NDC 70436-029 Voriconazole

Voriconazole

NDC Product Code 70436-029

NDC Code: 70436-029

Proprietary Name: Voriconazole Additional informationCallout TooltipWhat is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Voriconazole Additional informationCallout TooltipWhat is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.


Code Structure
  • 70436 - Slate Run Pharmaceuticals
    • 70436-029 - Voriconazole

NDC 70436-029-80

Package Description: 1 INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION in 1 BOX

NDC Product Information

Voriconazole with NDC 70436-029 is a a human prescription drug product labeled by Slate Run Pharmaceuticals. 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: Slate Run Pharmaceuticals

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 Additional informationCallout TooltipWhat 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)

Additional informationCallout TooltipWhat 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 200 mg/1

Inactive Ingredient(s)

Additional informationCallout TooltipAbout 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.

  • BETADEX SULFOBUTYL ETHER SODIUM (UNII: 2PP9364507)

Administration Route(s)

Additional informationCallout TooltipWhat 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)

Additional informationCallout TooltipWhat 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

Additional informationCallout TooltipWhat is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Slate Run Pharmaceuticals
Labeler Code: 70436
FDA Application Number: ANDA211661 Additional informationCallout TooltipWhat 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. Additional informationCallout TooltipWhat 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: 01-28-2019 Additional informationCallout TooltipWhat 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: 12-31-2020 Additional informationCallout TooltipWhat 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 Additional informationCallout TooltipWhat 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 Label Images

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 Indications And Usage

Voriconazole for injection is indicated for use in patients 12 years of age and older in the treatment of the following fungal infections:

2.1 Instructions For Use In All Patients

Voriconazole for injection requires reconstitution to 10 mg/mL and subsequent dilution to 5 mg/mL or less prior to administration as an infusion, at a maximum rate of 3 mg/kg per hour over 1 to 2 hours.Do not administer as an IV bolus injection.

Blood Products And Concentrated Electrolytes

Voriconazole for injection 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 therapy [


see


Warnings and Precautions (5.8)


].

Intravenous Solutions Containing (Non-Concentrated) Electrolytes

Voriconazole for injection 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 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.

Invasive Aspergillosis And Serious Fungal Infections Due To Fusarium Spp. And Scedosporium Apiospermum

See


Table 1. Therapy must be initiated with the specified loading dose regimen of intravenous voriconazole 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 may be utilized. The recommended oral maintenance dose of 200 mg achieves a voriconazole exposure similar to 3 mg/kg IV; a 300 mg oral dose achieves an exposure similar to 4 mg/kg IV. 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 Tissues Candida Infections

See


Table 1. Patients should be treated for at least 14 days following resolution of symptoms or following last positive culture, whichever is longer.

Esophageal Candidiasis

See


Table 1. Patients should be treated for a minimum of least 14 days and for at least 7 days following resolution of symptoms.


Table . Recommended Dosing RegimenInfectionLoading DoseMaintenance DoseIncrease dose when voriconazole is co-administered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment (2.7)In healthy volunteer studies, the 200 mg oral q12h dose provided an exposure (AUCτ) similar to a 3 mg/kg IV q12h dose; the 300 mg oral q12h dose provided an exposure (AUCτ) similar to a 4 mg/kg IV q12h dose [
see
Clinical Pharmacology (12)
].
IVIVOralAdult patients who weigh less than 40 kg should receive half of the oral maintenance dose.Invasive AspergillosisIn a clinical study of invasive aspergillosis, the median duration of intravenous voriconazole therapy was 10 days (range 2-85 days). The median duration of oral voriconazole therapy was 76 days (range 2-232 days)
[see
Clinical Studies (14.1)]
.
6 mg/kg q12h for the first 24 hours4 mg/kg q12h200 mg q12hCandidemia in non-neutropenic patients and other deep tissue


Candida infections


6 mg/kg q12h for the first 24 hours3-4 mg/kg q12h


In clinical trials, patients with candidemia received 3 mg/kg IV q12h as primary therapy, while patients with other deep tissue
Candida infections received 4 mg/kg q12h as salvage therapy. Appropriate dose should be based on the severity and nature of the infection.
200 mg q12hEsophageal CandidiasisNot evaluated in patients with esophageal candidiasis.200 mg q12hScedosporiosos and Fusariosis6 mg/kg for the first 24 hours4 mg/kg q12h200 mg q12h

2.4 Dosage Adjustment

If patient response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours (similar to 3 mg/kg IV q12h) to 300 mg every 12 hours (similar to 4 mg/kg IV q12h). For adult patients weighing less than 40 kg, the oral maintenance dose may be increased from 100 mg every 12 hours to 150 mg every 12 hours. If patient is unable to tolerate 300 mg orally every 12 hours, reduce the oral maintenance dose by 50 mg steps to a minimum of 200 mg every 12 hours (or to 100 mg every 12 hours for adult patients weighing less than 40 kg).If patient is unable to tolerate 4 mg/kg IV q12h, reduce the intravenous maintenance dose to 3 mg/kg q12h.The maintenance dose of voriconazole should be increased when co-administered with phenytoin or efavirenz [


see


Drug Interactions (


7)


].


The maintenance dose of voriconazole should be reduced in patients with mild to moderate hepatic impairment, Child-Pugh Class A and B [


see


Dosage and Administration (


2.7)


]. There are no PK data to allow for dosage adjustment recommendations in patients with severe hepatic impairment (Child-Pugh Class C).


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

Reconstitution

The powder is reconstituted with 19 mL of Water for Injection to obtain an extractable volume of 20 mL of clear concentrate containing 10 mg/mL of voriconazole. It is recommended that a standard 20 mL (non-automated) syringe be used to ensure that the exact amount (19.0 mL) of Water for Injection is dispensed. Discard the vial if a vacuum does not pull the diluent into the vial. Shake the vial until all the powder is dissolved.

Dilution

  • Voriconazole for injection must be infused over 1-2 hours, at a concentration of 5 mg/mL or less. Therefore, the required volume of the 10 mg/mL voriconazole for injection concentrate should be further diluted as follows (appropriate diluents listed below):Calculate the volume of 10 mg/mL voriconazole for injection concentrate required based on the patient’s weight (see
  • Table 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.
  • 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 1-2 hours at a maximum rate of 3 mg/kg per hour.Table . Required Volumes of 10 mg/mL Voriconazole for Injection ConcentrateBody 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)309.0 mL (1)12 mL (1)18 mL (1)3510.5 mL (1)14 mL (1)21 mL (2)4012.0 mL (1)16 mL (1)24 mL (2)4513.5 mL (1)18 mL (1)27 mL (2)5015.0 mL (1)20 mL (1)30 mL (2)5516.5 mL (1)22 mL (2)33 mL (2)6018.0 mL (1)24 mL (2)36 mL (2)6519.5 mL (1)26 mL (2)39 mL (2)7021.0 mL (2)28 mL (2)42 mL (3)7522.5 mL (2)30 mL (2)45 mL (3)8024.0 mL (2)32 mL (2)48 mL (3)8525.5 mL (2)34 mL (2)51 mL (3)9027.0 mL (2)36 mL (2)54 mL (3)9528.5 mL (2)38 mL (2)57 mL (3)10030.0 mL (2)40 mL (2)60 mL (3)Voriconazole for injection is a single dose unpreserved sterile lyophile. Therefore, from a microbiological point of view, once reconstituted, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2°C to 8°C (36° to 46°F). This medicinal product is for single dose only and any unused solution should be discarded. Only clear solutions without particles should be used.The reconstituted solution can be diluted with: 9 mg/mL (0.9%) Sodium Chloride USPLactated Ringers USP5% Dextrose and Lactated Ringers USP5% Dextrose and 0.45% Sodium Chloride USP5% Dextrose USP5% Dextrose and 20 mEq Potassium Chloride USP0.45% Sodium Chloride USP5% Dextrose and 0.9% Sodium Chloride USPThe compatibility of voriconazole for injection 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 must not be diluted with 4.2% Sodium Bicarbonate Infusion. The mildly alkaline nature of this diluent caused slight degradation of voriconazole after 24 hours storage at room temperature. Although refrigerated storage is recommended following reconstitution, use of this diluent is not recommended as a precautionary measure. Compatibility with other concentrations is unknown.

2.7 Use In Patients With Hepatic Impairment

In the clinical program, patients were included who had baseline liver function tests (ALT, AST) up to 5 times the upper limit of normal. No dose adjustment is necessary in patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended [


see


Warnings and Precautions (5.9)


].


It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) [


see


Clinical Pharmacology (12.3)


].


Voriconazole has not been studied in patients with severe hepatic cirrhosis (Child-Pugh Class C) or in patients with chronic hepatitis B or chronic hepatitis C disease. Voriconazole has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and should only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic impairment must be carefully monitored for drug toxicity.

2.8 Use In Patients With Renal Impairment

The 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), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral voriconazole therapy [


see


Warnings and Precautions (5.10)


].


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.

Powder For Solution For Injection

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

4 Contraindications

  • Voriconazole 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 terfenadine, astemizole, cisapride, pimozide or quinidine with voriconazole 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 with sirolimus is contraindicated because voriconazole significantly increases sirolimus concentrations [
  • See
  • Drug Interactions (7) and
  • Clinical Pharmacology (12.3)
  • ].
  • Coadministration of voriconazole with rifampin, carbamazepine and long-acting barbiturates is contraindicated because these drugs are likely to decrease plasma voriconazole concentrations significantly [
  • See
  • Drug Interactions (7) and
  • Clinical Pharmacology (12.3)
  • ].
  • Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg q24h or higher is contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations [
  • See
  • Drug Interactions (7) and
  • Clinical Pharmacology (12.3)
  • ].
  • Coadministration of voriconazole with high-dose ritonavir (400 mg q12h) is contraindicated because ritonavir (400 mg q12h) significantly decreases plasma voriconazole concentrations. Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole [
  • See
  • Drug Interactions (7) and
  • Clinical Pharmacology (12.3)
  • ].
  • Coadministration of voriconazole with rifabutin is contraindicated since voriconazole 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 with ergot alkaloids (ergotamine and dihydroergotamine) is contraindicated because voriconazole 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 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 Drug Interactions

See


Table 7 for a listing of drugs that may significantly alter voriconazole concentrations. Also, see


Table 8 for a listing of drugs that may interact with voriconazole resulting in altered pharmacokinetics or pharmacodynamics of the other drug [


see


Contraindications (4) and


Drug Interactions (7)


].

5.2 Hepatic Toxicity

In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with voriconazole (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly hematological malignancy). Hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction has usually been reversible on discontinuation of therapy [


see


Warnings and Precautions (5.9) and


Adverse Reactions (6.3)


].


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


see


Warnings and Precautions (5.9),


Dosage and Administration (2.4, 2.7), and


Adverse Reactions (6.3)].

5.3 Visual Disturbances

The effect of voriconazole on visual function is not known if treatment continues beyond 28 days. There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema. If treatment continues beyond 28 days, visual function including visual acuity, visual field and color perception should be monitored [


see


Adverse Reactions (6.2)


].

5.4 Embryo-Fetal Toxicity

Voriconazole can cause fetal harm when administered to a pregnant woman.In animals, voriconazole administration was associated with teratogenicity, embryotoxicity, increased gestational length, dystocia and embryomortality [


see


Use in Specific Populations (8.1)


].


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.

5.6 Arrhythmias And Qt Prolongation

  • Some azoles, including voriconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During clinical development and post-marketing surveillance, there have been rare cases of arrhythmias, (including ventricular arrhythmias such as
  • Torsade de pointes), cardiac arrests and sudden deaths in patients taking voriconazole. These cases usually involved seriously ill patients with multiple confounding risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medications that may have been contributory.
  • Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions, such as:Congenital or acquired QT-prolongation
  • Cardiomyopathy, in particular when heart failure is present
  • Sinus bradycardia
  • 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 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.

5.8 Laboratory Tests

Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of and during voriconazole therapy.Patient management should include laboratory evaluation of renal (particularly serum creatinine) and hepatic function (particularly liver function tests and bilirubin).

5.9 Patients With Hepatic Impairment

It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) receiving voriconazole [


see


Clinical Pharmacology (12.3) and


Dosage and Administration (2.7)


].


Voriconazole has not been studied in patients with severe cirrhosis (Child-Pugh Class C). Voriconazole has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and should only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic impairment must be carefully monitored for drug toxicity.

5.10 Patients With Renal Impairment

In patients with moderate to severe renal dysfunction (creatinine clearance <50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and if increases occur, consideration should be given to changing to oral voriconazole therapy [


see


Clinical Pharmacology (12.3) and


Dosage and Administration (2.8)


].

5.11 Monitoring Of Renal Function

Acute renal failure has been observed in patients undergoing treatment with voriconazole. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and 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, particularly serum creatinine.

5.12 Monitoring Of Pancreatic Function

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 treatment.

5.13 Dermatological Reactions

Serious exfoliative cutaneous reactions, such as Stevens-Johnson syndrome, have been reported during treatment with voriconazole. If a patient develops an exfoliative cutaneous reaction, voriconazole should be discontinued.Voriconazole has been associated with photosensitivity skin reaction. Patients, including children, should avoid exposure to direct sunlight during voriconazole 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 discontinuation should be considered. If voriconazole 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 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 should be discontinued.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.

5.14 Skeletal Adverse Events

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


see


Adverse Reactions (6.4)].

6 Adverse Reactions

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.

6.1 Overview

The most frequently reported adverse events (all causalities) in the 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 treatment-related adverse events which most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances [


see


Warning and Precautions (5.2, 5.3) and


Adverse Reactions (6.2, 6.3)


].

6.2 Clinical Trial Experience In Adults

The data described in


Table 3 reflect exposure to voriconazole in 1,655 patients in the 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 3 includes all adverse events 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 in the primary treatment of patients with acute invasive aspergillosis. 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 esophageal candidiasis. 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 . Treatment Emergent Adverse Events Rate ≥2% on Voriconazole or Adverse Events of Concern in All Therapeutic Studies Population, Studies 307/602-608 Combined, or Study 305. Possibly Related to Therapy or Causality Unknown


Study 307/602: invasive aspergillosis; Study 608: candidemia; Study 305: esophageal candidiasisAll Therapeutic StudiesStudies 307/602and 608(IV/oral therapy)Study 305(oral therapy)VoriconazoleN=1655VoriconazoleN=468Ampho BAmphotericin B followed by other licensed antifungal therapyN=185Ampho B→ FluconazoleN=131VoriconazoleN=200FluconazoleN=191N (%)N (%)N (%)N (%)N (%)N (%)Special SensesSee
Warnings and Precautions (5.3)
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)Vomiting72 (4.4)15 (3.2)18 (9.7)1 (0.8)2 (1.0)1 (0.5)Liver Function Tests Abnormal45 (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 and Nutritional SystemsAlkaline Phosphatase Increased59 (3.6)19 (4.1)4 (2.2)3 (2.3)10 (5.0)3 (1.6)Hepatic Enzymes Increased30 (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

6.3 Clinical Laboratory Values

The overall incidence of clinically significant transaminase abnormalities in all therapeutic studies was 12.4% (206/1,655) of patients treated with voriconazole. 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 following dose adjustment, including discontinuation of therapy.Voriconazole 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 therapy. Patients who develop abnormal liver function tests during voriconazole 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 must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to voriconazole [


see


Warnings and Precautions (5.2)


].


Acute renal failure has been observed in severely ill patients undergoing treatment with voriconazole. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and have concurrent conditions that may result in decreased renal function. It is recommended that patients are monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.Tables 4 to 6 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 esophageal candidiasis were randomized to either oral voriconazole or oral fluconazole. In study 307/602, patients with definite or probable invasive aspergillosis 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 . Protocol 305 - Patients with Esophageal Candidiasis Clinically Significant Laboratory Test AbnormalitiesCriteriaWithout regard to baseline valueVoriconazolen/N (%)Fluconazolen/N (%)T. Bilirubin>1.5x ULN8/185 (4.3)7/186 (3.8)AST>3.0x ULN38/187 (20.3)15/186 (8.1)ALT>3.0x ULN20/187 (10.7)12/186 (6.5)Alk Phos>3.0x ULN19/187 (10.2)14/186 (7.5)Table . Protocol 307/602 - Primary Treatment of Invasive Aspergillosis Clinically Significant Laboratory Test AbnormalitiesCriteriaWithout regard to baseline valueVoriconazolen/N (%)Amphotericin BAmphotericin B followed by other licensed antifungal therapyn/N (%)T. Bilirubin>1.5x ULN35/180 (19.4)46/173 (26.6)AST>3.0x ULN21/180 (11.7)18/174 (10.3)ALT>3.0 ULN34/180 (18.9)40/173 (23.1)Alk Phos>3.0 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)Table . Protocol 608 - Treatment of Candidemia Clinically Significant Laboratory Test AbnormalitiesCriteriaWithout regard to baseline valueVoriconazolen/N (%)Amphotericin B followed by Fluconazolen/N (%)T. Bilirubin>1.5x ULN50/261 (19.2)31/115 (27.0)AST>3.0x ULN40/261 (15.3)16/116 (13.8)ALT>3.0x ULN22/261 (8.4)15/116 (12.9)Alk Phos>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)

6.4 Postmarketing Experience

The following adverse reactions have been identified during post approval use of voriconazole. 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.

7 Drug Interactions

Table . Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]Drug/Drug Class (Mechanism of Interaction by the Drug)Voriconazole Plasma Exposure (C


max and AUC


τ after 200 mg q12h)


Recommendations for Voriconazole Dosage Adjustment/CommentsRifampin


Results based on
in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects
and Rifabutin


(CYP450 Induction)


Significantly ReducedContraindicatedEfavirenz (400 mg q24h)


Results based on
in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
(CYP450 Induction)


Efavirenz (300 mg q24h)


(CYP450 Induction)


Significantly ReducedSlight Decrease in AUC


τ ContraindicatedWhen voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24hHigh-Dose Ritonavir (400 mg q12h)


(CYP450 Induction)


Low-Dose Ritonavir (100 mg q12h)


(CYP450 Induction)


Significantly ReducedReducedContraindicatedCoadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazoleCarbamazepine(CYP450 Induction)Not Studied


In Vivo or


In Vitro, but Likely to Result in Significant Reduction


ContraindicatedLong Acting Barbiturates (CYP450 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 q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)St. John’s Wort (CYP450 inducer; P-gp inducer)Significantly ReducedContraindicatedOral Contraceptives


containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)


IncreasedMonitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptivesFluconazole


(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 24h 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 coadministered with indinavirFrequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitorsOther NNRTIs


Non-Nucleoside Reverse Transcriptase Inhibitors(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 (Decreased Plasma Exposure)Frequent monitoring for adverse events and toxicity related to voriconazoleCareful assessment of voriconazole effectivenessTable . Effect of Voriconazole on Phramacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]Drug/Drug Class (Mechanism of Interaction by Voriconazole)Drug Plasma Exposure (C


max and AUC


τ)


Recommendations for Drug Dosage Adjustment/CommentsSirolimus


Results based on
in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects
(CYP3A4 Inhibition)


Significantly IncreasedContraindicatedRifabutin


(CYP3A4 Inhibition)


Significantly IncreasedContraindicatedEfavirenz (400 mg q24h)


Results based on
in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects
(CYP3A4 Inhibition)


Efavirenz (300 mg q24h)


(CYP3A4 Inhibition)


Significantly IncreasedSlight Increase in AUC


τContraindicatedWhen voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24hHigh-Dose Ritonavir (400 mg q12h)


(CYP3A4 Inhibition)


Low-Dose Ritonavir (100 mg q12h)


No Significant Effect of Voriconazole on Ritonavir C


max or AUC


τSlight Decrease in Ritonavir C


max and AUC


τContraindicated because of significant reduction of voriconazole C


max and AUC


τCoadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C


max and AUC


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


Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine(CYP3A4 Inhibition)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 pointesErgot Alkaloids(CYP450 Inhibition)Not Studied


In Vivo or


In Vitro, but Drug Plasma Exposure Likely to be Increased


ContraindicatedCyclosporine*(CYP3A4 Inhibition)AUC


τ Significantly Increased; No Significant Effect on C


maxWhen initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.Methadone


Results based on
in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30-100 mg q24h)
(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 neededFentanyl (CYP3A4 Inhibition)IncreasedReduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-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. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [


see


Drug Interactions (7)


].


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


see


Drug Interactions (7)


].


NSAIDs


Non-Steroidal Anti-Inflammatory Drug 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 in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole 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 suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.Omeprazole


(CYP2C19/3A4 Inhibition)Significantly IncreasedWhen initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-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 inhibitors.Other HIV Protease Inhibitors (CYP3A4 Inhibition)In Vivo Studies Showed No Significant Effects on Indinavir Exposure


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


No dosage adjustment for indinavir when coadministered with voriconazoleFrequent monitoring for adverse events and toxicity related to other HIV protease inhibitorsOther NNRTIs


Non-Nucleoside Reverse Transcriptase Inhibitors(CYP3A4 Inhibition)A Voriconazole-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 NNRTIBenzodiazepines(CYP3A4 Inhibition)In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)


Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.HMG-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 channel 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. Adjustment 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 recommended.

Risk Summary

Voriconazole 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 teratogenic in rats and embryotoxic 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 recommended maintenance dose 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 (5.4)]


.


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.

No 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.

Animal Data

Voriconazole was administered orally to pregnant rats during organogenesis (gestation days 6-17) at 10, 30, and 60 mg/kg/day. Voriconazole was teratogenic 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 recommended human dose (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 produced embryofetal toxicity (increased post-implantation loss, 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/m2). 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.

Contraception

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

Safety and effectiveness in pediatric patients below the age of 12 years have not been established.A total of 22 patients aged 12 to 18 years with invasive aspergillosis were included in the therapeutic studies. Twelve out of 22 (55%) patients had successful response after treatment with a maintenance dose of voriconazole 4 mg/kg q12h.Sparse plasma sampling for pharmacokinetics in adolescents was conducted in the therapeutic studies [


see


Clinical Pharmacology (12.3)


]. A population pharmacokinetic analysis was conducted on pooled data from 35 immunocompromised pediatric patients aged 2 to <12 years old who were included in two pharmacokinetic studies of intravenous voriconazole (single dose and multiple dose). Twenty-four of these patients received multiple intravenous maintenance doses of 3 mg/kg and 4 mg/kg. A comparison of the pediatric and adult population pharmacokinetic data revealed that the predicted average steady state plasma concentrations were similar at the maintenance dose of 4 mg/kg every 12 hours in children and 3 mg/kg every 12 hours in adults (medians of 1.19 mcg/mL and 1.16 mcg/mL in children and adults, respectively).


There have been postmarketing reports of pancreatitis in pediatric patients.

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 (C


max) 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, film-coated tablets for oral administration, and as a powder for oral suspension. The structural formula is:Voriconazole is designated chemically as (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1


H-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 is a white lyophilized powder containing nominally 200 mg voriconazole and 3,200 mg sulfobutyl ether beta-cyclodextrin sodium in a 30 mL Type I clear glass vial.Voriconazole for injection 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 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)


].

Exposure-Response Relationship For Efficacy And Safety

In 10 clinical trials (N=1,121), the median values for the average and maximum voriconazole plasma concentrations in individual patients across these studies was 2.51 mcg/mL (inter-quartile range 1.21 to 4.44 mcg/mL) and 3.79 mcg/mL (inter-quartile range 2.06 to 6.31 mcg/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 Electrophysiology

A 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, 1,200, and 1,600 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 q12h to 300 mg q12h leads to an approximately 2.5-fold increase in exposure (AUC


τ); similarly, increasing the intravenous dose from 3 mg/kg q12h to 4 mg/kg q12h produces an approximately 2.5-fold increase in exposure (


Table 9).


Table . Geometric Mean (%CV) Plasma Voriconazole Pharmacokinetic Parameters in Adults Receiving Different Dosing Regimens6 mg/kg IV (loading dose)3 mg/kgIV q12h4 mg/kgIV q12h400 mg Oral (loading dose)200 mgOral q12h300 mgOral q12hN352340174816AUC


12 (mcg·h/mL)


13.9 (32)13.7 (53)33.9 (54)9.31 (38)12.4 (78)34.0 (53)C


max (mcg/mL)


3.13 (20)3.03 (25)4.77 (36)2.30 (19)2.31 (48)4.74 (35)C


min (mcg/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. AUC


12 = area under the curve over 12 hour dosing interval, C


max = maximum plasma concentration, C


min = 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 (eg, 6 mg/kg IV q12h on day 1 followed by 3 mg/kg IV q12h). 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.

Mechanism Of Action

Voriconazole is an azole antifungal drug. 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.

Drug Resistance

A 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 14-α-demethylase), upregulation of genes encoding the ATP-binding cassette efflux transporters i.e., Candida drug resistance (CDR) pumps and reduced access of the drug to the target, or some combination of those mechanisms. The frequency of drug resistance development for the various fungi for which this drug is indicated is not known.Fungal isolates exhibiting reduced susceptibility to fluconazole or itraconazole may also show reduced susceptibility to voriconazole, suggesting cross-resistance can occur among these azoles. The relevance of cross-resistance and clinical outcome has not been fully characterized. Clinical cases where azole cross-resistance is demonstrated may require alternative antifungal therapy.

Antimicrobial Activity

Voriconazole 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 albicansCandida glabrata (In clinical studies, the voriconazole MIC


90 was 4 mcg/mL)*


Candida kruseiCandida parapsilosis Candida tropicalisFusarium spp. including


Fusarium solaniScedosporium apiospermum* In clinical studies, voriconazole MIC


90 for C.


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


glabrata baseline isolates were resistant (MIC ≥4 mcg/mL) to voriconazole. However, based on 1,054 isolates tested in surveillance studies the MIC


90 was 1 mcg/mL.


The following data are available,


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


in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for voriconazole against isolates of similar genus or organism group. However, the effectiveness of voriconazole in treating clinical infections due to these fungi has not been established in adequate and well-controlled clinical trials:


Candida lusitaniae Candida guilliermondii

Susceptibility Testing Methods

For 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/STIC.

12.5 Pharmacogenomics

CYP2C19, 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 exposure (AUC


τ) 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 Pharmacology (12.3)


].

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Two-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 the recommended maintenance dose on a mg/m


2 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/m


2 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 vitro. Voriconazole was 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 RMD (recommended maintenance dose).

14 Clinical Studies

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


Aspergillus spp.,


Fusarium spp., and


Scedosporium spp.


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 intraabdominal 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.

16.1 How Supplied

Powder for Solution for InjectionVoriconazole for injection is supplied in a single dose vial as a sterile lyophilized powder equivalent to 200 mg voriconazole and 3,200 mg sulfobutyl ether beta-cyclodextrin sodium (SBECD).Individually packaged vials of 200 mg voriconazole for injection (NDC 70436-029-80).

16.2 Storage

Voriconazole for injection unreconstituted vials should be stored at 15°C to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Voriconazole for injection is a single dose unpreserved sterile lyophile. From a microbiological point of view, following reconstitution of the lyophile with Water for Injection, the reconstituted solution 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° to 46°F). Chemical and physical in-use stability has been demonstrated for 24 hours at 2° to 8°C (36° to 46°F). This medicinal product is for single dose 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

Fda-Approved Patient Labeling

  • Voriconazole for Injection(vor" i kon' a zole)Read the Patient Information that comes with voriconazole before you start 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 “aspergillosis,” “esophageal candidiasis,” “
  • Scedosporium,” “
  • Fusarium,” and “candidemia”.
  • It is not known if voriconazole for injection is safe and effective in children younger than 12 years old.Who should not take voriconazole for injection? Do not take voriconazole for injection if you:are allergic to voriconazole or any of the ingredients in voriconazole for injection. See the end of this leaflet for a complete list of ingredients in voriconazole for injection.
  • Are taking any of the following medicines:cisapride (Propulsid
  • ®)
  • Pimozide (Orap
  • ®)
  • Quinidine (like Quinaglute
  • ®)
  • Sirolimus (Rapamune
  • ®)
  • Rifampin (Rifadin
  • ®)
  • Carbamazepine (Tegretol
  • ®)
  • Long-acting barbiturates like phenobarbital (Luminal
  • ®)
  • Efavirenz (Sustiva
  • ®)
  • Ritonavir (Norvir
  • ®)
  • Rifabutin (Mycobutin
  • ®)
  • Ergotamine, dihydroergotamine (ergot alkaloids)
  • 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.What should I tell my healthcare provider before taking voriconazole for injection?Before you take voriconazole for injection, tell your healthcare provider 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.
  • Are breast-feeding or plan to breast-feed. It is not known if voriconazole 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 non-prescription 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 for injection 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:
  • Itchy skin
  • Yellowing of your eyes
  • Feeling very tired
  • Flu-like symptoms
  • Nausea or vomiting
  • Vision changes. Symptoms of vision changes may include:
  • Blurred vision
  • Changes in the way you see colors
  • 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:
  • Fever
  • Sweating
  • Feels like your heart is beating fast (tachycardia)
  • Chest tightness
  • Trouble breathing
  • Feel faint
  • Nausea
  • Itching
  • 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:
  • Rash or hives
  • Mouth sores
  • Blistering or peeling of your skin
  • 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:vision changes
  • Rash
  • Vomiting
  • Nausea
  • Headache
  • Fast heart beat (tachycardia)
  • Hallucinations (seeing or hearing things that are not there)
  • Abnormal liver function tests
  • 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. For more information, ask your healthcare provider or pharmacist.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, 59° to 86°F (15° to 30°C). 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.This Patient Information leaflet summarizes the most important information about voriconazole for injection. If you would like more information, talk to your healthcare provider. You can ask your healthcare provider or pharmacist for information about voriconazole for injection that is written for health professionals.This product’s label may have been updated. For more information visit www.SlateRunPharma.com.What are the ingredients of voriconazole for injection?Active ingredient: voriconazoleInactive ingredients: sulfobutyl ether beta-cyclodextrin sodiumThis Patient Information has been approved by the U.S. Food and Drug Administration.Manufactured by: Hainan Poly Pharm. Co., Ltd., Xingyang Road, Guilinyang Economic Development Area, Haikou, Hainan Province, China 571127Distributed by: Slate Run Pharmaceuticals, LLC, Columbus, Ohio 4321510000064/01Revised: 12/2018

* Please review the disclaimer below.

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