NDC 72266-131 Voriconazole

Voriconazole

NDC Product Information

Voriconazole with NDC 72266-131 is a a human prescription drug product labeled by Fosun Pharma Usa Inc.. The generic name of Voriconazole is voriconazole. The product's dosage form is injection, powder, lyophilized, for solution and is administered via intravenous form.

Labeler Name: Fosun Pharma Usa Inc.

Dosage Form: Injection, Powder, Lyophilized, For Solution - A dosage form intended for the solution prepared by lyophilization ("freeze drying"), a process which involves the removal of water from products in the frozen state at extremely low pressures; this is intended for subsequent addition of liquid to create a solution that conforms in all respects to the requirements for Injections.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Voriconazole Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • VORICONAZOLE 10 mg/mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • SULFOBUTYLETHER .BETA.-CYCLODEXTRIN (UNII: 2PP9364507)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Azole Antifungal - [EPC] (Established Pharmacologic Class)
  • Azoles - [CS]
  • Cytochrome P450 3A4 Inhibitors - [MoA] (Mechanism of Action)
  • Cytochrome P450 2C19 Inhibitors - [MoA] (Mechanism of Action)
  • Cytochrome P450 2C9 Inhibitors - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Fosun Pharma Usa Inc.
Labeler Code: 72266
FDA Application Number: ANDA211099 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 01-04-2021 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Voriconazole Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1.1 Invasive Aspergillosis

Voriconazole for injection is indicated in adults and 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) for the treatment of invasive aspergillosis (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

Voriconazole for injection is indicated in adults and 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) 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

Voriconazole for injection is indicated in adults and 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) for the treatment of esophageal candidiasis (EC) in adults and 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)


[see


Clinical Studies (14.3,


14.5) and


Microbiology (12.4)].

1.4  Scedosporiosis And Fusariosis

Voriconazole for injection 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 (aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight) 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.


Additional pediatric use information is approved for PF PRISM C.V.’s VFEND (voriconazole). However, due to PF PRISM C.V.’s marketing exclusivity rights, this drug product is not labeled with that information.

2.1 Important Administration Instructions For Use In All Patients

Voriconazole for injection I..V. 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 voriconazole for injection I.V. by intravenous infusion over 1 to 2 hours only. Do not administer as an IV bolus injection.

2.2 Use Of Voriconazole For Injection I.V. With Other Parenteral Drug Products

Blood  products and concentrated electrolytesVoriconazole for injection 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 voriconazole for injection therapy


[see


Warnings and Precautions (5.9)]


.


Intravenous solutions containing (non-concentrated) electrolytesVoriconazole for injection 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)Voriconazole for injection 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 voriconazole for injection I.V.

Invasive aspergillosis and serious fungal infections due to


Fusarium spp. and


Scedosporium apiospermumSee Table 1. Therapy must be initiated with the specified loading dose regimen of intravenous voriconazole for injection I.V 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 voriconazole for injection 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 infectionsSee Table 1. Patients should be treated for at least 14 days following resolution of symptoms or following last positive culture, whichever is longer.Esophageal CandidiasisSee 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)InfectionLoading doseMaintenance Dose


a,bIntravenousinfusionIntravenous infusionOral


CInvasive Aspergillosisd6 mg/kg every 12 hours for the first 24 hours


4 mg/kg every 12 hours


200 mg every 12 hours


Candidemia in nonneutropenics and other deep tissue


Candida  infections


6 mg/kg every 12 hours for the first


3-4 mg/kg every 12 hours


e200 mg every 12 hours


Esophageal CandidiasisNot Evaluated


fNot Evaluated


f200 mg every 12 hours


Scedosporiosis and Fusariosis6 mg/kg every 12 hours for the first 24 hours


4 mg/kg every 12 hours


200 mg every 12 hours


a Increase dose when voriconazole for injection is co-administered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment (2.5)


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).


c Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose.


d In a clinical study of IA, the median duration of intravenous voriconazole therapy was 10 days (range 2 to 85 days). The median duration of oral voriconazole for injection therapy was 76 days (range 2 to 232 days) (14.1).


e 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 AdultsIf 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

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 voriconazole for injection [see


Dosage and Administration (2.3)]. 


Initiate therapy with an intravenous infusion regimen. Consider an oral regimen only after there is a significant clinical improvement.  


Method for Adjusting the Dosing Regimen in Pediatric Patients: Pediatric patients 12 to 14 years of age weighing greater than or equal to 50kg 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)]. 


Additional pediatric use information is approved for PF PRISM C.V.’s VFEND (voriconazole). However, due to PF PRISM C.V.’s marketing exclusivity rights, this drug product is not labeled with that information.

2.5 Dosage Modifications In Patients With Hepatic Impairment

AdultsThe maintenance dose of voriconazole should be reduced in adult patients with mild to moderate hepatic impairment, Child-Pugh Class A and B. There are no PK data to allow for dosage adjustment recommendations in patients with severe hepatic impairment (Child-Pugh Class C).


Duration of therapy should be based on the severity of the patient’s underlying disease, recovery from immunosuppression, and clinical response.


Adult patients with baseline liver function tests (ALT, AST) of up to 5 times the upper limit of normal (ULN) were included in the clinical program. Dose adjustments are not necessary for adult patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended


[see


Warnings and Precautions (5.1)]


.


It is recommended that the recommended voriconazole 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)]


.


Voriconazole 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. Voriconazole has been associated with elevations in liver function tests and with clinical signs of liver damage, such as jaundice. Voriconazole 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 PatientsDosage adjustment of voriconazole 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 PatientsThe pharmacokinetics of orally administered voriconazole 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 voriconazole for injection, 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 for injection. 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 (5.7)]


.


 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 PatientsDosage adjustment of voriconazole 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 Voriconazole For Injection

ReconstitutionThe 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.


DilutionVoriconazole for injection 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 voriconazole for injection concentrate should be further diluted as follows (appropriate diluents listed below):


1. Calculate the volume of 10 mg/mL voriconazole for injection concentrate required based on the patient’s weight (see Table 3).


2. In order to allow the required volume of voriconazole for injection 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 voriconazole for injection 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 voriconazole for injection concentrate from the appropriate number of vials and add to the infusion bag or bottle.


Discard Partially Used Vials.The final voriconazole for injection 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 Voriconazole for injection Concentrate


Body weight (kg)Volume of Voriconazole for injection Concentrate (10 mg/mL) required for:3 mg/kg dose(number of vials)4 mg/kg dose(number of vials)6 mg/kg dose(number of vials)30


9 mL (1)


12 mL (1)


18 mL (1)


35


10.5 mL (1)


14 mL (1)


21 mL (2)


40


12 mL (1)


16 mL (1)


24 mL (2)


45


13.5 mL (1)


18 mL (1)


27 mL (2)


50


15 mL (1)


20 mL (1)


30 mL (2)


55


16.5 mL (1)


22 mL (2)


33 mL (2)


60


18 mL (1)


24 mL (2)


36 mL (2)


65


19.5 mL (1)


26 mL (2)


39 mL (2)


70


21 mL (2)


28 mL (2)


42 mL (3)


75


22.5 mL (2)


30 mL (2)


45 mL (3)


80


24 mL (2)


32 mL (2)


48 mL (3)


85


25.5 mL (2)


34 mL (2)


51 mL (3)


90


27 mL (2)


36 mL (2)


54 mL (3)


95


28.5 mL (2)


38 mL (2)


57 mL (3)


100


30 mL (2)


40 mL (2)


60 mL (3)


Voriconazole for injection I.V. 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 voriconazole for injection 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


Voriconazole for injection I.V. must not be diluted with 4.2% Sodium Bicarbonate Infusion. The mildly alkaline nature of this diluent caused slight degradation of voriconazole for injection 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.


Additional pediatric use information is approved for PF PRISM C.V.’s VFEND (voriconazole). However, due to PF PRISM C.V.’s marketing exclusivity rights, this drug product is not labeled with that information.

3 Dosage Forms And Strengths

Powder for Solution for InjectionVoriconazole for injection I.V. is supplied in a single-dose vial as a sterile lyophilized powder equivalent to 200 mg voriconazole and 3,200 mg sulfobutyl ether beta-cyclodextrin sodium (SBECD).

4 Contraindications

• Voriconazole for injection is contraindicated in patients with known hypersensitivity to voriconazole or its excipients. There is no information regarding cross-sensitivity between voriconazole and other azole antifungal agents. Caution should be used when prescribing voriconazole to patients with hypersensitivity to other azoles.


• Coadministration of cisapride, pimozide or quinidine with voriconazole for injection 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 voriconazole for injection with sirolimus is contraindicated because voriconazole for injection significantly increases sirolimus concentrations


[see 


Drug Interactions (7) and


Clinical Pharmacology (12.3)]


.


• Coadministration of voriconazole for injection with rifampin, carbamazepine and long-acting barbiturates is contraindicated because these drugs are likely to decrease plasma voriconazole concentrations significantly


[see 


Drug Interactions (7) and


Clinical Pharmacology (12.3)]


.


• Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg every 24 hours or higher is contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations


[see 


Drug Interactions (7) and


Clinical Pharmacology (12.3)]


.


• Coadministration of voriconazole for injection with high-dose ritonavir (400 mg every 12 hours) is contraindicated because ritonavir (400 mg every 12 hours) significantly decreases plasma voriconazole concentrations. Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole


[see 


Drug Interactions (7) and


Clinical Pharmacology (12.3)]


.


• Coadministration of voriconazole for injection with rifabutin is contraindicated since voriconazole for injection significantly increases rifabutin plasma concentrations and rifabutin also significantly decreases voriconazole plasma concentrations


[see 


Drug Interactions (7) and


Clinical Pharmacology (12.3)]


.


• Coadministration of voriconazole for injection with ergot alkaloids (ergotamine and dihydroergotamine) is contraindicated because voriconazole for injection may increase the plasma concentration of ergot alkaloids, which may lead to ergotism


[see 


Drug Interactions (7) and


Clinical Pharmacology (12.3)]


.


• Coadministration of voriconazole for injection 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)]


.

5.1 Hepatic Toxicity

In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with voriconazole for injection (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


Adverse Reactions (6.1)]


.


A higher frequency of liver enzyme elevations was observed in the pediatric population


[see


Adverse Reactions (6.1)]


.Hepatic function should be monitored in both adult and pediatric patients. 


Measure serum transaminase levels and bilirubin at the initiation of voriconazole for injection 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, voriconazole for injection should be discontinued unless the medical judgment of the benefit/risk of the treatment for the patient justifies continued use


[see 


Dosage and Administration (2.5) and


Adverse Reactions (6.1)]


.

5.2 Arrhythmias And Qt Prolongation

Some azoles, including voriconazole for injection, 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 for injection 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


• Existing symptomatic arrhythmias


• Concomitant medicinal product that is known to prolong QT interval


[see


Contraindications (4),


Drug Interactions (7), and


Clinical Pharmacology (12.3)]


Rigorous attempts to correct potassium, magnesium and calcium should be made before starting and during voriconazole therapy


[see


Clinical Pharmacology (12.3)]


.

During infusion of the intravenous formulation of voriconazole for injection in healthy subjects, anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus and rash, have occurred uncommonly. Symptoms appeared immediately upon initiating the infusion. Consideration should be given to stopping the infusion should these reactions occur.

5.4 Visual Disturbances

The effect of voriconazole for injection 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)]


.

5.5 Serious Exfoliative Cutaneous Reactions

Serious exfoliative cutaneous reactions, such as Stevens-Johnson syndrome, have been reported during treatment with voriconazole for injection. If a patient develops an exfoliative cutaneous reaction, voriconazole for injection should be discontinued.

5.6 Photosensitivity

Voriconazole for injection has been associated with photosensitivity skin reaction. Patients, including pediatric patients, should avoid exposure to direct sunlight during voriconazole for injection treatment and should use measures such as protective clothing and sunscreen with high sun protection factor (SPF). If phototoxic reactions occur, the patient should be referred to a dermatologist and voriconazole for injection discontinuation should be considered. If voriconazole for injection is continued despite the occurrence of phototoxicity-related lesions, dermatologic evaluation should be performed on a systematic and regular basis to allow early detection and management of premalignant lesions. Squamous cell carcinoma of the skin and melanoma have been reported during long-term voriconazole for injection therapy in patients with photosensitivity skin reactions. If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, voriconazole for injection should be discontinued. In addition, voriconazole for injection has been associated with photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus. Patients should avoid strong, direct sunlight during voriconazole for injection therapy.


The frequency of phototoxicity reactions is higher in the pediatric population. Because squamous cell carcinoma has been reported in patients who experience photosensitivity reactions, stringent measures for photoprotection are warranted in children. In children experiencing photoaging injuries such as lentigines or ephelides, sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation.

5.7 Renal Toxicity

Acute renal failure has been observed in patients undergoing treatment with voriconazole for injection. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and may have concurrent conditions that may result in decreased renal function.


Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation of serum creatinine


[see 


Clinical Pharmacology (12.3) and


Dosage and Administration (2.6)]


.

5.8 Embryo-Fetal Toxicity

Voriconazole can cause fetal harm when administered to a pregnant woman.


In animals, voriconazole administration was associated with fetal malformations, embryotoxicity, increased gestational length, dystocia and embryomortality


[see


Use in Specific Populations (8.1)]


.


If voriconazole for injection is used during pregnancy, or if the patient becomes pregnant while taking voriconazole for injection, inform the patient of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with voriconazole for injection


[see


Use in Specific Populations (8.3)]


.

5.9 Laboratory Tests

Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of and during voriconazole for injection therapy.


Patient management should include laboratory evaluation of renal (particularly serum creatinine) and hepatic function (particularly liver function tests and bilirubin).

5.10 Pancreatitis

Pancreatitis has been observed in patients undergoing treatment with voriconazole for injection


[see


Adverse Reactions (6.1,


6.2)]


Patients with risk factors for acute pancreatitis (e.g., recent chemotherapy, hematopoietic stem cell transplantation [HSCT]) should be monitored for the development of pancreatitis during voriconazole for injection treatment.

5.11 Skeletal Adverse Reactions

Fluorosis and periostitis have been reported during long-term voriconazole for injection therapy. If a patient develops skeletal pain and radiologic findings compatible with fluorosis or periostitis, voriconazole for injection should be discontinued


[see


Adverse Reactions (6.2)]


.

5.12  Clinically Significant Drug Interactions

See Table 10 for a listing of drugs that may significantly alter voriconazole concentrations. Also, see Table 11 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)]


.

6 Adverse Reactions

The following serious adverse reactions are described elsewhere in the labeling:


Hepatic Toxicity


[see


Warnings and Precautions (5.1)]


Arrhythmias and QT Prolongation


[see


Warnings and Precautions (5.2)]


Infusion Related Reactions


[see


Warnings and Precautions (5.3)]


Visual Disturbances


[see


Warnings and Precautions (5.4)]


Serious Exfoliative Cutaneous Reactions


[see


Warnings and Precautions (5.5)]


Photosensitivity


[see


Warnings and Precautions (5.6)]


Renal Toxicity


[see


Warnings and Precautions (5.7)]

6 .1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.


Clinical Trials Experience in AdultsOverviewThe most frequently reported adverse reactions (see Table 4) in the adult therapeutic trials were visual disturbances (18.7%), fever (5.7%), nausea (5.4%), rash (5.3%), vomiting (4.4%), chills (3.7%), headache (3.0%), liver function test increased (2.7%), tachycardia (2.4%), hallucinations (2.4%). The adverse reactions which most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances


[see


Warning and Precautions (5.1,


5.4) and


Adverse Reactions (6.1)]


.


The data described in Table 4 reflect exposure to voriconazole in 1655 patients in nine therapeutic studies. This represents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy or HIV and non- neutropenic patients. This subgroup does not include healthy subjects and patients treated in the compassionate use and non- therapeutic studies. This patient population was 62% male, had a mean age of 46 years (range 11-90, including 51 patients aged 12-18 years), and was 78% White and 10% Black. Five hundred sixty one patients had a duration of voriconazole therapy of greater than 12 weeks, with 136 patients receiving voriconazole for over six months. Table 4 includes all adverse reactions which were reported at an incidence of 2% during voriconazole therapy in the all therapeutic studies population, studies 307/602 and 608 combined, or study 305, as well as events of concern which occurred at an incidence of <2%.


In study 307/602, 381 patients (196 on voriconazole, 185 on amphotericin B) were treated to compare voriconazole to amphotericin B followed by other licensed antifungal therapy (OLAT) in the primary treatment of patients with acute IA. The rate of discontinuation from voriconazole study medication due to adverse events was 21.4% (42/196 patients). In study 608, 403 patients with candidemia were treated to compare voriconazole (272 patients) to the regimen of amphotericin B followed by fluconazole (131 patients). The rate of discontinuation from voriconazole study medication due to adverse events was 19.5% out of 272 patients. Study 305 evaluated the effects of oral voriconazole (200 patients) and oral fluconazole (191 patients) in the treatment of EC. The rate of discontinuation from voriconazole study medication in Study 305 due to adverse events was 7% (14/200 patients). Laboratory test abnormalities for these studies are discussed under Clinical Laboratory Values below.


Table 4:Treatment Emergent Adverse Events Rate ³


 2% on Voriconazole or Adverse Events of Concern in Therapeutic Studies Population, Studies 307/602-608 Combined, or Study 305. Possibly Related to Therapy or Causality Unknown†TherapeuticStudies*


Studies 307/602 and 608 (IV/ oral therapy)Study 305 (oral therapy)Voriconaz


oleN =1655VoriconazoleN =468 Ampho B ** N=185 Ampho B→ FluconazoleN =131VoriconazoleN=200FluconazoleN=191N   ( %)N   ( %)N   ( %)N   ( %)N   ( %)N   ( %)Special Senses ***Abnormal vision310 (18.7)63  (13.5)1  (0.5)031  (15.5)8  (4.2)Photophobia37 (2.2)8  (1.7)005  (2.5)2  (1.0)Chromatopsia20 (1.2)2  (0.4)002  (1.0)0Body as a WholeFever94 (5.7)8  (1.7)25  (13.5)5  (3.8)00Chills61 (3.7)1  (0.2)36  (19.5)8  (6.1)1  (0.5)0Headache49 (3.0)9  (1.9)8  (4.3)1  (0.8)01  (0.5)Cardiovascular SystemTachycardia39 (2.4)6  (1.3)5  (2.7)000Digestive SystemNausea89 (5.4)18 (3.8)29  (15.7)2  (1.5)2  (1.0)3  (1.6)Vomiting 72 (4.4)15 (3.2)18 (9.7)1  (0.8)2  (1.0)1  (0.5)Liver function tests


abnormal


45 (2.7)15 (3.2)4 (2. 2)1  (0.8)6  (3.0)2  (1.0)Cholestatic jaundice17 (1.0)8  (1.7)01  (0.8)3  (1.5)0Metabolic andNutritional Syste msAlkaline phosphatase


increased


59 (3.6)19 (4.1)4  (2.2)3  (2.3)10 (5.0)3  (1.6)Hepatic enzymes


increased


30 (1.8)11  (2.4)5  (2.7)1  (0.8)3  (1.5)0SGOT increased31 (1.9)9  (1.9)01  (0.8)8  (4.0)2  (1.0)SGPT increased29 (1.8)9  (1.9)1  (0.5)2  (1.5)6  (3.0)2  (1.0)Hypokalemia26 (1.6)3  (0.6)36  (19.5)16  (12.2)00Bilirubinemia15 (0.9)5  (1.1)3  (1.6)2 (1. 5)1  (0.5)0Creatinine increased4  (0.2)059  (31.9)10 (7.6)1  (0.5)0Nervous SystemHallucinations39 (2.4)13 (2.8)1  (0.5)000Skin and AppendagesRash88 (5.3)20 (4.3)7  (3.8)1  (0.8)3  (1.5)1  (0.5) UrogenitalKidney function abnormal10 (0.6)6  (1.3)40  (21.6)9  (6.9)1  (0.5)1  (0.5)Acute kidney failure7  (0.4)2  (0.4)11 (5.9)7  (5.3)00† Study 307/602: IA; Study 608: candidemia; Study 305: EC


* Studies 303, 304, 305, 307, 309, 602, 603, 604, 608


**Amphotericin B followed by other licensed antifungal therapy


***See Warnings and Precautions (5.4)


Visual DisturbancesVoriconazole for injection treatment-related visual disturbances are common. In therapeutic trials, approximately 21% of patients experienced abnormal vision, color vision change and/or photophobia. Visual disturbances may be associated with higher plasma concentrations and/or doses. The mechanism of action of the visual disturbance is unknown, although the site of action is most likely to be within the retina. In a study in healthy subjects investigating the effect of 28-day treatment with voriconazole on retinal function, voriconazole for injection caused a decrease in the electroretinogram (ERG) waveform amplitude, a decrease in the visual field, and an alteration in color perception. The ERG measures electrical currents in the retina. These effects were noted early in administration of voriconazole for injection and continued through the course of study drug treatment. Fourteen days after the end of dosing, ERG, visual fields and color perception returned to normal


[see


Warnings and Precautions (5.4)]


.


Dermatological ReactionsDermatological reactions were common in patients treated with voriconazole for injection. The mechanism underlying these dermatologic adverse events remains unknown.


Serious cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme have been reported during treatment with voriconazole for injection


[see


Warnings and Precautions (5.5)]


.


Voriconazole for injection has also been associated with additional photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus


[see


Warnings and Precautions (5.6)]


.


Less Common Adverse ReactionsThe following adverse reactions occurred in <2% of all voriconazole-treated patients in all therapeutic studies (N=1655). This listing includes events where a causal relationship to voriconazole cannot be ruled out or those which may help the physician in managing the risks to the patients. The list does not include events included in Table 4 above and does not include every event reported in the voriconazole clinical program.


Body as a Whole: abdominal pain, abdomen enlarged, allergic reaction, anaphylactoid reaction


[see


Warnings and Precautions (5.3)]


, ascites, asthenia, back pain, chest pain, cellulitis, edema, face edema, flank pain, flu syndrome, graft versus host reaction, granuloma, infection, bacterial infection, fungal infection, injection site pain, injection site infection/inflammation, mucous membrane disorder, multi-organ failure, pain, pelvic pain, peritonitis, sepsis, substernal chest pain.


Cardiovascular: atrial arrhythmia, atrial fibrillation, AV block complete, bigeminy, bradycardia, bundle branch block, cardiomegaly, cardiomyopathy, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, congestive heart failure, deep thrombophlebitis, endocarditis, extrasystoles, heart arrest, hypertension, hypotension, myocardial infarction, nodal arrhythmia, palpitation, phlebitis, postural hypotension, pulmonary embolus, QT interval prolonged, supraventricular extrasystoles, supraventricular tachycardia, syncope, thrombophlebitis, vasodilatation, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia (including torsade de pointes)


[see


Warnings and Precautions (5.2)]


.


Digestive: anorexia, cheilitis, cholecystitis, cholelithiasis, constipation, diarrhea, duodenal ulcer perforation, duodenitis, dyspepsia, dysphagia, dry mouth, esophageal ulcer, esophagitis, flatulence, gastroenteritis, gastrointestinal hemorrhage, GGT/LDH elevated, gingivitis, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hepatic coma, hepatic failure, hepatitis, intestinal perforation, intestinal ulcer, jaundice, enlarged liver, melena, mouth ulceration, pancreatitis, parotid gland enlargement, periodontitis, proctitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, stomach ulcer, stomatitis, tongue edema.


Endocrine: adrenal cortex insufficiency, diabetes insipidus, hyperthyroidism, hypothyroidism.


Hemic and Lymphatic: agranulocytosis, anemia (macrocytic, megaloblastic, microcytic, normocytic), aplastic anemia, hemolytic anemia, bleeding time increased, cyanosis, DIC, ecchymosis, eosinophilia, hypervolemia, leukopenia, lymphadenopathy, lymphangitis, marrow depression, pancytopenia, petechia, purpura, enlarged spleen, thrombocytopenia, thrombotic thrombocytopenic purpura.


Metabolic and Nutritional: albuminuria, BUN increased, creatine phosphokinase increased, edema, glucose tolerance decreased, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperuricemia, hypocalcemia, hypoglycemia, hypomagnesemia, hyponatremia, hypophosphatemia, peripheral edema, uremia.


Musculoskeletal: arthralgia, arthritis, bone necrosis, bone pain, leg cramps, myalgia, myasthenia, myopathy, osteomalacia, osteoporosis.


Nervous System: abnormal dreams, acute brain syndrome, agitation, akathisia, amnesia, anxiety, ataxia, brain edema, coma, confusion, convulsion, delirium, dementia, depersonalization, depression, diplopia, dizziness, encephalitis, encephalopathy, euphoria, Extrapyramidal Syndrome, grand mal convulsion, Guillain-Barré syndrome, hypertonia, hypesthesia, insomnia, intracranial hypertension, libido decreased, neuralgia, neuropathy, nystagmus, oculogyric crisis, paresthesia, psychosis, somnolence, suicidal ideation, tremor, vertigo.


Respiratory System: cough increased, dyspnea, epistaxis, hemoptysis, hypoxia, lung edema, pharyngitis, pleural effusion, pneumonia, respiratory disorder, respiratory distress syndrome, respiratory tract infection, rhinitis, sinusitis, voice alteration.


Skin and Appendages: alopecia, angioedema, contact dermatitis, discoid lupus erythematosis, eczema, erythema multiforme, exfoliative dermatitis, fixed drug eruption, furunculosis, herpes simplex, maculopapular rash, melanoma, melanosis, photosensitivity skin reaction, pruritus, pseudoporphyria, psoriasis, skin discoloration, skin disorder, skin dry, Stevens-Johnson syndrome, squamous cell carcinoma, sweating, toxic epidermal necrolysis, urticaria.


Special Senses: abnormality of accommodation, blepharitis, color blindness, conjunctivitis, corneal opacity, deafness, ear pain, eye pain, eye hemorrhage, dry eyes, hypoacusis, keratitis, keratoconjunctivitis, mydriasis, night blindness, optic atrophy, optic neuritis, otitis externa, papilledema, retinal hemorrhage, retinitis, scleritis, taste loss, taste perversion, tinnitus, uveitis, visual field defect.


Urogenital: anuria, blighted ovum, creatinine clearance decreased, dysmenorrhea, dysuria, epididymitis, glycosuria, hemorrhagic cystitis, hematuria, hydronephrosis, impotence, kidney pain, kidney tubular necrosis, metrorrhagia, nephritis, nephrosis, oliguria, scrotal edema, urinary incontinence, urinary retention, urinary tract infection, uterine hemorrhage, vaginal hemorrhage.


Clinical Laboratory Values in AdultsThe overall incidence of transaminase increases >3x upper limit of normal (not necessarily comprising an adverse reaction) was 17.7% (268/1514) in adult subjects treated with voriconazole for injection for therapeutic use in pooled clinical trials. Increased incidence of liver function test abnormalities may be associated with higher plasma concentrations and/or doses. The majority of abnormal liver function tests either resolved during treatment without dose adjustment or resolved following dose adjustment, including discontinuation of therapy.


Voriconazole for injection has been infrequently associated with cases of serious hepatic toxicity including cases of jaundice and rare cases of hepatitis and hepatic failure leading to death. Most of these patients had other serious underlying conditions.


Liver function tests should be evaluated at the start of and during the course of voriconazole for injection therapy. Patients who develop abnormal liver function tests during voriconazole for injection therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of voriconazole for injection must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to voriconazole for injection


[see


Warnings and Precautions (5.1)]


.


Acute renal failure has been observed in severely ill patients undergoing treatment with voriconazole for injection. Patients being treated with voriconazole for injection are likely to be treated concomitantly with nephrotoxic medications and may have concurrent conditions that can result in decreased renal function. It is recommended that patients are monitored for the development of abnormal renal function. This should include laboratory evaluation of serum creatinine.


Tables 5 to 7 show the number of patients with hypokalemia and clinically significant changes in renal and liver function tests in three randomized, comparative multicenter studies. In study 305, patients with EC were randomized to either oral voriconazole or oral fluconazole. In study 307/602, patients with definite or probable IA were randomized to either voriconazole or amphotericin B therapy. In study 608, patients with candidemia were randomized to either voriconazole or the regimen of amphotericin B followed by fluconazole.


Table 5:Protocol 305 – Patients with Esophageal CandidiasisClinically Significant Laboratory Test AbnormalitiesCriteria*VoriconazoleFluconazolen/N  ( %) n /N   ( %)T. Bilirubin>1.5x ULN8/185 (4.3)7/186 (3.8)A ST>3.0x ULN38/187 (20.3)15/186 (8.1)ALT>3.0x ULN20/187 (10.7)12/186 (6.5)Alkaline  Phosp ha tase>3.0x ULN19/187 (10.2)14/186 (7.5)*Without regard to baseline value


n = number of patients with a clinically significant abnormality while on study therapy


N = total number of patients with at least one observation of the given lab test while on study therapy


AST = Aspartate aminotransferase; ALT= alanine aminotransferase


ULN = upper limit of normal


Table 6:Protocol 307/602 – Primary Treatment of Invasive AspergillosisClinically Significant Laboratory Test AbnormalitiesCriteria*Voriconazole A mphotericin  B**n/N  ( %) n /N   ( %)T. Bilirubin>1.5x ULN35/180 (19.4)46/173 (26.6)A ST>3.0x ULN21/180 (11.7)18/174 (10.3)ALT>3.0x ULN34/180 (18.9)40/173 (23.1)Alkaline Phosphatase>3.0x ULN29/181 (16.0)38/173 (22.0)Creatinine>1.3x ULN39/182 (21.4)102/177 (57.6)Potassium<0.9x  LLN30/181 (16.6)70/178 (39.3)*Without regard to baseline value


**Amphotericin B followed by other licensed antifungal therapy


n = number of patients with a clinically significant abnormality while on study therapy


N = total number of patients with at least one observation of the given lab test while on study therapy


AST = Aspartate aminotransferase; ALT = alanine aminotransferase


ULN = upper limit of normal


LLN = lower limit of normal


Table 7:Protocol 608 – Treatment of CandidemiaClinically Significant Laboratory Test AbnormalitiesCriteria*VoriconazoleAmphotericin B followed by Fluconazolen/N  ( %) n /N   ( %)T. Bilirubin>1.5x ULN50/261 (19.2)31/115 (27.0)A ST>3.0x ULN40/261 (15.3)16/116 (13.8)ALT>3.0x ULN22/261 (8.4)15/116 (12.9)Alkaline Phosphatase>3.0x ULN59/261 (22.6)26/115 (22.6)Creatinine>1.3x ULN39/260 (15.0)32/118 (27.1)Potassium<0.9x  LLN43/258 (16.7)35/118 (29.7)*Without regard to baseline value


n = number of patients with a clinically significant abnormality while on study therapy


N = total number of patients with at least one observation of the given lab test while on study therapy


AST = Aspartate aminotransferase; ALT = alanine aminotransferase


ULN = upper limit of normal


LLN = lower limit of normal


Clinical Trials Experience in Pediatric Patients The safety of Voriconazole for injection was investigated in pediatric patients, including 52 pediatric patients less than 18 years of age who were enrolled in the adult therapeutic studies. 


Hepatic-Related Adverse Reactions in Pediatric Patients The frequency of  hepatic-related adverse reactions in pediatric patients exposed to Voriconazole for injection in therapeutic studies was numerically higher than that of adults (28.6% compared to 24.1%, respectively).The higher frequency of hepatic adverse reactions in the pediatric population was mainly due to an increased frequency of liver enzyme elevations (21.9% in pediatric patients compared to 16.1% in adults), including transaminase elevations (ALT and AST combined) 7.6% in the pediatric patients compared to 5.1% in adults.


Additional pediatric use information is approved for PF PRISM C.V.’s VFEND (voriconazole). However, due to PF PRISM C.V.’s marketing exclusivity rights, this drug product is not labeled with that information.

6.2 Postmarketing Experience In Adult And Pediatric Patients

The following adverse reactions have been identified during post-approval use of voriconazole for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.


AdultsSkeletal: fluorosis and periostitis have been reported during long-term voriconazole therapy 


[see


Warnings and Precautions (5.11)]


.


Eye disorders: prolonged visual adverse reactions, including optic neuritis and papilledema 


[see


Warnings and Precautions (5.4)]


.


Pediatric PatientsThere  have been postmarketing reports of pancreatitis in pediatric patients.

7 Drug Interactions

Voriconazole is metabolized by, and inhibits the activity of, cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively, and there is potential for voriconazole to increase the plasma concentrations of substances metabolized by these CYP450 isoenzymes.


Tables 10 and 11 provide the clinically significant interactions between voriconazole and other medical products.


Table 10:Effect of Other Drugs on Voriconazole Pharmacokinetics


[see


Clinical Pharmacology (12.3)]


Drug/Drug Class (Mechanism of Interaction by the Drug)Voriconazole Plasma Exposure (Cmax  and AUCtafter 200   mg   every   12   hours)Recommendations for Voriconazole Dosage Adjustment/CommentsRifampin* and Rifabutin*


(CYP450 Induction)


Significantly ReducedContraindicatedEfavirenz (400   mg   every   24   hours ) **


(CYP450 Induction)


Efavirenz (300   mg  every 24   hours )** (CYP450 Induction)


Significantly Reduced


Slight Decrease in AUC


τContraindicatedWhen voriconazole is coadministered with efavirenz, voriconazole  oral maintenance dose should be increased


to  400  mg every 12   hours  and efavirenz should be decreased to 300 mg every   24


hours.


Hig h-dose Ritonavir ( 4 00   mg  every   12   hours )**


(CYP450 Induction)


Lo w-dose Ritonavir (100   mg  every 12   hours )** (CYP450 Induction)


Significantly Reduced


Reduced


ContraindicatedCoadministration of voriconazole and lo w-dose ritonavir (100 mg every 12 hours) should be avoi ded, unless an assessment of the benefit/risk to the patient justifies the use of voriconazol e.


Carbamazepine (CYP450 Induction)Not Studied  


In Vivo   or  


In  Vitro, but Likely to Result in Significant Reduction


ContraindicatedLong Acting Barbiturates (CYP4 50  Induction)Not Studied  


In Vivo   or  


In  Vitro, but Likely to Result in Significant Reduction


ContraindicatedPhenytoin* (CYP450 Induction)Significantly ReducedIncrease voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12   hours  (100 mg to 200 mg orally every 12   hours in patients weighing less than 40 kg).St. John’s Wort


(CYP450 inducer; P-gp inducer)


Significantly ReducedContraindicatedOral Contraceptives**


containing ethinyl estradiol a nd norethindrone


(CYP2C19 Inhibition)


IncreasedMonitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives.Fluconazole**  (CYP2C9, CYP2C19 and CYP3A4


Inhibition)


Significantly IncreasedAvoid concomitant  administration   of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 hours after the last dose of fluconazole.Other HIV Protease Inhibitors (CYP3A4 Inhibition)In  Vivo Studies Showed No Significant Effects of


Indinavir on Voriconazole Exposure


In  Vitro  Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)


No dosage adjustment in the voriconazole dosage needed when coadminist ered with indinavir.


Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors.


Other NNRTIs***


(CYP3A4 Inhibition or CYP450 Induction)


In Vitro  Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)


A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs


(De creased Plasma Exposure)


Frequent monitoring for adverse events and toxicity related to voriconazol e.


Careful assessment of voriconazole effectivenes s.


* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjects


** Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects


*** Non-Nucleoside Reverse Transcriptase Inhibitors


Table 11:Effect of Voriconazole on Pharmacokinetics of Other Drugs


[see


Clinical Pharmacology (12.3)]


Drug/Drug Class (Mechanism of Interaction by Voriconazole)Drug Plasma Exposure(C


max  and AUC


t)Recommendations for Drug Dosage Adjustment/CommentsSirolimus* (CYP3A4 Inhibition)Significantly IncreasedContraindicatedRifabutin* (CYP3A4 Inhibition)Significantly IncreasedContraindicatedEfavirenz (400  mg every 24   hours ) **


(CYP3A4 Inhibition)


Efavirenz (300 mg every   24   hours )** (CYP3A4 Inhibition)


Significantly Increased


Slight Increase in AUC


tContraindicatedWhen voriconazole is coadministered with efavirenz, voriconazole  oral maintenance dose should be increased


to  400  mg every   12   hours  and efavirenz should be decreased to 300 mg every   24 hours.


High-dose Ritonavir (400 mg every 12  hours)**(CYP3A4 Inhibition)


Lo w-dose Ritonavir (100   mg   every   12   hours )**


No Significant Effect of Voriconazole on Ritonavir C


max  or  AUC


tSlight Decrease in Ritonavir   C


max  and AUC


tContraindicated  because of significant reduction of voriconazole C m ax   and


AUC t. 


Coadministration of voriconazole and lo w-dose ritonavir  (100  mg every   12 hours) should be avoided (due to the reduction in voriconazole C


max and AUC


t) unless an  assessment of the benefit/risk to the patient justifies the use of voriconazole.


Cisapride, Pimozide, Quinidine (CYP3A4  Inh ibition)Not Studied  


In Vivo   or  


In  Vitro, but Drug Plasma Exposure Likely to be Increased


Contraindicated because of potential for QT prolongation and rare occurrence of


torsade de pointes.Ergot Alkaloids (CYP450 Inhibition)Not Studied  


In Vivo   or  


In Vitro, but Drug Plasma Exposure Likely to be Increased


ContraindicatedCyclosporine* (CYP3A4 Inhibition)AUC


T  Significantly Increased; No Significant Effect on C


maxWhen initiating therapy with voriconazole for injection in patients already receiving cyclosporine, reduce the cyclosporine dose to on e-half of the starting dose and follow with frequent monitoring of cyclosporine blood  levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole for injection is discontinued, cyclosporine concentrations must be freque ntly monitored and the dose increased as necessary.Methadone*** (CYP3A4 Inhibition)IncreasedIncreased plasma concentrations of methadone have been associated with toxicity including QT prolongation.


Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be


needed.


Fentanyl (CYP3A4 Inhibition)IncreasedReduction in the dose of fentanyl and other  lon g-acting opiates metabolized by CYP3A4 should be consi dered  when coadministered with voriconazole for injection. Extended and frequent monitoring for opiat e- associated adverse events may be necessary  


[see


Drug Interactions (7 ) ]


.


Alfentanil (CYP3A4 Inhibition)Significantly IncreasedReduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole for injection. A l onger period for monitoring respiratory and other opiat e-associated adverse events may be necessary  


[ see  


Drug Interactions (7 ) ]


.


Oxycodone (CYP3A4 Inhibition)Significantly IncreasedReduction in the dose of oxycodone and other  lon g-acting  opiates metabolized by CYP3A4  should be considered when coadministered with voriconazole for injection. Extended and frequent monitoring for opiat e-associated adverse events may be necessary  


[see


Drug Interactions (7 ) ]


.


NSAID s**** including. ibuprofen and diclofenac


(CYP2C9 Inhibition)


IncreasedFrequent monitoring for adverse events and toxicity related to NSAIDs.  Dose reduction of NSAIDs may be needed


[see


Drug Interactions (7 ) ]


.


Tacrolimus* (CYP3A4 Inhibition)Significantly IncreasedWhen initiating therapy with voriconazole for injection in patients already receiving tacrolimus, reduce the tacrolimus dose to on e-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole for injection is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.Phenytoin* (CYP2C9 Inhibition)Significantly IncreasedFrequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)**IncreasedMonitoring for adverse events related to oral contraceptives is recommended during coadministration.Warfarin* (CYP2C9 Inhibition)Prothrombin Time Significantly IncreasedMonitor PT or other s uitable ant i-


coagulation tests.  Adjustment of warfarin dosage may be needed.


Omeprazole* (CYP2C19/3A4 Inhibiti o n)Significantly IncreasedWhen initiating therapy with voriconazole for injection in patients already receiving omeprazole doses of 40 mg or greater, reduce t he omeprazole dose by on e-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibi tors.Other HIV Protease Inhibitors (CYP3A4 Inhibition)In  Vivo  Studies Showed No Significant Effects on Indinavir Exposure


In Vitro  Studies Demonstr ated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)


No dosage adjustment for indinavir when coadministered with voriconazole for injection.


Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitor s.


Other NNRTIs***** (CYP3A4 Inhibition)A Voriconazol e-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)Frequent monitoring for adverse events and toxicity related to NNRTI.Benzodiazepines (CYP3A4 Inhibition)In Vitro  Studies Demonstrated Potential for Voriconazole to Inhibit M etabolism (Increased Plasma Exposure)


Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines m e tabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.HM G-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)In Vitro  Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased  Plasma Exposure)


Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)In Vitro  Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)


Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium chan nel blocker dosage may be needed.Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)Not Studied  


In Vivo   or  


In  Vitro, but Drug Plasma Exposure Likely to be Increased


Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustm ent  of  oral hypoglycemic drug dosage may be needed.Vinca Alkaloids (CYP3A4 Inhibition)Not Studied  


In Vivo   or  


In  Vitro, but Drug Plasma Exposure Likely to be Increased


Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids.  Reserve  azole antifungals, including voriconazole, for patients receiving a vinca alkaloid who have no alternative antifungal treatment options.Everolimus (CYP3A4 Inhibition)Not Studied  


In Vivo   or  


In  Vitro, but Drug Plasma Exposure Likely to be Increased


Concomitant administration of voriconazole and everolimus  is not recommende d.* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects


** Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects


*** Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects receiving a methadone maintenance dose (30-100 mg every 24 hours)


**** Non-Steroidal Anti-Inflammatory Drug


***** Non-Nucleoside Reverse Transcriptase Inhibitors

8.1 Pregnancy

Risk SummaryVoriconazole can cause fetal harm when administered to a pregnant woman. There are no available data on the use of voriconazole in pregnant women. In animal reproduction studies, oral voriconazole was associated with fetal malformations in rats and fetal toxicity in rabbits. Cleft palates and hydronephrosis/hydroureter were observed in rat pups exposed to voriconazole during organogenesis at and above 10 mg/kg (0.3 times the RMD of 200 mg every 12 hours based on body surface area comparisons). In rabbits, embryomortality, reduced fetal weight and increased incidence of skeletal variations, cervical ribs and extrasternal ossification sites were observed in pups when pregnant rabbits were orally dosed at 100 mg/kg (6 times the RMD based on body surface area comparisons) during organogenesis. Rats exposed to voriconazole from implantation to weaning experienced increased gestational length and dystocia, which were associated with increased perinatal pup mortality at the 10 mg/kg dose


[see Data]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus


[see


Warnings and Precautions (5.8)]


.


The background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20% respectively.


DataAnimal DataVoriconazole was administered orally to pregnant rats during organogenesis (gestation days 6-17) at 10, 30, and 60 mg/kg/day..Voriconazole was associated with increased incidences in hydroureter and hydronephrosis at 10 mg/kg/day or greater, approximately 0.3 times the recommended human dose (RMD) based on mg/m


2, and cleft palate at 60 mg/kg, approximately 2 times the RMD based on mg/m


2. Reduced ossification of sacral and caudal vertebrae, skull, pubic, and hyoid bone, supernumerary ribs, anomalies of the sternbrae, and dilatation of the ureter/renal pelvis were also observed at doses of 10 mg/kg or greater. There was no evidence of maternal toxicity at any dose.


Voriconazole was administered orally to pregnant rabbits during the period of organogenesis (gestation days 7-19) at 10, 40, and 100 mg/kg/day. Voriconazole was associated with increased post-implantation loss and decreased fetal body weight, in association with maternal toxicity (decreased body weight gain and food consumption) at 100 mg/kg/day (6 times the RMD based on mg/m


2). Fetal skeletal variations (increases in the incidence of cervical rib and extra sternebral ossification sites) were observed at 100 mg/kg/day.


In a peri- and postnatal toxicity study in rats, voriconazole was administered orally to female rats from implantation through the end of lactation at 1, 3, and 10 mg/kg/day. Voriconazole prolonged the duration of gestation and labor and produced dystocia with related increases in maternal mortality and decreases in perinatal survival of F1 pups at 10 mg/kg/day, approximately 0.3 times the RMD.

8.2 Lactation

Risk SummaryNo data are available regarding the presence of voriconazole in human milk, the effects of voriconazole on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for voriconazole and any potential adverse effects on the breastfed child from voriconazole or from the underlying maternal condition.

8.3 Females And Males Of Reproductive Potential

ContraceptionAdvise females of reproductive potential to use effective contraception during treatment with voriconazole for injection. The coadministration of voriconazole with the oral contraceptive, Ortho-Novum


® (35 mcg ethinyl estradiol and 1 mg norethindrone), results in an interaction between these two drugs, but is unlikely to reduce the contraceptive effect. Monitoring for adverse reactions associated with oral contraceptives and voriconazole is recommended


[see 


Drug Interactions (7) and


Clinical Pharmacology (12.3)]


.

8.4 Pediatric Use

The safety and effectiveness of Voriconazole for injection have been established in 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 based on evidence from adequate and well-controlled studies in adult and pediatric patients and additional pediatric pharmacokinetic and safety data. A total of 51 pediatric patients aged 12 to less than 18[N=51] from eight adult therapeutic trials provided safety information for Voriconazole for injection use in the pediatric population [see


Adverse Reactions (6.1),


Clinical Pharmacology(12.3), and


Clinical Studies (14)]. Safety and effectiveness in pediatric patients below the age of 2 years has not been established. Therefore, Voriconazole for injection is not recommended for pediatric patients less than 2 years of age. 


A higher frequency of liver enzyme elevations was observed in the pediatric patients [see


Dosage and Administration (2.5),


Warnings and Precautions (5.1), and


Adverse Reactions (6.1)].


The frequency of phototoxicity reactions is higher in the pediatric population. Squamous cellcarcinoma has been reported in patients who experience photosensitivity reactions. Stringent measures for photo protection are warranted. Sun avoidance and dermatologic follow-up are recommended in pediatric patients experiencing photo aging injuries, such as lentigines or ephelides, even after treatment discontinuation [see


Warnings and Precautions (5.6)]. 


Voriconazole for injection has not been studied in pediatric patients with hepatic or renal impairment [see


Dosage and Administration(2.5,


2.6)]. Hepatic function and serum creatinine levels should be closely monitored in pediatric patients [see 


Dosage and Administration (2.6) and


Warnings and Precautions (5.1,


5.9)]. 


Additional pediatric use information is approved for PF PRISM C.V.’s VFEND (voriconazole). However, due to PF PRISM C.V.’s marketing exclusivity rights, this drug product is not labeled with that information.

8.5 Geriatric Use

In multiple dose therapeutic trials of voriconazole, 9.2% of patients were ≥65 years of age and 1.8% of patients were ≥75 years of age. In a study in healthy subjects, the systemic exposure (AUC) and peak plasma concentrations (Cmax) were increased in elderly males compared to young males. Pharmacokinetic data obtained from 552 patients from 10 voriconazole therapeutic trials showed that voriconazole plasma concentrations in the elderly patients were approximately 80% to 90% higher than those in younger patients after either IV or oral administration. However, the overall safety profile of the elderly patients was similar to that of the young so no dosage adjustment is recommended


[see


Clinical Pharmacology (12.3)].

10 Overdosage

In clinical trials, there were three cases of accidental overdose. All occurred in pediatric patients who received up to five times the recommended intravenous dose of voriconazole. A single adverse event of photophobia of 10 minutes duration was reported.


There is no known antidote to voriconazole.


Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. In an overdose, hemodialysis may assist in the removal of voriconazole and SBECD from the body.

11 Description

Voriconazole, an azole antifungal agent is available as a lyophilized powder for solution for intravenous infusion. The structural formula is:voriconazole-strucVoriconazole is designated chemically as (2R,3S)-2-(2, 4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2- butanol with an empirical formula of C


16H


14F


3N


5O and a molecular weight of 349.3.


Voriconazole drug substance is a white to light-colored powder.


Voriconazole for injection I.V. is a white lyophilized powder containing nominally 200 mg voriconazole and 3200 mg sulfobutyl ether beta-cyclodextrin sodium in a 30 mL Type I clear glass vial.


Voriconazole for injection I.V. is intended for administration by intravenous infusion. It is a single-dose, unpreserved product. Vials containing 200 mg lyophilized voriconazole are intended for reconstitution with Water for Injection to produce a solution containing 10 mg/mL voriconazole for injection and 160 mg/mL of sulfobutyl ether beta-cyclodextrin sodium. The resultant solution is further diluted prior to administration as an intravenous infusion


[see


Dosage and Administration (2)]


.

12.1 Mechanism Of Action

Voriconazole is an antifungal drug


[see


Microbiology (12.4)]


.

12.2 Pharmacodynamics

Exposure-Response Relationship For Efficacy and SafetyIn 10 clinical trials (N=1121), the median values for the average and maximum voriconazole plasma concentrations in individual patients across these studies was 2.51 µg/mL (inter-quartile range 1.21 to 4.44 µg/mL) and 3.79 µg/mL (inter-quartile range 2.06 to 6.31 µg/mL), respectively. A pharmacokinetic-pharmacodynamic analysis of patient data from 6 of these 10 clinical trials (N=280) could not detect a positive association between mean, maximum or minimum plasma voriconazole concentration and efficacy.


However, pharmacokinetic/pharmacodynamic analyses of the data from all 10 clinical trials identified positive associations between plasma voriconazole concentrations and rate of both liver function test abnormalities and visual disturbances [see


Adverse Reactions (6)].


Cardiac ElectrophysiologyA placebo-controlled, randomized, crossover study to evaluate the effect on the QT interval of healthy male and female subjects was conducted with three single oral doses of voriconazole and ketoconazole. Serial ECGs and plasma samples were obtained at specified intervals over a 24-hour post dose observation period. The placebo-adjusted mean maximum increases in QTc from baseline after 800, 1200, and 1600 mg of voriconazole and after ketoconazole 800 mg were all <10 msec. Females exhibited a greater increase in QTc than males, although all mean changes were <10 msec. Age was not found to affect the magnitude of increase in QTc. No subject in any group had an increase in QTc of ≥60 msec from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec. However, the QT effect of voriconazole combined with drugs known to prolong the QT interval is unknown


[see 


Contraindications (4) and


Drug Interactions (7)]


.

12.3 Pharmacokinetics

The pharmacokinetics of voriconazole have been characterized in healthy subjects, special populations and patients.


The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. The interindividual variability of voriconazole pharmacokinetics is high. Greater than proportional increase in exposure is observed with increasing dose. It is estimated that, on average, increasing the oral dose from 200 mg every 12 hours to 300 mg every 12 hours leads to an approximately 2.5-fold increase in exposure (AUC); similarly, increasing the intravenous dose from 3 mg/kg every 12 hours to 4 mg/kg every 12 hours produces an approximately 2.5-fold increase in exposure (Table 12).


Table 12:Geometric Mean (%CV) Plasma Voriconazole Pharmacokinetic Parameters in Adults Receiving Different Dosing Regimens


6   m g/ kg  IV (loading dose) 3 mg/kg IV  every   12 hours4   m g/ kg IV  every   12 hours 400   mg Oral(loading dose) 200   mg Oral every   12 hours 300   mg Oral every   12 hoursN


35 


23 


40 


17 


48 


16 


AUC12   (μ g∙h/mL)


13.9  (32)


13.7  (53)


33 .9   ( 54)


9.31  (38)


12 .4   ( 78)


34.0  (53)


C m ax  (μg/mL)


3.13  (20)


3.03  (25)


4.77   ( 36)


2.30  (19)


2. 31   ( 48)


4.74  (35)


C min  (μg/mL)


--


0.46  (97)


1.73 (74)


--


0.46 (120)


1.63  (79)


Note: Parameters were estimated based on non-compartmental analysis from 5 pharmacokinetic studies.


AUC12 = area under the curve over 12 hour dosing interval, Cmax = maximum plasma concentration, Cmin = minimum plasma concentration. CV = coefficient of variation


When the recommended intravenous loading dose regimen is administered to healthy subjects, plasma concentrations close to steady state are achieved within the first 24 hours of dosing (e.g., 6 mg/kg IV every 12 hours on day 1 followed by 3 mg/kg IV every 12 hours). Without the loading dose, accumulation occurs during twice daily multiple dosing with steady state plasma voriconazole concentrations being achieved by day 6 in the majority of subjects.


AbsorptionThe pharmacokinetic properties of voriconazole are similar following administration by the intravenous and oral routes. Based on a population pharmacokinetic analysis of pooled data in healthy subjects (N=207), the oral bioavailability of voriconazole is estimated to be 96% (CV 13%). Bioequivalence was established between the 200 mg tablet and the 40 mg/mL oral suspension when administered as a 400 mg every 12 hours loading dose followed by a 200 mg every 12 hours maintenance dose.


Maximum plasma concentrations (Cmax) are achieved 1-2 hours after dosing. When multiple doses of voriconazole are administered with high-fat meals, the mean Cmax and AUC are reduced by 34% and 24%, respectively when administered as a tablet and by 58% and 37% respectively when administered as the oral suspension


[see


Dosage and Administration (2)]


.


In healthy subjects, the absorption of voriconazole is not affected by coadministration of oral ranitidine, cimetidine, or omeprazole, drugs that are known to increase gastric pH.


DistributionThe volume of distribution at steady state for voriconazole is estimated to be 4.6 L/kg, suggesting extensive distribution into tissues. Plasma protein binding is estimated to be 58% and was shown to be independent of plasma concentrations achieved following single and multiple oral doses of 200 mg or 300 mg (approximate range: 0.9-15 g/mL). Varying degrees of hepatic and renal impairment do not affect the protein binding of voriconazole.


EliminationMetabolismIn vitro studies showed that voriconazole is metabolized by the human hepatic cytochrome P450 enzymes, CYP2C19, CYP2C9 and CYP3A4


[see


Drug Interactions (7)]


.


In vivo studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism


[see


Clinical Pharmacology (12.5)]


.


The major metabolite of voriconazole is the N-oxide, which accounts for 72% of the circulating radiolabelled metabolites in plasma. Since this metabolite has minimal antifungal activity, it does not contribute to the overall efficacy of voriconazole.


ExcretionVoriconazole is eliminated via hepatic metabolism with less than 2% of the dose excreted unchanged in the urine. After administration of a single radiolabelled dose of either oral or IV voriconazole, preceded by multiple oral or IV dosing, approximately 80% to 83% of the radioactivity is recovered in the urine. The majority (>94%) of the total radioactivity is excreted in the first 96 hours after both oral and intravenous dosing.


As a result of non-linear pharmacokinetics, the terminal half-life of voriconazole is dose dependent and therefore not useful in predicting the accumulation or elimination of voriconazole.


Specific PopulationsMale and Female PatientsIn a multiple oral dose study, the mean Cmax and AUCt for healthy young females were 83% and 113% higher, respectively, than in healthy young males (18-45 years), after tablet dosing. In the same study, no significant differences in the mean Cmax and AUC were observed between healthy elderly males and healthy elderly females (>65 years). In a similar study, after dosing with the oral suspension, the mean AUC for healthy young females was 45% higher than in healthy young males whereas the mean Cmax was comparable between genders. The steady state trough voriconazole concentrations (Cmin) seen in females were 100% and 91% higher than in males receiving the tablet and the oral suspension, respectively.


In the clinical program, no dosage adjustment was made on the basis of gender. The safety profile and plasma concentrations observed in male and female subjects were similar. Therefore, no dosage adjustment based on gender is necessary.


Geriatric PatientsIn an oral multiple dose study the mean Cmax and AUC in healthy elderly males (65 years) were 61% and 86% higher, respectively, than in young males (18-45 years). No significant differences in the mean Cmax and AUC were observed between healthy elderly females (65 years) and healthy young females (18-45 years).


In the clinical program, no dosage adjustment was made on the basis of age. An analysis of pharmacokinetic data obtained from 552 patients from 10 voriconazole clinical trials showed that the median voriconazole plasma concentrations in the elderly patients (>65 years) were approximately 80% to 90% higher than those in the younger patients (65 years) after either IV or oral administration. However, the safety profile of voriconazole in young and elderly subjects was similar and, therefore, no dosage adjustment is necessary for the elderly


[see


Use in Special Populations (8.5)]


.


Pediatric PatientsVoriconazole exposures in the majority of pediatric patients aged 12 to less than 17 years were comparable to those in adults receiving the same dosing regimens. However, lower voriconazole exposure was observed in some pediatric patients aged 12 to less than 17 years with low body weight compared to adults [see


Dosage and Administration (2.4)]. 


Additional pediatric use information is approved for PF PRISM C.V.’s VFEND (voriconazole). However, due to PF PRISM C.V.’s marketing exclusivity rights, this drug product is not labeled with that information. Patients with Hepatic ImpairmentAfter a single oral dose (200 mg) of voriconazole in 8 patients with mild (Child-Pugh Class A) and 4 patients with moderate (Child- Pugh Class B) hepatic impairment, the mean systemic exposure (AUC) was 3.2-fold higher than in age and weight matched controls with normal hepatic function. There was no difference in mean peak plasma concentrations (C


max) between the groups. When only the patients with mild (Child-Pugh Class A) hepatic impairment were compared to controls, there was still a 2.3-fold increase in the mean AUC in the group with hepatic impairment compared to controls.


In an oral multiple dose study, AUCt was similar in 6 subjects with moderate hepatic impairment (Child-Pugh Class B) given a lower maintenance dose of 100 mg twice daily compared to 6 subjects with normal hepatic function given the standard 200 mg twice daily maintenance dose. The mean peak plasma concentrations (Cmax) were 20% lower in the hepatically impaired group. No pharmacokinetic data are available for patients with severe hepatic cirrhosis (Child-Pugh Class C) [see


Dosage and Administration (2.5)].


Patients with Renal ImpairmentIn a single oral dose (200 mg) study in 24 subjects with normal renal function and mild to severe renal impairment, systemic exposure (AUC) and peak plasma concentration (C


max) of voriconazole were not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment.


In a multiple dose study of IV voriconazole (6 mg/kg IV loading dose x 2, then 3 mg/kg IV x 5.5 days) in 7 patients with moderate renal dysfunction (creatinine clearance 30-50 mL/min), the systemic exposure (AUC) and peak plasma concentrations (Cmax) were not significantly different from those in 6 subjects with normal renal function.


However, in patients with moderate renal dysfunction (creatinine clearance 30-50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. The mean systemic exposure (AUC) and peak plasma concentrations (C


max) of SBECD were increased 4-fold and almost 50%, respectively, in the moderately impaired group compared to the normal control group.


A pharmacokinetic study in subjects with renal failure undergoing hemodialysis showed that voriconazole is dialyzed 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


[see


Dosage and Administration (2.6)]


.


Patients at Risk of Aspergillosis


The observed voriconazole pharmacokinetics in patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or hematopoietic tissue) were similar to healthy subjects.


Drug Interaction StudiesEffects of Other Drugs on VoriconazoleVoriconazole is metabolized by the human hepatic cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. Results of in vitro metabolism studies indicate that the affinity of voriconazole is highest for CYP2C19, followed by CYP2C9, and is appreciably lower for CYP3A4. Inhibitors or inducers of these three enzymes may increase or decrease voriconazole systemic exposure (plasma concentrations), respectively.


The systemic exposure to voriconazole is significantly reduced or is expected to be reduced by the concomitant administration of the following agents and their use is contraindicated:Rifampin (potent CYP450 inducer)–Rifampin (600 mg once daily) decreased the steady state Cmax and AUCt of voriconazole (200 mg every 12 hours x 7 days) by an average of 93% and 96%, respectively, in healthy subjects. Doubling the dose of voriconazole to 400 mg every 12 hours does not restore adequate exposure to voriconazole during coadministration with rifampin.


Coadministration of voriconazole and rifampin is contraindicated[see 


Contraindications (4) and


Warnings and Precautions (5.12)]


.


Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate)–The effect of the coadministration of voriconazole and ritonavir (400 mg and 100 mg) was investigated in two separate studies. High-dose ritonavir (400 mg every 12 hours for 9 days) decreased the steady state Cmax and AUCt of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) by an average of 66% and 82%, respectively, in healthy subjects. Low-dose ritonavir (100 mg every 12 hours for 9 days) decreased the steady state Cmax and AUC of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) by an average of 24% and 39%, respectively, in healthy subjects. Although repeat oral administration of voriconazole did not have a significant effect on steady state Cmax and AUCt of high-dose ritonavir in healthy subjects, steady state Cmax and AUCt of low- dose ritonavir decreased slightly by 24% and 14% respectively, when administered concomitantly with oral voriconazole in healthy subjects.


Coadministration of voriconazole and high-dose ritonavir (400 mg every 12 hours) is contraindicated. Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole[see


Contraindications (4)and


Warnings and Precautions (5.12)]


.


St. John’s Wort (CYP450 inducer; P-gp inducer)–In an independent published study in healthy volunteers who were given multiple oral doses of St. John’s Wort (300 mg LI 160 extract three times daily for 15 days) followed by a single 400 mg oral dose of voriconazole, a 59% decrease in mean voriconazole AUC0-∞ was observed. In contrast, coadministration of single oral doses of St. John’s Wort and voriconazole had no appreciable effect on voriconazole AUC0-∞. Because long-term use of St. John’s Wort could lead to reduced voriconazole exposure,


concomitant use of voriconazole with St. John’s Wort is contraindicated[see


Contraindications (4)]


.


Carbamazepine and long-acting barbiturates (potent CYP450 inducers)–Although not studied in vitro or in vivo, carbamazepine and long-acting barbiturates (e.g., phenobarbital, mephobarbital) are likely to significantly decrease plasma voriconazole concentrations.


Coadministration of voriconazole with carbamazepine or long-acting barbiturates is contraindicated[see 


Contraindications (4) and


Warnings and Precautions (5.12)]


.


Significant drug interactions that may require voriconazole dosage adjustment, or frequent monitoring of voriconazole-related adverse events/toxicity:Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Concurrent administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) to 6 healthy male subjects resulted in an increase in Cmax and AUCt of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow-on clinical study involving 8 healthy male subjects, reduced dosing and/or frequency of voriconazole and fluconazole did not eliminate or diminish this effect. Concomitant administration of voriconazole and fluconazole at any dose is not recommended. Close monitoring for adverse events related to voriconazole is recommended if voriconazole is used sequentially after fluconazole, especially within 24 hours of the last dose of fluconazole


[see


Warnings and Precautions (5.12)]


.


Minor or no significant pharmacokinetic interactions that do not require dosage adjustment:Cimetidine (non-specific CYP450 inhibitor and increases gastric pH)–Cimetidine (400 mg every 12 hours x 8 days) increased voriconazole steady state C


max and AUCt by an average of 18% (90% CI: 6%, 32%) and 23% (90% CI: 13%, 33%), respectively, following oral doses of 200 mg every 12 hours x 7 days to healthy subjects.


Ranitidine (increases gastric pH)–Ranitidine (150 mg every 12 hours) had no significant effect on voriconazole C


max and AUCt following oral doses of 200 mg every 12 hours x 7 days to healthy subjects.


Macrolide antibiotics–Coadministration of


erythromycin (CYP3A4 inhibitor; 1g every 12 hours for 7 days) or


azithromycin (500 mg every 24 hours for 3 days) with voriconazole 200 mg every 12 hours for 14 days had no significant effect on voriconazole steady state Cmax and AUC in healthy subjects. The effects of voriconazole on the pharmacokinetics of either erythromycin or azithromycin are not known.


Effects of Voriconazole on Other DrugsIn vitro studies with human hepatic microsomes show that voriconazole inhibits the metabolic activity of the cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. In these studies, the inhibition potency of voriconazole for CYP3A4 metabolic activity was significantly less than that of two other azoles, ketoconazole and itraconazole. In vitro studies also show that the major metabolite of voriconazole, voriconazole N-oxide, inhibits the metabolic activity of CYP2C9 and CYP3A4 to a greater extent than that of CYP2C19. Therefore, there is potential for voriconazole and its major metabolite to increase the systemic exposure (plasma concentrations) of other drugs metabolized by these CYP450 enzymes.


The systemic exposure of the following drugs is significantly increased or is expected to be significantly increased by coadministration of voriconazole and their use is contraindicated:Sirolimus (CYP3A4 substrate)–Repeat dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) increased the Cmax and AUC of sirolimus (2 mg single dose) an average of 7-fold (90% CI: 5.7, 7.5) and 11- fold (90% CI: 9.9, 12.6), respectively, in healthy male subjects.


Coadministration of voriconazole and sirolimus is contraindicated[see


Contraindications (4)and


Warnings and Precautions (5.12)]


.


Cisapride, pimozide and quinidine (CYP3A4 substrates)–Although not studied in vitro or in vivo, concomitant administration of voriconazole with cisapride, pimozide or quinidine may result in inhibition of the metabolism of these drugs. Increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of torsade de pointes.


Coadministration of voriconazole, cisapride, pimozide and quinidine is contraindicated[see 


Contraindications (4) and


Warnings and Precautions (5.12)].


Ergot alkaloids–Although not studied in vitro or in vivo, voriconazole may increase the plasma concentration of ergot alkaloids (ergotamine and dihydroergotamine) and lead to ergotism.


Coadministration of voriconazole with ergot alkaloids is contraindicated[see


Contraindications (4)and


Warnings and Precautions (5.12)]


.


Everolimus (CYP3A4 substrate, P-gp substrate)–Although not studied in vitro or in vivo, voriconazole may increase plasma concentrations of everolimus, which could potentially lead to exacerbation of everolimus toxicity. Currently there are insufficient data to allow dosing recommendations in this situation. Therefore, co-administration of voriconazole with everolimus is not recommended


[see


Drug Interactions (7)].


Coadministration of voriconazole with the following agents results in increased exposure or is expected to result in increased exposure to these drugs. Therefore, careful monitoring and/or dosage adjustment of these drugs is needed:Alfentanil (CYP3A4 substrate)–Coadministration of multiple doses of oral voriconazole (400 mg every 12 hours on day 1, 200 mg every 12 hours on day 2) with a single 20 mcg/kg intravenous dose of alfentanil with concomitant naloxone resulted in a 6-fold increase in mean alfentanil AUC0-∞ and a 4-fold prolongation of mean alfentanil elimination half-life, compared to when alfentanil was given alone. An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting during co-administration of voriconazole and alfentanil was also observed. Reduction in the dose of alfentanil or other opiates that are also metabolized by CYP3A4 (e.g., sufentanil), and extended close monitoring of patients for respiratory and other opiate-associated adverse events, may be necessary when any of these opiates is coadministered with voriconazole


[see


Warnings and Precautions (5.12)]


.


Fentanyl (CYP3A4 substrate): In an independent published study, concomitant use of voriconazole (400 mg every 12 hours on Day 1, then 200 mg every 12 hours on Day 2) with a single intravenous dose of fentanyl (5 µg/kg) resulted in an increase in the mean AUC0-∞ of fentanyl by 1.4-fold (range 0.81- to 2.04-fold). When voriconazole is co-administered with fentanyl IV, oral or transdermal dosage forms, extended and frequent monitoring of patients for respiratory depression and other fentanyl-associated adverse events is recommended, and fentanyl dosage should be reduced if warranted


[see


Warnings and Precautions (5.12)]


.


Oxycodone (CYP3A4 substrate): In an independent published study, coadministration of multiple doses of oral voriconazole (400 mg every 12 hours, on Day 1 followed by five doses of 200 mg every 12 hours on Days 2 to 4) with a single 10 mg oral dose of oxycodone on Day 3 resulted in an increase in the mean Cmax and AUC0–∞ of oxycodone by 1.7-fold (range 1.4- to 2.2-fold) and 3.6- fold (range 2.7- to 5.6-fold), respectively. The mean elimination half-life of oxycodone was also increased by 2.0-fold (range 1.4- to 2.5-fold). Voriconazole also increased the visual effects (heterophoria and miosis) of oxycodone. A reduction in oxycodone dosage may be needed during voriconazole treatment to avoid opioid related adverse effects. Extended and frequent monitoring for adverse effects associated with oxycodone and other long-acting opiates metabolized by CYP3A4 is recommended


[see


Warnings and Precautions (5.12)]


.


Cyclosporine (CYP3A4 substrate)–In stable renal transplant recipients receiving chronic cyclosporine therapy, concomitant administration of oral voriconazole (200 mg every 12 hours for 8 days) increased cyclosporine Cmax and AUC an average of 1.1 times (90% CI: 0.9, 1.41) and 1.7 times (90% CI: 1.5, 2.0), respectively, as compared to when cyclosporine was administered without voriconazole. When initiating therapy with voriconazole in patients already receiving cyclosporine, it is recommended that the cyclosporine dose be reduced to one-half of the original dose and followed with frequent monitoring of the cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity.


When voriconazole is discontinued,  cyclosporine  levels should  be   frequently monitored and the dose increased as necessary[see


Warnings and Precautions (5.12)]


.


Methadone (CYP3A4, CYP2C19, CYP2C9 substrate)–Repeat dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days) increased the Cmax and AUC of pharmacologically active Rmethadone by 31% (90% CI: 22%, 40%) and 47% (90% CI: 38%, 57%), respectively, in subjects receiving a methadone maintenance dose (30-100 mg every 24 hours). The Cmax and AUC of (S)-methadone increased by 65% (90% CI: 53%, 79%) and 103% (90% CI: 85%, 124%), respectively. Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed


[see


Warnings and Precautions (5.12)]


.


Tacrolimus (CYP3A4 substrate)–Repeat oral dose administration of voriconazole (400 mg every 12 hours x 1 day, then 200 mg every 12 hours x 6 days) increased tacrolimus (0.1 mg/kg single dose) Cmax and AUC in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively. When initiating therapy with voriconazole in patients already receiving tacrolimus, it is recommended that the tacrolimus dose be reduced to one-third of the original dose and followed with frequent monitoring of the tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus levels should be carefully monitored and the dose increased as necessary


[see


Warnings and Precautions (5.12)]


.


Warfarin (CYP2C9 substrate)–Coadministration of voriconazole (300 mg every 12 hours x 12 days) with warfarin (30 mg single dose) significantly increased maximum prothrombin time by approximately 2 times that of placebo in healthy subjects. Close monitoring of prothrombin time or other suitable anticoagulation tests is recommended if warfarin and voriconazole are coadministered and the warfarin dose adjusted accordingly


[see


Warnings and Precautions (5.12)]


.


Oral Coumarin Anticoagulants (CYP2C9, CYP3A4 substrates)–Although not studied in vitro or in vivo, voriconazole may increase the plasma concentrations of coumarin anticoagulants and therefore may cause an increase in prothrombin time. If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anticoagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly


[see Warnings and Precautions (5.12)].


Statins (CYP3A4 substrates)–Although not studied clinically, voriconazole has been shown to inhibit lovastatin metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase the plasma concentrations of statins that are metabolized by CYP3A4. It is recommended that dose adjustment of the statin be considered during coadministration. Increased statin concentrations in plasma have been associated with rhabdomyolysis


[see


Warnings and Precautions (5.12)]


.


Benzodiazepines (CYP3A4 substrates)–Although not studied clinically, voriconazole has been shown to inhibit midazolam metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase the plasma concentrations of benzodiazepines that are metabolized by CYP3A4 (e.g., midazolam, triazolam, and alprazolam) and lead to a prolonged sedative effect. It is recommended that dose adjustment of the benzodiazepine be considered during coadministration


[see


Warnings and Precautions (5.12)]


.


Calcium Channel Blockers (CYP3A4 substrates)–Although not studied clinically, voriconazole has been shown to inhibit felodipine metabolism in vitro (human liver microsomes). Therefore, voriconazole may increase the plasma concentrations of calcium channel blockers that are metabolized by CYP3A4. Frequent monitoring for adverse events and toxicity related to calcium channel blockers is recommended during coadministration. Dose adjustment of the calcium channel blocker may be needed


[see


Warnings and Precautions (5.12)]


.


Sulfonylureas (CYP2C9 substrates)–Although not studied in vitro or in vivo, voriconazole may increase plasma concentrations of sulfonylureas (e.g., tolbutamide, glipizide, and glyburide) and therefore cause hypoglycemia. Frequent monitoring of blood glucose and appropriate adjustment (i.e., reduction) of the sulfonylurea dosage is recommended during coadministration


[see


Warnings and Precautions (5.12)]


.


Vinca Alkaloids (CYP3A4 substrates)–Although not studied in vitro or in vivo, voriconazole may increase the plasma concentrations of the vinca alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity. Therefore, reserve azole antifungals, including voriconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options


[see


Warnings and Precautions (5.12)]


.


Non-Steroidal Anti-Inflammatory Drugs (NSAIDs; CYP2C9 substrates): In two independent published studies, single doses of ibuprofen (400 mg) and diclofenac (50 mg) were coadministered with the last dose of voriconazole (400 mg every 12 hours on Day 1, followed by 200 mg every 12 hours on Day 2). Voriconazole increased the mean Cmax and AUC of the pharmacologically active isomer, S (+)-ibuprofen by 20% and 100%, respectively. Voriconazole increased the mean Cmax and AUC of diclofenac by 114% and 78%, respectively.


A reduction in ibuprofen and diclofenac dosage may be needed during concomitant administration with voriconazole. Patients receiving voriconazole concomitantly with other NSAIDs (e.g., celecoxib, naproxen, lornoxicam, meloxicam) that are also metabolized by CYP2C9 should be carefully monitored for NSAID-related adverse events and toxicity, and dosage reduction should be made if warranted


[see


Warnings and Precautions (5.12)]


.


No significant pharmacokinetic interactions were observed when voriconazole was coadministered with the following agents. Therefore, no dosage adjustment for these agents is recommended:Prednisolone (CYP3A4 substrate)–Voriconazole (200 mg every 12 hours x 30 days) increased Cmax and AUC of prednisolone (60 mg single dose) by an average of 11% and 34%, respectively, in healthy subjects.


Digoxin (P-glycoprotein mediated transport)–Voriconazole (200 mg every 12 hours x 12 days) had no significant effect on steady state Cmax and AUC of digoxin (0.25 mg once daily for 10 days) in healthy subjects.


Mycophenolic acid (UDP-glucuronyl transferase substrate)–Voriconazole (200 mg every 12 hours x 5 days) had no significant effect on the Cmax and AUCt of mycophenolic acid and its major metabolite, mycophenolic acid glucuronide after administration of a 1 gram single oral dose of mycophenolate mofetil.


Two-Way Interactions Concomitant use of the following agents with voriconazole is contraindicated:Rifabutin (potent CYP450 inducer)–Rifabutin (300 mg once daily) decreased the Cmax and AUC of voriconazole at 200 mg twice daily by an average of 67% (90% CI: 58%, 73%) and 79% (90% CI: 71%, 84%), respectively, in healthy subjects. During coadministration with rifabutin (300 mg once daily), the steady state Cmax and AUCt of voriconazole following an increased dose of 400 mg twice daily were on average approximately 2 times higher, compared with voriconazole alone at 200 mg twice daily.


Coadministration of voriconazole at 400 mg twice daily with rifabutin 300 mg twice daily increased the Cmax and AUCt of rifabutin by an average of 3-times (90% CI: 2.2, 4.0) and 4 times (90% CI: 3.5, 5.4), respectively, compared to rifabutin given alone.


Coadministration of voriconazole and rifabutin is contraindicated[see


Contraindications (4)]


.


Significant drug interactions that may require dosage adjustment, frequent monitoring of drug levels and/or frequent monitoring of drug-related adverse events/toxicity:Efavirenz, a non-nucleoside reverse transcriptase inhibitor (CYP450 inducer; CYP3A4 inhibitor and substrate)–Standard doses of voriconazole and efavirenz (400 mg every 24 hours or higher) must not be coadministered [see


Drug Interactions (7)]. Steady state efavirenz (400 mg PO every 24 hours) decreased the steady state Cmax and AUC of voriconazole (400 mg PO every 12 hours for 1 day, then 200 mg PO every 12 hours for 8 days) by an average of 61% and 77%, respectively, in healthy male subjects. Voriconazole at steady state (400 mg PO every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) increased the steady state Cmax and AUC of efavirenz (400 mg PO every 24 hours for 9 days) by an average of 38% and 44%, respectively, in healthy subjects.


The pharmacokinetics of adjusted doses of voriconazole and efavirenz were studied in healthy male subjects following administration of voriconazole (400 mg PO every 12 hours on Days 2 to 7) with efavirenz (300 mg PO every 24 hours on Days 1-7), relative to steady state administration of voriconazole (400 mg for 1 day, then 200 mg PO every 12 hours for 2 days) or efavirenz (600 mg every 24 hours for 9 days). Coadministration of voriconazole 400 mg every 12 hours with efavirenz 300 mg every 24 hours, decreased voriconazole AUCt by 7% (90% CI: -23%, 13%) and increased Cmax by 23% (90% CI: -1%, 53%); efavirenz AUCt was increased by 17% (90% CI: 6%, 29%) and Cmax was equivalent.


Coadministration of standard doses of voriconazole and efavirenz (400 mg every 24 hours or higher) is contraindicated. Voriconazole may be coadministered with efavirenz if the voriconazole maintenance dose is increased to 400 mg every 12 hours and the efavirenz dose is decreased to 300 mg every 24 hours. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored


[see


Dosage and Administration (2.7),


Contraindications (4), and


Drug Interactions (7)]


.


Phenytoin (CYP2C9 substrate and potent CYP450 inducer)–Repeat dose administration of phenytoin (300 mg once daily) decreased the steady state Cmax and AUCt of orally administered voriconazole (200 mg every 12 hours x 14 days) by an average of 50% and 70%, respectively, in healthy subjects. Administration of a higher voriconazole dose (400 mg every 12 hours x 7 days) with phenytoin (300 mg once daily) resulted in comparable steady state voriconazole Cmax and AUC estimates as compared to when voriconazole was given at 200 mg every 12 hours without phenytoin.


Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased from 4 mg/kg to 5 mg/kg intravenously every 12 hours or from 200 mg to 400 mg orally, every 12 hours (100 mg to 200 mg orally, every 12 hours in patients less than 40 kg)


[see 


Dosage and Administration (2.7) and


Drug Interactions (7)].


Repeat dose administration of voriconazole (400 mg every 12 hours x 10 days) increased the steady state Cmax and AUCt of phenytoin (300 mg once daily) by an average of 70% and 80%, respectively, in healthy subjects. The increase in phenytoin Cmax and AUC when coadministered with voriconazole may be expected to be as high as 2 times the Cmax and AUC estimates when phenytoin is given without voriconazole. Therefore, frequent monitoring of plasma phenytoin concentrations and phenytoin-related adverse effects is recommended when phenytoin is coadministered with voriconazole


[see


Warnings and Precautions (5.12)]


.


Omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate)–Coadministration of omeprazole (40 mg once daily x 10 days) with oral voriconazole (400 mg every 12 hours x 1 day, then 200 mg every 12 hours x 9 days) increased the steady state Cmax and AUCt of voriconazole by an average of 15% (90% CI: 5%, 25%) and 40% (90% CI: 29%, 55%), respectively, in healthy subjects. No dosage adjustment of voriconazole is recommended.


Coadministration of voriconazole (400 mg every 12 hours x 1 day, then 200 mg x 6 days) with omeprazole (40 mg once daily x 7 days) to healthy subjects significantly increased the steady state Cmax and AUCt of omeprazole an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole is given without voriconazole. When initiating voriconazole in patients already receiving omeprazole doses of 40 mg or greater, it is recommended that the omeprazole dose be reduced by one-half


[see


Warnings and Precautions (5.12)]


.


The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of these drugs.


Oral Contraceptives (CYP3A4 substrate; CYP2C19 inhibitor)–Coadministration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 3 days) and oral contraceptive (Ortho-Novum1/35® consisting of 35 mcg ethinyl estradiol and 1 mg norethindrone, every 24 hours) to healthy female subjects at steady state increased the Cmax and AUCτ of ethinyl estradiol by an average of 36% (90% CI: 28%, 45%) and 61% (90% CI: 50%, 72%), respectively, and that of norethindrone by 15% (90% CI: 3%, 28%) and 53% (90% CI: 44%, 63%), respectively in healthy subjects. Voriconazole Cmax and AUCτ increased by an average of 14% (90% CI: 3%, 27%) and 46% (90% CI: 32%, 61%), respectively. Monitoring for adverse events related to oral contraceptives, in addition to those for voriconazole, is recommended during coadministration [see


Warnings and Precautions (5.12)].


No significant pharmacokinetic interaction was seen and no dosage adjustment of these drugs is recommended:Indinavir (CYP3A4 inhibitor and substrate)–Repeat dose administration of indinavir (800 mg TID for 10 days) had no significant effect on voriconazole Cmax and AUC following repeat dose administration (200 mg every 12 hours for 17 days) in healthy subjects.


Repeat dose administration of voriconazole (200 mg every 12 hours for 7 days) did not have a significant effect on steady state Cmax and AUCt of indinavir following repeat dose administration (800 mg TID for 7 days) in healthy subjects.


Other Two-Way Interactions Expected to be Significant Based on In Vitro and In Vivo Findings:Other HIV Protease Inhibitors (CYP3A4 substrates and inhibitors)–In vitro studies (human liver microsomes) suggest that voriconazole may inhibit the metabolism of HIV protease inhibitors (e.g., saquinavir, amprenavir and nelfinavir). In vitro studies (human liver microsomes) also show that the metabolism of voriconazole may be inhibited by HIV protease inhibitors (e.g., saquinavir and amprenavir). Patients should be frequently monitored for drug toxicity during the coadministration of voriconazole and HIV protease inhibitors


[see


Warnings and Precautions (5.12)]


.


Other Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (CYP3A4 substrates, inhibitors or CYP450 inducers)–In vitro studies (human liver microsomes) show that the metabolism of voriconazole may be inhibited by a NNRTI (e.g., delavirdine). The findings of a clinical voriconazole-efavirenz drug interaction study in healthy male subjects suggest that the metabolism of voriconazole may be induced by a NNRTI. This in vivo study also showed that voriconazole may inhibit the metabolism of a NNRTI [see 


Drug Interactions (7) and


Warnings and Precautions (5.1)]. Patients should be frequently monitored for drug toxicity during the coadministration of voriconazole and other NNRTIs (e.g., nevirapine and delavirdine) [see


Warnings and Precautions (5.12)]. Dose adjustments are required when voriconazole is co-administered with efavirenz


[see 


Drug Interactions (7) and


Warnings and Precautions (5.12)]


.

12.4 Microbiology

Mechanism of ActionVoriconazole  is  an  azole  antifungal   dru g.  The  primary  mode  of  action  of  voriconazole  is  the  inhibition  of  fungal  cytochrome   P - 450- mediated  14  alpha -lanosterol   demethylation,  an  essential  step  in  fungal  ergosterol  biosynthesis.  The  accumulation  of  14  alpha -methyl sterols  correlates   with  the  subsequent  loss  of  ergosterol  in  the  fungal  cell  wall  and  may  be  responsible  for  the  antifungal  activity  of voriconazole.


ResistanceA  potential   for  development  of  resistance  to  voriconazole  is  well  known.  The  mechanisms  of  resistance  may  include  mutations  in  the gene  ERG11  (encodes  for  the  target  enzyme,  lanosterol  1 4-α - de methylase),  upregulation  of  genes  encoding  the  AT P -binding  cassette efflux  t ransporters  i.e.,  Candida  drug  resistance  (CDR)  pumps  and  reduced  access  of  the  drug  to  the  target,  or  some  c o m bination  of those  mechanism s.  The  frequency  of  drug  resistance  development  for  the  various  fungi  for  which  this  drug  is  indicated  is  not  known. 


F ungal  isolates  exhibiting  reduced  susceptibility  to  fluconazole  or  itraconazole  may  also  show  reduced  susceptibility  to  voric onazole, suggesting  cros s -resistance  can  occur  among  these  azoles.  The  relevance  of  cros s -resistance  and  clinical  outcome  has  not  been  fully characterized.  Clinical  cases  where  azole  cros s -resistance  is  demonstrated  may  require  alternative  antifungal  therapy.


Antimicrobial  


ActivityVoriconazole  has  been  shown  to  be  active  against  most  isolates  of  the  following  microorganisms,  


both  


in  vitro  and  in  clinical infections.


Aspergillus  fumigatus


Aspergillus  flavus


Aspergillus  niger


Aspergillus  terreus


Candida  albicans Candida   glabrata  (In  clinical  studies,  the  voriconazole  MI C90   w as  4  µg/mL )


*Candida  kruseiCandida  parapsilosis Candida   tropicalisFusarium  spp.  including  


Fusarium   solaniScedosporium  apiospermum*  In clinical studies, voriconazole MI C90  for


C. glabrata  baseline isolates was 4 µg/mL; 13/50 (26%)


C. glabrata  baseline isolates were resistant (MIC  ≥4 µg/mL) to voriconazole. Howe ver, based on 1054 isolates tested in surveillance studies the MI C90   was  1  µg/mL.


The   follo wing  data  are  available,  


but  their  clinical  significance  is  unknown.  At  least  90  percent  of  the  following  fungi  exhibit  an  


in vitro m inimum  inhibitory  concentration   (MIC)  less  than  or  equal  to  the  susceptible  breakpoint  for  voriconazole  against  isolates  of similar  genus  or  organism  grou p.  H o wever,  the  effectiveness  of  voriconazole  in  treating  clinical  infections  due  to  these  fungi has  not been  established  in  adequate   a nd   w ell -controlled  clinical  trials:


Candida   lusitaniae Candida  guilliermondiiSusceptibility  TestingFor  specific  information  regarding  susceptibility  test  interpretive  criteria  and  associated  test  methods  and  quality  control  standards recognized  by  FDA   for  this  drug,  please  see:  https://www.fda.gov/STI C.

12.5 Pharmacogenomics

CYP2C1 9,  significantly  involved  in  the  metabolism  of  voriconazole,  exhibits  genetic  polymorphism.  Approximately   15-20%  of  Asian populations  may  be  expected  to  be  poor  metabolizers.  For  Caucasians  and  Blacks,  the  prevalence  of  poor  metabolizers  is   3 -5%.  Studies conducted  in  Caucasian  and  Japanese  healthy  subjects  have  shown  that  poor  metabolizers  have,  on  average,  4 -fold  higher  voriconazole e x posure   (AU C t)  than  their  homozygous  extensive  metabolizer  counterparts.  Subjects  who  are  heterozygous  extensive  metabolizers  have,  on  average,   2 -fold  higher  voriconazole  exposure  than  their  homozygous  extensive  metabolizer  counterparts  


[see  


Clinical Pharm acology  (12. 3 ) ]


.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

T w o -year  carcinogenicity  studies  were  conducted  in  rats  and  mice.  Rats  were  given  oral  doses  of  6,  18  or  50  mg/kg  voriconazole,   or 0.2,  0.6,  or  1.6  times  t he  RMD  on  a  mg/ m2   basis.  Hepatocellular  adenomas  were  detected  in  females  at  50  mg/kg  and  hepatocellular carcinomas  were  found  in  males  at  6  and  50  mg/kg.  Mice  were  given  oral  doses  of  10,  30  or  100  mg/kg  voriconazole,  or  0.1,  0 .4,  or 1.4  times  the  RMD  on  a  mg/ m2  basis.  In  mice,  hepatocellular  adenomas  were  detected  in  males  and  females  and  hepatocellular carcinomas  were  detected  in  males  at  1.4  times  the  RMD  of  voriconazole.


Voriconazole  demonstrated  clastogenic  activity  (mostly  chromosome  breaks)  in  human  lymphocyte  cultures  


in  vitr o.  Voriconazole w as  not  genotoxic  in  the  Ames  assay,  CHO   HGPRT  assay,  the  mouse  micronucleus  assay  or  the  


in  vivo  DNA  repair  test  (Unscheduled DNA  Synthesis  assay).


Voriconazole  administration  induced  no  impairment  of  male  or  female  fertility  in  rats  dosed  at 50  mg/kg,  or  1.6  times  the  RM D.

14 Clinical Studies

Voriconazole,  administered  orally  or  parenterally,  has  been  evaluated  as  primary  or  salvage  therapy  in  520  patien ts  aged  12  years  and older   with  infections  caused  by  


Aspergillus   spp.,  


Fusarium   spp.,   and  


Scedosporium   spp.

14 .1 Invasive Aspergillosis

Voriconazole   was  studied  in  patients  for  primary  therapy  of IA  (randomized,  controlled  study   307/602),  for  primary  and  salvage therapy  of  aspergillosis  (no n - co mparative  study  304)  and  for  treatment  of  patients  with   IA  who  were  refractory  to,  or  intolerant  of, other  antifungal  therapy  (no n-comparative  study  309/604).


Study   307/602  –  Primary  Therapy  of  Invasive  AspergillosisThe  efficacy  of  voriconazole  compared  to  amphotericin  B  in  the  primary  treatment  of  acute   IA  was  demonstrated  in  277  patients treated   for   12   weeks  in  a  randomized,  controlled  study   (Study  307/60 2).  The  majority  of  study  patients  had  underlying  hematologic malignancies,  including  bone  marrow  transplantation.  The  study  also  included  patients  with  solid  organ  transplantation,  solid  tumors, and  AIDS.  The  patients  were  mainly  treated  for  defi nite  or  probable   IA  of  the  lungs.  Other  aspergillosis  infections  included disseminated  disease,  CNS  infections  and  sinus  infections.  Diagnosis  of  definite  or  probable   IA  was  made  according  to  criteria m odified  fr om  those  established  by  the  National  Institute  of  Allergy  and  Infectious  Diseases  Mycoses  Study  Group/European Organisation  for  Research  and  Treatment  of  Cancer  (NIAID  MSG/EORTC).


Voriconazole   was  administered  intravenously  with  a loading  dose  of  6 mg/kg  e v ery  12  hours  for  the  first  24  hours  followed  by  a maintenance  dose  of  4  mg/kg  every  12  hours  for  a  minimum  of  7  days.  Therapy  could  then  be  s witched  to  the  oral  formulation  at  a dose  of  200  mg   every   12 h our s.  Median  duration  of  IV  voriconazole  thera py   was  10  days  (range   2 - 85   da ys).  After  IV  voriconazole therapy,  the  median  duration  of  PO  voriconazole  therapy  was  76  days  (range   2 - 232   days).


Patients  in  the  comparator  group  received  conventional  amphotericin  B  as  a  slow  inf usion  at  a  daily  dose  of  1. 0 - 1.5  mg/kg/day. Median  duration  of  IV  amphotericin  therapy  was  12  days  (range   1 -85  days).  Treatment  was  then  continued   with  OLA T,  including itraconazole  and  lipid  amphotericin  B  formulations.  Although  initial  therapy  with  conventional  amphotericin  B was  to  be  continued for  at  least  two  weeks,  actual  duration  of  therapy  was  at  the   discretion  of  the  investigator.  Patients  who  discontinued  initial randomized  therapy  due  to  toxicity  or  lack  of  efficacy  were  eligible  to  contin ue   in   the   study   with  OLAT  treatment.


A satisfactory  global  response  at 12   weeks  (complete  or  partial  resolution  of  all  attribu tible  symptoms,  signs, radiographic/bronchoscopic  abnormalities  present  at baseline)   was  seen  in  53%  of  voriconazole  treated  pati ents  compared  to  32%  of a mphote ricin  B treated  patients  (Table   15).  A  benefit  of  voriconazole  compared  to  amphotericin  B  on  patient  survival  at  Day  84   was seen  with  a  71%  survival  rate  on  voriconazole  compared  to  58%  on  amphotericin  B  (Table   13).


Table   13 also  summarizes  the  response  (success)  based  on  mycological  confirmation  and  species.


Table   13:


Overall  Efficacy  and  Success  by  Species  in  the  Primary  Treat ment  of  Acute  Invasive  AspergillosisStudy  307/602


Voriconazole Ampho  B  cStratified Difference (95%  CI)  


dn/N  ( %)n/N  ( %)Efficacy as Primary TherapySatisfactory Global Response


a76/144 (53)42/133 (32)21.8%


(10.5%, 33.0%)


p<0.0001


Survival at Day 84  b102/144  (71)77/133 (58)13.1%


(2.1%, 24.2%)


Success by Spec i esSuccess n/N (%)Overall success76/144 (53)42/133 (32)Mycologically confirmed e37/84  (44)16/67  (24)Aspergillus  spp .f


A. fumigatus28/63  (44)12/47  (26)A. flavus3/6 4/9 A. terreus2/3 0/3 A. niger1/4 0/9 A. ni dulans1/1 0/0 a  Assessed  by  independent  Data  Review  Committee  (DRC)


b  Proportion of subjects alive


c  Amphotericin B followed by other licensed antifungal therapy


d  Difference and corresponding 95% confidence interval are stratified by protocol


e  Not all  mycologically confirmed specimens were speciated


f  Some patients had more than one species isolated at baseline


Study  304  –  Primary  and  Salvage  Therapy  of  AspergillosisIn  this   no n - co m parative  study,  an  overall  success  rate  of  52%  (26/50)   was  seen  in  pat ients   treated   with  voriconazole  for  primary therapy.  Success  was  seen  in  17/29  (59%) with  


Aspergillus   fumigatus  infections  and  3/6  (50%)  patients  with  infections  due  to  no n-


fumigatus  species   [


A.  flavus  (1/1);  


A.  nidulans  (0/2);  


A.  niger   (2/2);  


A.  terreus   (0/1)]


.  Success  in  patients  who  received  voriconazole  as salvage  therapy  is presented  in  Table   14.


Study  309/604  –  Treatment  of  Patients  with  Invasive  Aspergillosis  who  were  Refractory  to,  or  Intolerant  of,  other  Antifun gal TherapyAdditional  data  regard ing  response  rates  in  patients  who  were  refractory  to,  or  intolerant  of,  other  antifungal  ag ents  are  also  provided in   Table   1 6.  In  this  no n -comparative  study,   overall  mycological  eradication  for  culture - docu mented  infections  due  to  


fumigatus  and no n -


fumi gatus  species  of  


Aspergillus  was  36/82  (44%)  and  12/30  (40%),  respectively,  in  voriconazole  treated  patients.  Patients  had various  underlying  diseases  and  species  other  than  


A.  fumigatus  contributed  to  mixed  infections  in  some  cases.


For  patients  who  were   i nfected with  a  single  pathogen  and  were  refractory  to,  or  intolerant  of,  other  antifungal  agents,  the  satisfactory response  rates  for  voriconazole  in  studies  304  and  309/604  are  presented  in  Table   1 4.


Table   14:Combined  Response  Data  in  Salvage  Patients  with  Single  


Aspergillus  Species


(Studies304and309/604)Success n/NA. fumigatus43/97 (44%)A. flavus5/12A.  nidulans1/3 A. niger4/5 A. terreus3/8 A. versicolor0/1 Nineteen  patients  had  more  than  one  species  of  


Aspergillus  isolated.  Success  was  seen  in  4/17  (24%)  of  these  patients.

14.2 Candidemia In Non-Neutropenic Patients And Other Deep Tissue Candida Infections

Voriconazole was compared to the regimen of amphotericin B followed by fluconazole in Study 608, an open-label, comparative study in nonneutropenic patients with candidemia associated with clinical signs of infection. Patients were randomized in 2:1 ratio to receive either voriconazole (n=283) or the regimen of amphotericin B followed by fluconazole (n=139). Patients were treated with randomized study drug for a median of 15 days. Most of the candidemia in patients evaluated for efficacy was caused by


C. albicans (46%), followed by


C. tropicalis (19%),


C. parapsilosis (17%), C. glabrata (15%), and


C. krusei (1%).An independent Data Review Committee (DRC), blinded to study treatment, reviewed the clinical and mycological data from this study, and generated one assessment of response for each patient. A successful response required all of the following: resolution or improvement in all clinical signs and symptoms of infection, blood cultures negative for Candida, infected deep tissue sites negative for Candida or resolution of all local signs of infection, and no systemic antifungal therapy other than study drug. The primary analysis, which counted DRC-assessed successes at the fixed time point (12 weeks after End of Therapy [EOT]), demonstrated that voriconazole was comparable to the regimen of amphotericin B followed by fluconazole (response rates of 41% and 41%, respectively) in the treatment of candidemia. Patients who did not have a 12-week assessment for any reason were considered a treatment failure.


The overall clinical and mycological success rates by Candida species in Study 150-608 are presented in Table 15.


Table 15:Overall Success Rates Sustained From EOT To The Fixed 12-Week Follow-Up Time Point By Baseline Pathogen


a,bBaseline PathogenClinical and Mycological Success ( %)Voriconazole Amphotericin B  --> FluconazoleC.  albicans46/107 (43%)30/63 (48%)C.  tro picalis17/53 (32%)1/16  (6%)C. parapsilosis24/45 (53%)10/19 (53%)C. glabrata12/36 (33%)7/21 (33%)C. krusei1/4 0/1 a A few patients had more than one pathogen at baseline.


b Patients who did not have a 12-week assessment for any reason were considered a treatment failure.


In a secondary analysis, which counted DRC-assessed successes at any time point (EOT, or 2, 6, or 12 weeks after EOT), the response rates were 65% for voriconazole and 71% for the regimen of amphotericin B followed by fluconazole.


In Studies 608 and 309/604 (non-comparative study in patients with invasive fungal infections who were refractory to, or intolerant of, other antifungal agents), voriconazole was evaluated in 35 patients with deep tissue Candida infections. A favorable response was seen in 4 of 7 patients with intra-abdominal infections, 5 of 6 patients with kidney and bladder wall infections, 3 of 3 patients with deep tissue abscess or wound infection, 1 of 2 patients with pneumonia/pleural space infections, 2 of 4 patients with skin lesions, 1 of 1 patients with mixed intra-abdominal and pulmonary infection, 1 of 2 patients with suppurative phlebitis, 1 of 3 patients with hepatosplenic infection, 1 of 5 patients with osteomyelitis, 0 of 1 with liver infection, and 0 of 1 with cervical lymph node infection.

14 .3 Esophageal Candidiasis

The  efficacy  of  oral  voriconazole  200  mg  twice  daily   co mpared  to  oral  fluconazole  200  mg  once  daily  in  the  primary  treatment  of   EC w as  demonstrated  in  Study  15 0 - 305,  a double -blind,  double -dummy  study  in  immunocompromised  patients  with  endoscopicall y- proven   E C.  Patients  were  treated  for  a  median  of  15  days  (range  1  to  49  days).  Outcome  was  assessed  by  repeat  endos copy  at  end  of treatment  (EOT ).  A  successful  response   was  defined  as  a  normal  endoscopy  


at  EOT  or  at  least  a  1  grade  improvement  over  baseline endoscopic  score.  For  patients  in  the  Intent -t o -Treat  (ITT)  population  with  only  a baseline  endoscopy,  a successful  response  was defined  as   symptomatic  cure  or  improvement  at EOT  compared  to  baseline.  Voriconazole  and  fluconazole  (200  mg   once   dail y) showed comparable  efficacy  rates  against   E C,  as  presented  in  Table   1 6.


Table   16:SuccessRatesinPatientsTreatedforE s


ophagealCandidiasisPopulationVoriconazoleFluconazoleDifference % (95%  CI)aP Pb 113/115 (98.2%)134/141 (95.0%) 3.2  (-1.1, 7.5) IT Tc175/200 (87.5%) 171/191 (89.5%) -2.0  (-8.3, 4.3) a Confidence Interval for the difference (Voriconazole –   Fluconazo le) in success rates. 


b  PP (Per Protocol) patients had confirmation of


Candida esophagitis by endoscopy, received at least 12 days of treatment, and had a repeat endoscopy at EOT (end of treatment).


c   ITT ( Intent to Treat) patients without endoscopy or clinical assessment at EOT were treated as failures.


Microbiologic  success  rates  by  


Candida  species  are  presented  in  Table   17.


Table   17:Clinical  and   Mycological   Outco me  by   Baseline   Pathogen  in   Patients  with   Esophag eal  Candidiasis  (Stud y-150-305)


Pathogen


aVoriconazoleFluconazoleFavorable endoscopic response


bMycological eradication


bFavorable endoscopic response


bMycological eradication


bSuccess/Total ( %)Eradication/Total (%)Success/Total ( %)Eradication/Total (%)C.  albicans134/140 (96%)90/107 (84%)147/156 (94%)91/115 (79%)C. glabrata8/8 (100%)4/7  (57%)4/4 (100%)1/4  (25%)C. krusei1/1 1/1 2/2 (100%)0/0 a  Some patients had more than one species isolated at baselin e. 


b  Patients with endoscopic  and/or mycological  assessment at end of therap y.

14 .4 Other Serious Fungal Pathogens

In  pooled  analyses  of  patients,  voriconazole   was  shown  to  be  effective  against  the  following  additional  fungal  pathogens:


Scedosporium  apiospermum  -  Successful  response  to  voriconazole  therapy  was  seen  in  15  of  24  patients  (63%).  Three  of  these patients  relapsed  within  4 weeks,  including  1  patient  with  pulmonary,  skin  and  eye  infections,  1  patient  with  cerebral  disease,  and  1 patient  with  skin  infection.  Ten  patients  had  evidence  of  cerebral  disease  and  6 of  these  had  a  successful  outcome  (1  relapse).  In addition,  a successful  response   was  seen  in  1  of  3  patients  with  mixed  organism  infections.


Fusarium   spp.  -  Nine  of  21  (43%)  patients  were  successfully  treated with  voriconazole.  Of  these  9  patients,  3  had   e ye  infections,  1 had an  eye  and  blood  infection,  1  had  a  skin  infection,  1  had  a  blood  infection  alone,  2  had  sinus  infections,  and  1  had  dissemi nated infection  (pulmonary,  skin,  hepatosplenic).  Three  of  these  patients  (1   with  disseminated  disease,  1 w ith   an e ye   infection   and  1 with  a blood  infection)  had  


Fusarium   solani   and   were  complete  successes.   T wo  of  these  patients  relapsed,  1 with  a sinus  infection  and profound  neutropenia  and  1  post  surgical  patient  with  blood  and  eye  infections.

14.5 Pediatric Studies

A total of 22 patients aged 12 to 18 years with IA were included in the adult therapeutic studies. Twelve out of 22 (55%) patients had successful response after treatment with a maintenance dose of voriconazole 4mg/kg every12hours. Additional pediatric use information is approved for PF PRISM C.V.’s VFEND (voriconazole). However, due to PF PRISM C.V.’s marketing exclusivity rights, this drug product is not labeled with that information.

16 .1 How Supplied

Powder  for  Solution  for  InjectionVoriconazole for injection  I.V.  is  supplied  in  a  singl e - dose  vial  as  a  sterile  lyophilized   po wder  equivalent  to  200  mg  voriconazole  and   3,200 mg  sulfobutyl  ether  beta -cyclodextrin  sodium  (SBECD).  It  does  not  contain  preservatives  and  is  not  made  with  natural  rubber  latex.


Individually  packaged vials of 200 mg voriconazole for injection I.V.


(NDC 72266-131-01)

16 .2 Storage

Voriconazole for injection  I.V.  unreconstituted  vials  should   be   stored   at Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].  Voriconazole for injection  is  a  single  dose  unpreserved  sterile  lyophile.  From  a  microbiological  point  of  view,  following  reconstit ution  of the  lyophile  with  Water  for  Injection,  the  reconsti tuted  solution  should  be  used  immediately.  If  not  used  immediately,  i n -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  (3 6°F   to 46°F).  Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C   to   8°C  (3 6°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  


[see


Dosage  and  Administration  (2.1 ) ]


.

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).


 Embryo-Fetal Toxicity • Advise female patients of the potential risks to a fetus.


• Advise females of reproductive potential to use effective contraception during treatment with voriconazole for injection.


Distributed by:Fosun Pharma USA Inc.


Princeton, NJ 08540


Made in India.


April 2020


LEA-020330-00

Patient Information

Voriconazole for injection, for intravenous useRead  the  Patient  Information  that  comes  with  voriconazole for injection  before  you  st art  taking  it and  each  time  you  get  a refill.  There  may be  new  information.  This  information  does  not  take  the  place  of  talking  with  your  healthcare  provider  about  your  condition or  treatment.


What  is  voriconazole for injection?Voriconazole for injection  is  a  prescription  medicine  used  to  treat   certain  serious  fungal  infections  in  your  blood  and  body.  These  infections are  called  “aspergillo sis,”  “esophageal  candidiasis,”   “


Scedosporium,”   “


Fusarium,”   and   “candidemia”.


It  is  not  known  if  voriconazole for injection  is  safe  and  effective  in  children  younger  than  2  years  old.


Do  not  take  voriconazole for injection  if you:


·  


are  allergic  to  voriconazole  or  any  of  the  ingredients  in  voriconazole for injection.  S ee  the  end  of  this  leaflet  for  a  complete  list  of ingredients  in  voriconazole for injection.


·  


are  taking  any  of  the  following  medicines:o     cisapride


o     pimozide


o     quinidine


o     sirolimus


o     rifampin


o     carbamazepine


o     long-acting barbiturates like phenobarbital


o     efavirenz


o     ritonavir


o     rifabutin


o     ergotamine, dihydroergotamine (ergot alkaloids)


o     St. John’s Wort (herbal supplement)


Ask your healthcare provider or pharmacist if you are not sure if you are taking any of the medicines listed above. Do not start taking a new medicine without talking to your healthcare provider or pharmacist.


Before you take voriconazole for injection, tell your healthcare provider about all of your medical conditions, including if you:• have or ever had heart disease, or an abnormal heart rate or rhythm. Your healthcare provider may order a test to check your heart (EKG) before starting voriconazole for injection.• have liver or kidney problems. Your healthcare provider may do blood tests to make sure you can take voriconazole for injection.• are pregnant or plan to become pregnant. Voriconazole for injection can harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant. Women who can become pregnant should use effective birth control while taking voriconazole for injection. Talk to your healthcare provider about birth control methods that may be right for you.• are breast-feeding or plan to breast-feed. It is not known if voriconazole for injection passes into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take voriconazole for injection.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.


Voriconazole for injection may affect the way other medicines work, and other medicines may affect how voriconazole for injection works.Know what medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.How should I take voriconazole for injection?• 


voriconazole may be prescribed to you as:        o  voriconazole for injection I.V. (intravenous infusion)


• Voriconazole for injection I.V. will be given to you by a healthcare provider over 1 to 2 hours.


• If you take too much voriconazole for injection, call your healthcare provider or go to the nearest hospital emergency room.


What should I avoid while taking voriconazole for injection?• You should not drive at night while taking voriconazole for injection. Voriconazole for injection can cause changes in your vision such as blurring or sensitivity to light.


• Do not drive or operate machinery, or do other dangerous activities until you know how voriconazole for injection affects you.


• Avoid direct sunlight. Voriconazole for injection can make your skin sensitive to the sun and the light from sunlamps and tanning beds.


You could get a severe sunburn. Use sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight. Talk to your healthcare provider if you get sunburn.


What are possible side effects of voriconazole for injection?Voriconazole for injection may cause serious side effects including:


• 


liver problems. Symptoms of liver problems may include:


        o itchy skin


        o yellowing of your eyes


        o feeling very tired


        o flu-like symptoms


        o nausea or vomiting


• vision changes. Symptoms of vision changes may include:


        o blurred vision


        o changes in the way you see colors


        o sensitivity to light (photophobia)


• serious heart problems. Voriconazole for injection may cause changes in your heart rate or rhythm, including your heart stopping (cardiac arrest).


• allergic reactions. Symptoms of an allergic reaction may include:


        o fever


        o sweating


        o feels like your heart is beating fast (tachycardia)


        o chest tightness


        o trouble breathing


        o feel faint


        o nausea


        o itching


        o skin rash


• kidney problems. Voriconazole for injection may cause new or worse problems with kidney function, including kidney failure. Your healthcare provider should check your kidney function while you are taking voriconazole for injection. Your healthcare provider will decide if you can keep taking voriconazole for injection.


• serious skin reactions. Symptoms of serious skin reactions may include:


        o rash or hives


        o mouth sores


        o blistering or peeling of your skin


        o trouble swallowing or breathing


Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the symptoms listed above.


The most common side effects of voriconazole for injection include:        o vision changes


        o rash


        o vomiting


        o nausea


        o headache


        o fast heart beat (tachycardia)


        o hallucinations (seeing or hearing things that are not there)


        o abnormal liver function tests


        o fever


        o chills


Tell your healthcare provider if you have any side effect that bothers you or that does not go away.


These are not all the possible side effects of voriconazole for injection.


Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.


How should I store voriconazole for injection?• Store voriconazole for injection at room temperature  Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Do not refrigerate or freeze.


• Safely throw away medicine that is out of date or no longer needed.


• Keep voriconazole for injection, as well as all other medicines, out of the reach of children.


General information about the safe and effective use of voriconazole for injectionMedicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use voriconazole for injection for a condition for which it was not prescribed. Do not give voriconazole for injection to other people, even if they have the same symptoms that you have. It may harm them.


You can ask your healthcare provider or pharmacist for information about voriconazole for injection that is written for health professionals.


What are the ingredients of voriconazole for injection?Active ingredient: voriconazole


Inactive ingredients in voriconazole for injection IV: sulfobutyl ether beta-cyclodextrin sodium


For more information, contact Fosun Pharma at 1-866-611-3762.


Additional pediatric use information is approved for PF PRISM C.V.’s VFEND (voriconazole). However, due to PF PRISM C.V.’s marketing exclusivity rights, this drug product is not labeled with that information.Distributed by:Fosun Pharma USA Inc.


Princeton, NJ 08540


Made in India.


April 2020


LEA-020330-0

* Please review the disclaimer below.