`
`• Coadministration of VFEND with sirolimus is contraindicated because VFEND significantly increases
`
`
`
`sirolimus concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
`
`
`
`• Coadministration of VFEND with rifampin, carbamazepine and long-acting barbiturates is contraindicated
`
`because these drugs are likely to decrease plasma voriconazole concentrations significantly [see Drug
`
`
`
`
`Interactions (7) and Clinical Pharmacology (12.3)].
`
`
`
`
`• Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg q24h or higher is
`
`
`contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy
`subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations [see
`
`Drug Interactions (7) and Clinical Pharmacology (12.3)].
`
`
`
`
`
`• Coadministration of VFEND with high-dose ritonavir (400 mg q12h) is contraindicated because ritonavir
`
`
`
`(400 mg q12h) significantly decreases plasma voriconazole concentrations. Coadministration of
`
`voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the
`
`benefit/risk to the patient justifies the use of voriconazole [see Drug Interactions (7) and Clinical
`
`
`Pharmacology (12.3)].
`
`
`
`
`• Coadministration of VFEND with rifabutin is contraindicated since VFEND significantly increases
`rifabutin plasma concentrations and rifabutin also significantly decreases voriconazole plasma
`
`concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
`
`
`
`
`
`• Coadministration of VFEND with ergot alkaloids (ergotamine and dihydroergotamine) is contraindicated
`
`
`
`
`
`because VFEND may increase the plasma concentration of ergot alkaloids, which may lead to ergotism
`
`
`[see Drug Interactions (7) and Clinical Pharmacology (12.3)].
`
`
`
`
` 7
`
`Reference ID: 3696601
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2025, Page 7
`
`

`

`
`
`
`
`
`
`
` • Coadministration of VFEND with St. John’s Wort is contraindicated because this herbal supplement may
`
` decrease voriconazole plasma concentration [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
` 5.1 Drug Interactions
`
`
`
`
` See Table 7 for a listing of drugs that may significantly alter voriconazole concentrations. Also, see Table 8 for a
`
` listing of drugs that may interact with voriconazole resulting in altered pharmacokinetics or pharmacodynamics of
`
` the other drug [see Contraindications (4) and Drug Interactions (7)].
`
`
`
`
` 5.2 Hepatic Toxicity
`
` In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with VFEND
` (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances of hepatic
`
`
`
` reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly
`
`
`
`
` hematological malignancy). Hepatic reactions, including hepatitis and jaundice, have occurred among patients with
`
`
`no other identifiable risk factors. Liver dysfunction has usually been reversible on discontinuation of therapy [see
`
` Warnings and Precautions (5.9) and Adverse Reactions (6.3)].
`
` Measure serum transaminase levels and bilirubin at the initiation of VFEND therapy and monitor at least weekly for
`
`
`
`
`
`the first month of treatment. Monitoring frequency can be reduced to monthly during continued use if no clinically
`
`
`
`
`significant changes are noted. If liver function tests become markedly elevated compared to baseline, VFEND
`
`
`
`should be discontinued unless the medical judgment of the benefit-risk of the treatment for the patient justifies
`
`
`
`continued use [see Warnings and Precautions (5.9), Dosage and Administration (2.4, 2.7), and Adverse Reactions
`
`(6.3)].
`
`
`
`5.3 Visual Disturbances
`
`
`The effect of VFEND on visual function is not known if treatment continues beyond 28 days. There have been
`
`
`
`post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema. If treatment
`
`
`
`
`
`continues beyond 28 days, visual function including visual acuity, visual field and color perception should be
`
`
`
`monitored [see Adverse Reactions (6.2)].
`
`
`
`5.4 Embryo-Fetal Toxicity
`
`
`
`
`Voriconazole can cause fetal harm when administered to a pregnant woman.
`
`
`
`
`In animals, voriconazole administration was associated with teratogenicity, embryotoxicity, increased gestational
`
`
`length, dystocia and embryomortality. Please refer to section 8.1 (Use in Pregnancy) for additional details.
`
`
`If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be
`
`informed of the potential hazard to the fetus.
`
`
`5.5 Galactose Intolerance
`
`
`VFEND tablets contain lactose and should not be given to patients with rare hereditary problems of galactose
`
`
`intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
`
`
`
`5.6 Arrhythmias and QT Prolongation
`
`
`
`
`Some azoles, including voriconazole, have been associated with prolongation of the QT interval on the
`
`electrocardiogram. During clinical development and post-marketing surveillance, there have been rare cases of
`
`arrhythmias, (including ventricular arrhythmias such as torsade de pointes), cardiac arrests and sudden deaths in
`
`
`
`
`
`patients taking voriconazole. These cases usually involved seriously ill patients with multiple confounding risk
`
`
`
`
`factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medications
`
`
`
`that may have been contributory.
`
`
`Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions, such as:
`
`
`• Congenital or acquired QT-prolongation
`
`
`
`
`• Cardiomyopathy, in particular when heart failure is present
`• Sinus bradycardia
`
`
`
`
`
`
`
`
`
`
` 8
`
`
`Reference ID: 3696601
`
`