These Highlights Do Not Include All The Information Needed To Use Voriconazole For Injection Safely And Effectively. See Full Prescribing Information For Voriconazole For Injection.

SPL v8

SPL

SPL Set ID 9ec6eda2-2f15-423b-9ec6-819379a426e1

Route

INTRAVENOUS

Published

Effective Date 2023-01-31

Document Type 34391-3 HUMAN PRESCRIPTION DRUG LABEL

Drug Facts

Composition & Product

Active Ingredients

Voriconazole (10 mg)

Inactive Ingredients

Hydroxypropyl Betadex

Identifiers & Packaging

Marketing Status

NDA Active Since 2023-08-24

Description

Contraindications ( 4 ) 1/2023 Warnings and Precautions, Photosensitivity ( 5.6 ) 1/2023

Indications and Usage

Voriconazole for injection is an azole antifungal indicated for use in the treatment of 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 with: Invasive aspergillosis ( 1.1 ) Candidemia in non-neutropenics and other deep tissue Candida infections ( 1.2 ) Serious fungal infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani , in patients intolerant of, or refractory to, other therapy ( 1.3 )

Dosage and Administration

Dosage in Adults ( 2.3 ) Infection Loading dose Maintenance Dose Intravenous infusion Intravenous infusion Invasive Aspergillosis 6 mg/kg every 12 hours for the first 24 hours 4 mg/kg every 12 hours Candidemia in nonneutropenics and other deep tissue Candida infections 3–4 mg/kg every 12 hours Scedosporiosis and Fusariosis 4 mg/kg every 12 hours Hepatic Impairment : Use half the maintenance dose in adult patients with mild to moderate hepatic impairment (Child-Pugh Class A and B) ( 2.5 ) Renal Impairment : Avoid intravenous administration in adult patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) ( 2.6 ) Dosage in Pediatric Patients ( 2.4 ) For pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight use adult dosage. ( 2.4 ) Dosage adjustment of Voriconazole for injection in pediatric patients with renal or hepatic impairment has not been established. ( 2.5 , 2.6 ) See full prescribing information for instructions on reconstitution of Voriconazole for injection lyophilized powder for intravenous use ( 2.8 )

Warnings and Precautions

Hepatic Toxicity : Serious hepatic reactions reported. Evaluate liver function tests at start of and during Voriconazole for injection therapy ( 5.1 ) Arrhythmias and QT Prolongation : Correct potassium, magnesium and calcium prior to use; caution patients with proarrhythmic conditions ( 5.2 ) Infusion Related Reactions (including anaphylaxis) : Stop the infusion ( 5.3 ) Visual Disturbances (including optic neuritis and papilledema): Monitor visual function if treatment continues beyond 28 days ( 5.4 ) Severe Cutaneous Adverse Reactions : Discontinue for exfoliative cutaneous reactions ( 5.5 ) Photosensitivity : Avoid sunlight due to risk of photosensitivity ( 5.6 ) Adrenal Dysfunction : Carefully monitor patients receiving Voriconazole for injection and corticosteroids (via all routes of administration) for adrenal dysfunction both during and after Voriconazole for injection treatment. Instruct patients to seek immediate medical care if they develop signs and symptoms of Cushing's syndrome or adrenal insufficiency ( 5.8 ) Embryo-Fetal Toxicity : Voriconazole can cause fetal harm when administered to a pregnant woman. Inform pregnant patients of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with Voriconazole for injection ( 5.9 , 8.1 , 8.3 ) Skeletal Adverse Reactions : Fluorosis and periostitis with long-term voriconazole therapy. Discontinue if these adverse reactions occur ( 5.12 ) Clinically Significant Drug Interactions : Review patient's concomitant medications ( 5.13 , 7 )

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 for injection (voriconazole) and other azole antifungal agents. Caution should be used when prescribing Voriconazole for injection to patients with hypersensitivity to other azoles. Coadministration of pimozide, quinidine or ivabradine 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) ] . 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, long-acting barbiturates and St. John's Wort 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) ] . Coadministration of Voriconazole for injection with naloxegol is contraindicated because Voriconazole for injection may increase plasma concentrations of naloxegol which may precipitate opioid withdrawal symptoms [see Drug Interactions (7) ]. Coadministration of Voriconazole for injection with tolvaptan is contraindicated because Voriconazole for injection may increase tolvaptan plasma concentrations and increase risk of adverse reactions [see Drug Interactions (7) ]. Coadministration of Voriconazole for injection with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome [see Drug Interactions (7) ]. Coadministration of Voriconazole for injection with lurasidone is contraindicated since it may result in significant increases in lurasidone exposure and the potential for serious adverse reactions [see Drug Interactions (7) ] .

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) ] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5) ] Photosensitivity [see Warnings and Precautions (5.6) ] Renal Toxicity [see Warnings and Precautions (5.7) ]

Drug Interactions

Voriconazole is metabolized by cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Therefore, inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively. Voriconazole is a strong inhibitor of CYP3A4, and also inhibits CYP2C19 and CYP2C9. Therefore, voriconazole may increase the plasma concentrations of substances metabolized by these CYP450 isoenzymes. Tables 6 and 7 provide the clinically significant interactions between voriconazole and other medical products. Table 6: 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 every 12 hours) Recommendations for Voriconazole Dosage Adjustment/Comments Rifampin and Rifabutin (CYP450 Induction) Significantly Reduced Contraindicated Efavirenz (400 mg every 24 hours) (CYP450 Induction) Significantly Reduced Contraindicated High-dose Ritonavir (400 mg every 12 hours) (CYP450 Induction) Significantly Reduced Contraindicated Low-dose Ritonavir (100 mg every 12 hours) (CYP450 Induction) Reduced 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 Carbamazepine (CYP450 Induction) Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction Contraindicated Long Acting Barbiturates (e.g., phenobarbital, mephobarbital) (CYP450 Induction) Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction Contraindicated Phenytoin (CYP450 Induction) Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every12 hours Letermovir (CYP2C9/2C19 Induction) Reduced If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole. St. John's Wort (CYP450 inducer; P-gp inducer) Significantly Reduced Contraindicated Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) Increased Monitoring for adverse reactions and toxicity related to voriconazole is recommended when coadministered with oral contraceptives Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions 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 No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir. In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to voriconazole when coadministered with other HIV protease inhibitors Other 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). Frequent monitoring for adverse reactions and toxicity related to voriconazole 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) Careful assessment of voriconazole effectiveness Table 7: 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 τ ) Recommendations for Drug Dosage Adjustment/Comments Sirolimus (CYP3A4 Inhibition) Significantly Increased Contraindicated Rifabutin (CYP3A4 Inhibition) Significantly Increased Contraindicated Efavirenz (400 mg every 24 hours) (CYP3A4 Inhibition) Significantly Increased Contraindicated High-dose Ritonavir (400 mg every 12 hours) (CYP3A4 Inhibition) No Significant Effect of Voriconazole on Ritonavir C max or AUC τ Contraindicated because of significant reduction of voriconazole C max and AUC τ Low-dose Ritonavir (100 mg every 12 hours) Slight Decrease in Ritonavir C max and AUC τ Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) 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 Pimozide, Quinidine, Ivabradine (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 pointes Ergot Alkaloids (CYP450 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Contraindicated Naloxegol (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions Contraindicated Tolvaptan (CYP3A4 Inhibition) Although Not Studied Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Tolvaptan Contraindicated Venetoclax (CYP3A4 Inhibition) Not studied In Vivo or In Vitro , but Venetoclax Plasma Exposure Likely to be Significantly Increased Coadministration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering Voriconazole for injection with venetoclax. Refer to the venetoclax prescribing information for dosing instructions. Lemborexant (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Avoid concomitant use of Voriconazole for injection with lemborexant. Glasdegib (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Consider alternative therapies. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions including QTc interval prolongation. Tyrosine kinase inhibitors (including but not limited to axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Avoid concomitant use of Voriconazole for injection. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product. Lurasidone (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone Contraindicated Cyclosporine (CYP3A4 Inhibition) AUC τ Significantly Increased; No Significant Effect on C max When initiating therapy with Voriconazole for injection 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 for injection is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. Methadone (CYP3A4 Inhibition) Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse reactions and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed. Fentanyl (CYP3A4 Inhibition) Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with Voriconazole for injection. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary. Alfentanil (CYP3A4 Inhibition) Significantly Increased An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when coadministered with Voriconazole for injection. Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with Voriconazole for injection. A longer period for monitoring respiratory and other opiate-associated adverse reactions may be necessary. Oxycodone (CYP3A4 Inhibition) Significantly Increased Increased visual effects (heterophoria and miosis) of oxycodone were observed when coadministered with Voriconazole for injection. Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with Voriconazole for injection. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary. NSAIDs Non-Steroidal Anti-Inflammatory Drug including ibuprofen and diclofenac (CYP2C9 Inhibition) Increased Frequent monitoring for adverse reactions and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. Tacrolimus (CYP3A4 Inhibition) Significantly Increased When initiating therapy with Voriconazole for injection 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 for injection is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. Phenytoin (CYP2C9 Inhibition) Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) Increased Monitoring for adverse reactions related to oral contraceptives is recommended during coadministration. Prednisolone and other corticosteroids (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects of Voriconazole for injection on Prednisolone Exposure No dosage adjustment for prednisolone when coadministered with Voriconazole for injection [see Clinical Pharmacology (12.3) ] . Not Studied In vitro or In vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased Monitor for potential adrenal dysfunction when Voriconazole for injection is administered with other corticosteroids [see Warnings and Precautions (5.8) ] . Warfarin (CYP2C9 Inhibition) Prothrombin Time Significantly Increased 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. Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition) Not Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be Increased Ivacaftor (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions Dose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor Eszopiclone (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Sedative Effect of Eszopiclone Dose reduction of eszopiclone is recommended. Refer to the prescribing information for eszopiclone. Omeprazole (CYP2C19/3A4 Inhibition) Significantly Increased When initiating therapy with Voriconazole for injection 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 No dosage adjustment for indinavir when coadministered with Voriconazole for injection In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to other HIV protease inhibitors Other 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 reactions and toxicity related to NNRTI. Tretinoin (CYP3A4 Inhibition) Although Not Studied, Voriconazole may Increase Tretinoin Concentrations and Increase the Risk of Adverse Reactions Frequent monitoring for signs and symptoms of pseudotumor cerebri or hypercalcemia. Midazolam (CYP3A4 Inhibition) Significantly Increased Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines. Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Refer to drug-specific labeling for details. HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse reactions 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 reactions 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 reactions and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including Voriconazole for injection, 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 for injection and everolimus is not recommended.

How Supplied

Voriconazole for injection is supplied in a single dose-vial as a sterile white to off white lyophilized cake or powder equivalent to 200 mg voriconazole and 3,200 mg hydroxypropyl β-cyclodextrin (HPβCD). It does not contain preservatives and is not made with natural rubber latex. Individually packaged vials of Voriconazole for injection, 200 mg, NDC 70594-067-01.

Medication Information

Warnings and Precautions

Indications and Usage

Dosage and Administration

Contraindications

Adverse Reactions

Drug Interactions

How Supplied

Description

Contraindications ( 4 ) 1/2023 Warnings and Precautions, Photosensitivity ( 5.6 ) 1/2023

Section 42229-5

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 for injection therapy [see Warnings and Precautions (5.10)].

Section 43683-2

Contraindications (4)	1/2023
Warnings and Precautions, Photosensitivity (5.6)	1/2023

1.4 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) for injection. However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information.

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, HPβCD, is hemodialyzed with clearance of 37.5±24 mL/min. In an overdose, hemodialysis may assist in the removal of voriconazole and HPβCD from the body.

11 Description

Voriconazole for injection, an azole antifungal is available as a sterile lyophilized cake or powder for solution for intravenous infusion. The structural formula is:

Voriconazole 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 C₁₆H₁₄F₃N₅O and a molecular weight of 349.3.

Voriconazole drug substance is a white or almost white powder.

Voriconazole for injection is a white to off white lyophilized cake or powder containing nominally 200 mg voriconazole and 3200 mg hydroxypropyl β-cyclodextrin (HPβCD) in a 30 mL Type I clear glass vial.

Voriconazole for injection is intended for administration by intravenous infusion. It is an unpreserved product in a single dose vial. 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 hydroxypropyl β-cyclodextrin (HPβCD). The resultant solution is further diluted prior to administration as an intravenous infusion [see Dosage and Administration (2)].

16.1 How Supplied

Individually packaged vials of Voriconazole for injection, 200 mg, NDC 70594-067-01.

5.11 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.

8.4 Pediatric Use

The safety and effectiveness of voriconazole 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 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 cell carcinoma has been reported in patients who experience photosensitivity reactions. Stringent measures for photoprotection are warranted. Sun avoidance and dermatologic follow-up are recommended in pediatric patients experiencing photoaging 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, 5.10)].

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)].

5.7 Renal Toxicity

Hydroxypropyl-β-cyclodextrin (HPβCD), the intravenous vehicle of Voriconazole for injection, is eliminated through glomerular filtration. Therefore, in patients with moderate to severe renal dysfunction (creatinine clearance <50 mL/min), accumulation of HPβCD occurs. Serum creatinine (Scr) levels should be closely monitored in patients with renal impairment. If increases in Scr occur, consideration should be given to changing to alternate antifungal therapy with similar coverage, unless an assessment of the benefit/risk to the patient justifies the continued use of intravenous Voriconazole for injection [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].

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)].

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.

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 for injection (voriconazole) and other azole antifungal agents. Caution should be used when prescribing Voriconazole for injection to patients with hypersensitivity to other azoles.
Coadministration of pimozide, quinidine or ivabradine 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)].
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, long-acting barbiturates and St. John's Wort 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)].
Coadministration of Voriconazole for injection with naloxegol is contraindicated because Voriconazole for injection may increase plasma concentrations of naloxegol which may precipitate opioid withdrawal symptoms [see Drug Interactions (7)].
Coadministration of Voriconazole for injection with tolvaptan is contraindicated because Voriconazole for injection may increase tolvaptan plasma concentrations and increase risk of adverse reactions [see Drug Interactions (7)].
Coadministration of Voriconazole for injection with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome [see Drug Interactions (7)].
Coadministration of Voriconazole for injection with lurasidone is contraindicated since it may result in significant increases in lurasidone exposure and the potential for serious adverse reactions [see 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)]

Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5)]

Photosensitivity [see Warnings and Precautions (5.6)]

Renal Toxicity [see Warnings and Precautions (5.7)]

7 Drug Interactions

Tables 6 and 7 provide the clinically significant interactions between voriconazole and other medical products.

Table 6: 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 every 12 hours)	Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin and Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg every 24 hours) (CYP450 Induction)	Significantly Reduced	Contraindicated
High-dose Ritonavir (400 mg every 12 hours) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg every 12 hours) (CYP450 Induction)	Reduced	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
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (e.g., phenobarbital, mephobarbital) (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every12 hours
Letermovir (CYP2C9/2C19 Induction)	Reduced	If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole.
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse reactions and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions 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	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir.
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other 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).	Frequent monitoring for adverse reactions and toxicity related to voriconazole
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)	Careful assessment of voriconazole effectiveness

Table 7: 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_τ)	Recommendations for Drug Dosage Adjustment/Comments
Sirolimus (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg every 24 hours) (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
High-dose Ritonavir (400 mg every 12 hours) (CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ
Low-dose Ritonavir (100 mg every 12 hours)	Slight Decrease in Ritonavir C_max and AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) 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
Pimozide, Quinidine, Ivabradine (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 pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Naloxegol (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Contraindicated
Tolvaptan (CYP3A4 Inhibition)	Although Not Studied Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Tolvaptan	Contraindicated
Venetoclax (CYP3A4 Inhibition)	Not studied In Vivo or In Vitro, but Venetoclax Plasma Exposure Likely to be Significantly Increased	Coadministration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering Voriconazole for injection with venetoclax. Refer to the venetoclax prescribing information for dosing instructions.
Lemborexant (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of Voriconazole for injection with lemborexant.
Glasdegib (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Consider alternative therapies. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions including QTc interval prolongation.
Tyrosine kinase inhibitors (including but not limited to axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of Voriconazole for injection. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product.
Lurasidone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone	Contraindicated
Cyclosporine (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with Voriconazole for injection 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 for injection is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse reactions and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed.
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with Voriconazole for injection. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary.
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when coadministered with Voriconazole for injection. Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with Voriconazole for injection. A longer period for monitoring respiratory and other opiate-associated adverse reactions may be necessary.
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Increased visual effects (heterophoria and miosis) of oxycodone were observed when coadministered with Voriconazole for injection. Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with Voriconazole for injection. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary.
NSAIDs Non-Steroidal Anti-Inflammatory Drug including ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse reactions and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed.
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with Voriconazole for injection 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 for injection is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse reactions related to oral contraceptives is recommended during coadministration.
Prednisolone and other corticosteroids (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Voriconazole for injection on Prednisolone Exposure	No dosage adjustment for prednisolone when coadministered with Voriconazole for injection [see Clinical Pharmacology (12.3)].
Not Studied In vitro or In vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased	Monitor for potential adrenal dysfunction when Voriconazole for injection is administered with other corticosteroids [see Warnings and Precautions (5.8)].
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	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.
Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition)	Not Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be Increased
Ivacaftor (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Dose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor
Eszopiclone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased which may Increase the Sedative Effect of Eszopiclone	Dose reduction of eszopiclone is recommended. Refer to the prescribing information for eszopiclone.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with Voriconazole for injection 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	No dosage adjustment for indinavir when coadministered with Voriconazole for injection
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to other HIV protease inhibitors
Other 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 reactions and toxicity related to NNRTI.
Tretinoin (CYP3A4 Inhibition)	Although Not Studied, Voriconazole may Increase Tretinoin Concentrations and Increase the Risk of Adverse Reactions	Frequent monitoring for signs and symptoms of pseudotumor cerebri or hypercalcemia.
Midazolam (CYP3A4 Inhibition)	Significantly Increased	Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines.
Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Refer to drug-specific labeling for details.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions 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 reactions 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 reactions and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including Voriconazole for injection, 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 for injection and everolimus is not recommended.

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)].

5.6 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 (including cutaneous SCC in situ, or Bowen's disease) 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, as well as increased risk of skin toxicity with concomitant use of methotrexate, a drug associated with ultraviolet (UV) reactivation. There is the potential for this risk to be observed with other drugs associated with UV reactivation. 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.

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 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 8).

Table 8: Geometric Mean (%CV) Plasma Voriconazole Pharmacokinetic Parameters in Adults Receiving Different Dosing Regimens

	6 mg/kg IV (loading dose)	3 mg/kg IV every 12 hours	4 mg/kg IV every 12 hours
Note: Parameters were estimated based on non-compartmental analysis from 5 pharmacokinetic studies. AUC₁₂ = area under the curve over 12 hour dosing interval, C_max = maximum plasma concentration, C_min = minimum plasma concentration. CV = coefficient of variation.
N	35	23	40
AUC₁₂ (μg∙h/mL)	13.9 (32)	13.7 (53)	33.9 (54)
C_max (μg/mL)	3.13 (20)	3.03 (25)	4.77 (36)
C_min (μg/mL)	--	0.46 (97)	1.73 (74)

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.

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)].

5.10 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).

14.4 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 4 mg/kg every 12 hours.

1 Indications and Usage

Invasive aspergillosis (1.1)
Candidemia in non-neutropenics and other deep tissue Candida infections (1.2)
Serious fungal infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani, in patients intolerant of, or refractory to, other therapy (1.3)

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 reactions, 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)].

5.8 Adrenal Dysfunction

Reversible cases of azole-induced adrenal insufficiency have been reported in patients receiving azoles, including Voriconazole for injection. Adrenal insufficiency has been reported in patients receiving azoles with or without concomitant corticosteroids. In patients receiving azoles without corticosteroids adrenal insufficiency is related to direct inhibition of steroidogenesis by azoles. In patients taking corticosteroids, voriconazole associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. Cushing's syndrome with and without subsequent adrenal insufficiency has also been reported in patients receiving Voriconazole for injection concomitantly with corticosteroids.

Patients receiving Voriconazole for injection and corticosteroids (via all routes of administration) should be carefully monitored for adrenal dysfunction both during and after Voriconazole for injection treatment. Patients should be instructed to seek immediate medical care if they develop signs and symptoms of Cushing's syndrome or adrenal insufficiency.

12.1 Mechanism of Action

Voriconazole is an antifungal drug [see Microbiology (12.4)].

5.9 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)].

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) and Microbiology (12.4)].

5 Warnings and Precautions

Hepatic Toxicity: Serious hepatic reactions reported. Evaluate liver function tests at start of and during Voriconazole for injection therapy (5.1)
Arrhythmias and QT Prolongation: Correct potassium, magnesium and calcium prior to use; caution patients with proarrhythmic conditions (5.2)
Infusion Related Reactions (including anaphylaxis): Stop the infusion (5.3)
Visual Disturbances (including optic neuritis and papilledema): Monitor visual function if treatment continues beyond 28 days (5.4)
Severe Cutaneous Adverse Reactions: Discontinue for exfoliative cutaneous reactions (5.5)
Photosensitivity: Avoid sunlight due to risk of photosensitivity (5.6)
Adrenal Dysfunction: Carefully monitor patients receiving Voriconazole for injection and corticosteroids (via all routes of administration) for adrenal dysfunction both during and after Voriconazole for injection treatment. Instruct patients to seek immediate medical care if they develop signs and symptoms of Cushing's syndrome or adrenal insufficiency (5.8)
Embryo-Fetal Toxicity: Voriconazole can cause fetal harm when administered to a pregnant woman. Inform pregnant patients of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with Voriconazole for injection (5.9, 8.1, 8.3)
Skeletal Adverse Reactions: Fluorosis and periostitis with long-term voriconazole therapy. Discontinue if these adverse reactions occur (5.12)
Clinically Significant Drug Interactions: Review patient's concomitant medications (5.13, 7)

2 Dosage and Administration

Dosage in Adults (2.3)

Infection	Loading dose	Maintenance Dose
Intravenous infusion	Intravenous infusion
Invasive Aspergillosis	6 mg/kg every 12 hours for the first 24 hours	4 mg/kg every 12 hours
Candidemia in nonneutropenics and other deep tissue Candida infections	3–4 mg/kg every 12 hours
Scedosporiosis and Fusariosis	4 mg/kg every 12 hours

Hepatic Impairment: Use half the maintenance dose in adult patients with mild to moderate hepatic impairment (Child-Pugh Class A and B) (2.5)
Renal Impairment: Avoid intravenous administration in adult patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) (2.6)

Dosage in Pediatric Patients (2.4)
For pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight use adult dosage. (2.4)
Dosage adjustment of Voriconazole for injection in pediatric patients with renal or hepatic impairment has not been established. (2.5, 2.6)
See full prescribing information for instructions on reconstitution of Voriconazole for injection lyophilized powder for intravenous use (2.8)

3 Dosage Forms and Strengths

For Injection: Lyophilized white to off white cake or powder containing 200 mg voriconazole and 3,200 mg of hydroxypropyl β-cyclodextrin (HPβCD); after reconstitution 10 mg/mL of voriconazole and 160 mg/mL of HPβCD (3)

8 Use in Specific Populations

Pediatrics: Safety and effectiveness in patients younger than 2 years has not been established (8.4)

5.3 Infusion Related Reactions

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.

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.

5.12 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)].

14.1 Invasive Aspergillosis (ia)

Voriconazole was studied in patients for primary therapy of IA (randomized, controlled study 307/602), for primary and salvage therapy of aspergillosis (non-comparative study 304) and for treatment of patients with IA who were refractory to, or intolerant of, other antifungal therapy (non-comparative study 309/604).

1.3 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 adult 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 (14.3) and Microbiology (12.4)].

14.3 Other Serious Fungal Pathogens

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

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 for injection. 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)].

5.5 Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with Voriconazole for injection. If a patient develops a severe cutaneous adverse reaction, Voriconazole for injection should be discontinued [see Adverse Reactions (6.1, 6.2)].

Principal Display Panel 200 Mg Vial Label

NDC 70594-067-01

Rx Only

Voriconazole

for Injection

200 MG* per vial

Not made with natural rubber latex

No Preservatives

Sterile Single Dose Vial

Must be reconstituted then diluted

For Intravenous Infusion Only

Discard Unused Portion

5.13 Clinically Significant Drug Interactions

See Table 6 for a listing of drugs that may significantly alter voriconazole concentrations. Also, see Table 7 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)].

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.

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 RMD on a body surface area 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 body surface area 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.

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.

2.1 Important Administration 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 3 hours.

Administer diluted Voriconazole for injection by intravenous infusion over 1 to 3 hours only. Do not administer as an IV bolus injection.

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)].

1.2 Candidemia in Non Neutropenic Patients and Other Deep Tissue Candida

Voriconazole for injection is indicated in adult 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) and Microbiology (12.4)].

14.2 Candidemia in Non Neutropenic Patients and Other Deep Tissue Candida

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 11.

Table 11: Overall Success Rates Sustained From EOT To The Fixed 12-Week Follow-Up Time Point By Baseline Pathogen

A few patients had more than one pathogen at baseline.

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

Baseline Pathogen	Clinical and Mycological Success (%)
	Voriconazole	Amphotericin B --> Fluconazole
C. albicans	46/107 (43%)	30/63 (48%)
C. tropicalis	17/53 (32%)	1/16 (6%)
C. parapsilosis	24/45 (53%)	10/19 (53%)
C. glabrata	12/36 (33%)	7/21 (33%)
C. krusei	1/4	0/1

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.

Structured Label Content

Section 42229-5 (42229-5)

Blood products and concentrated electrolytes

Section 43683-2 (43683-2)

Contraindications (4)	1/2023
Warnings and Precautions, Photosensitivity (5.6)	1/2023

1.4 Usage

10 Overdosage (10 OVERDOSAGE)

There is no known antidote to voriconazole.

11 Description (11 DESCRIPTION)

Voriconazole for injection, an azole antifungal is available as a sterile lyophilized cake or powder for solution for intravenous infusion. The structural formula is:

Voriconazole drug substance is a white or almost white powder.

16.1 How Supplied

Individually packaged vials of Voriconazole for injection, 200 mg, NDC 70594-067-01.

5.11 Pancreatitis

Pancreatitis has been observed in patients undergoing treatment with Voriconazole for injection [see Adverse Reactions (6.1, 6.2)].

8.4 Pediatric Use

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)].

8.5 Geriatric Use

5.7 Renal Toxicity

14 Clinical Studies (14 CLINICAL STUDIES)

4 Contraindications (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 for injection (voriconazole) and other azole antifungal agents. Caution should be used when prescribing Voriconazole for injection to patients with hypersensitivity to other azoles.
Coadministration of pimozide, quinidine or ivabradine 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)].
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, long-acting barbiturates and St. John's Wort 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)].
Coadministration of Voriconazole for injection with naloxegol is contraindicated because Voriconazole for injection may increase plasma concentrations of naloxegol which may precipitate opioid withdrawal symptoms [see Drug Interactions (7)].
Coadministration of Voriconazole for injection with tolvaptan is contraindicated because Voriconazole for injection may increase tolvaptan plasma concentrations and increase risk of adverse reactions [see Drug Interactions (7)].
Coadministration of Voriconazole for injection with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome [see Drug Interactions (7)].
Coadministration of Voriconazole for injection with lurasidone is contraindicated since it may result in significant increases in lurasidone exposure and the potential for serious adverse reactions [see Drug Interactions (7)].

6 Adverse Reactions (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)]

Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5)]

Photosensitivity [see Warnings and Precautions (5.6)]

Renal Toxicity [see Warnings and Precautions (5.7)]

7 Drug Interactions (7 DRUG INTERACTIONS)

Tables 6 and 7 provide the clinically significant interactions between voriconazole and other medical products.

Table 6: 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 every 12 hours)	Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin and Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg every 24 hours) (CYP450 Induction)	Significantly Reduced	Contraindicated
High-dose Ritonavir (400 mg every 12 hours) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg every 12 hours) (CYP450 Induction)	Reduced	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
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (e.g., phenobarbital, mephobarbital) (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every12 hours
Letermovir (CYP2C9/2C19 Induction)	Reduced	If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole.
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse reactions and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions 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	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir.
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other 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).	Frequent monitoring for adverse reactions and toxicity related to voriconazole
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)	Careful assessment of voriconazole effectiveness

Table 7: 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_τ)	Recommendations for Drug Dosage Adjustment/Comments
Sirolimus (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg every 24 hours) (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
High-dose Ritonavir (400 mg every 12 hours) (CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ
Low-dose Ritonavir (100 mg every 12 hours)	Slight Decrease in Ritonavir C_max and AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) 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
Pimozide, Quinidine, Ivabradine (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 pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Naloxegol (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Contraindicated
Tolvaptan (CYP3A4 Inhibition)	Although Not Studied Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Tolvaptan	Contraindicated
Venetoclax (CYP3A4 Inhibition)	Not studied In Vivo or In Vitro, but Venetoclax Plasma Exposure Likely to be Significantly Increased	Coadministration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering Voriconazole for injection with venetoclax. Refer to the venetoclax prescribing information for dosing instructions.
Lemborexant (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of Voriconazole for injection with lemborexant.
Glasdegib (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Consider alternative therapies. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions including QTc interval prolongation.
Tyrosine kinase inhibitors (including but not limited to axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Avoid concomitant use of Voriconazole for injection. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product.
Lurasidone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone	Contraindicated
Cyclosporine (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with Voriconazole for injection 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 for injection is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse reactions and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed.
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with Voriconazole for injection. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary.
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when coadministered with Voriconazole for injection. Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with Voriconazole for injection. A longer period for monitoring respiratory and other opiate-associated adverse reactions may be necessary.
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Increased visual effects (heterophoria and miosis) of oxycodone were observed when coadministered with Voriconazole for injection. Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with Voriconazole for injection. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary.
NSAIDs Non-Steroidal Anti-Inflammatory Drug including ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse reactions and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed.
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with Voriconazole for injection 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 for injection is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse reactions related to oral contraceptives is recommended during coadministration.
Prednisolone and other corticosteroids (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Voriconazole for injection on Prednisolone Exposure	No dosage adjustment for prednisolone when coadministered with Voriconazole for injection [see Clinical Pharmacology (12.3)].
Not Studied In vitro or In vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased	Monitor for potential adrenal dysfunction when Voriconazole for injection is administered with other corticosteroids [see Warnings and Precautions (5.8)].
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	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.
Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition)	Not Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be Increased
Ivacaftor (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions	Dose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor
Eszopiclone (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased which may Increase the Sedative Effect of Eszopiclone	Dose reduction of eszopiclone is recommended. Refer to the prescribing information for eszopiclone.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with Voriconazole for injection 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	No dosage adjustment for indinavir when coadministered with Voriconazole for injection
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions and toxicity related to other HIV protease inhibitors
Other 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 reactions and toxicity related to NNRTI.
Tretinoin (CYP3A4 Inhibition)	Although Not Studied, Voriconazole may Increase Tretinoin Concentrations and Increase the Risk of Adverse Reactions	Frequent monitoring for signs and symptoms of pseudotumor cerebri or hypercalcemia.
Midazolam (CYP3A4 Inhibition)	Significantly Increased	Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines.
Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Refer to drug-specific labeling for details.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse reactions 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 reactions 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 reactions and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including Voriconazole for injection, 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 for injection and everolimus is not recommended.

5.1 Hepatic Toxicity

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.

5.6 Photosensitivity

12.3 Pharmacokinetics

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

Table 8: Geometric Mean (%CV) Plasma Voriconazole Pharmacokinetic Parameters in Adults Receiving Different Dosing Regimens

	6 mg/kg IV (loading dose)	3 mg/kg IV every 12 hours	4 mg/kg IV every 12 hours
Note: Parameters were estimated based on non-compartmental analysis from 5 pharmacokinetic studies. AUC₁₂ = area under the curve over 12 hour dosing interval, C_max = maximum plasma concentration, C_min = minimum plasma concentration. CV = coefficient of variation.
N	35	23	40
AUC₁₂ (μg∙h/mL)	13.9 (32)	13.7 (53)	33.9 (54)
C_max (μg/mL)	3.13 (20)	3.03 (25)	4.77 (36)
C_min (μg/mL)	--	0.46 (97)	1.73 (74)

12.5 Pharmacogenomics

5.10 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).

14.4 Pediatric Studies

1 Indications and Usage (1 INDICATIONS AND USAGE)

Invasive aspergillosis (1.1)
Candidemia in non-neutropenics and other deep tissue Candida infections (1.2)
Serious fungal infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani, in patients intolerant of, or refractory to, other therapy (1.3)

5.4 Visual Disturbances

5.8 Adrenal Dysfunction

12.1 Mechanism of Action

Voriconazole is an antifungal drug [see Microbiology (12.4)].

5.9 Embryo Fetal Toxicity (5.9 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)].

1.1 Invasive Aspergillosis

5 Warnings and Precautions (5 WARNINGS AND PRECAUTIONS)

Hepatic Toxicity: Serious hepatic reactions reported. Evaluate liver function tests at start of and during Voriconazole for injection therapy (5.1)
Arrhythmias and QT Prolongation: Correct potassium, magnesium and calcium prior to use; caution patients with proarrhythmic conditions (5.2)
Infusion Related Reactions (including anaphylaxis): Stop the infusion (5.3)
Visual Disturbances (including optic neuritis and papilledema): Monitor visual function if treatment continues beyond 28 days (5.4)
Severe Cutaneous Adverse Reactions: Discontinue for exfoliative cutaneous reactions (5.5)
Photosensitivity: Avoid sunlight due to risk of photosensitivity (5.6)
Adrenal Dysfunction: Carefully monitor patients receiving Voriconazole for injection and corticosteroids (via all routes of administration) for adrenal dysfunction both during and after Voriconazole for injection treatment. Instruct patients to seek immediate medical care if they develop signs and symptoms of Cushing's syndrome or adrenal insufficiency (5.8)
Embryo-Fetal Toxicity: Voriconazole can cause fetal harm when administered to a pregnant woman. Inform pregnant patients of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with Voriconazole for injection (5.9, 8.1, 8.3)
Skeletal Adverse Reactions: Fluorosis and periostitis with long-term voriconazole therapy. Discontinue if these adverse reactions occur (5.12)
Clinically Significant Drug Interactions: Review patient's concomitant medications (5.13, 7)

2 Dosage and Administration (2 DOSAGE AND ADMINISTRATION)

Dosage in Adults (2.3)

Infection	Loading dose	Maintenance Dose
Intravenous infusion	Intravenous infusion
Invasive Aspergillosis	6 mg/kg every 12 hours for the first 24 hours	4 mg/kg every 12 hours
Candidemia in nonneutropenics and other deep tissue Candida infections	3–4 mg/kg every 12 hours
Scedosporiosis and Fusariosis	4 mg/kg every 12 hours

Hepatic Impairment: Use half the maintenance dose in adult patients with mild to moderate hepatic impairment (Child-Pugh Class A and B) (2.5)
Renal Impairment: Avoid intravenous administration in adult patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) (2.6)

Dosage in Pediatric Patients (2.4)
For pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight use adult dosage. (2.4)
Dosage adjustment of Voriconazole for injection in pediatric patients with renal or hepatic impairment has not been established. (2.5, 2.6)
See full prescribing information for instructions on reconstitution of Voriconazole for injection lyophilized powder for intravenous use (2.8)

3 Dosage Forms and Strengths (3 DOSAGE FORMS AND STRENGTHS)

8 Use in Specific Populations (8 USE IN SPECIFIC POPULATIONS)

Pediatrics: Safety and effectiveness in patients younger than 2 years has not been established (8.4)

5.3 Infusion Related Reactions

6.1 Clinical Trials Experience

5.12 Skeletal Adverse Reactions

14.1 Invasive Aspergillosis (ia) (14.1 Invasive Aspergillosis (IA))

1.3 Scedosporiosis and Fusariosis

14.3 Other Serious Fungal Pathogens

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

5.2 Arrhythmias and Qt Prolongation (5.2 Arrhythmias and QT Prolongation)

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)].

5.5 Severe Cutaneous Adverse Reactions

Principal Display Panel 200 Mg Vial Label (PRINCIPAL DISPLAY PANEL - 200 MG Vial Label)

NDC 70594-067-01

Rx Only

Voriconazole

for Injection

200 MG* per vial

Not made with natural rubber latex

No Preservatives

Sterile Single Dose Vial

Must be reconstituted then diluted

For Intravenous Infusion Only

Discard Unused Portion

5.13 Clinically Significant Drug Interactions

2.4 Recommended Dosing Regimen in Pediatric Patients

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

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

6.2 Postmarketing Experience in Adult and Pediatric Patients

2.1 Important Administration Instructions for Use in All Patients

Administer diluted Voriconazole for injection by intravenous infusion over 1 to 3 hours only. Do not administer as an IV bolus injection.

2.7 Dosage Adjustment When Co Administered With Phenytoin Or Efavirenz (2.7 Dosage Adjustment When Co-Administered With Phenytoin or Efavirenz)

1.2 Candidemia in Non Neutropenic Patients and Other Deep Tissue Candida (1.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue Candida)

14.2 Candidemia in Non Neutropenic Patients and Other Deep Tissue Candida (14.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue Candida)

The overall clinical and mycological success rates by Candida species in Study 150-608 are presented in Table 11.

Table 11: Overall Success Rates Sustained From EOT To The Fixed 12-Week Follow-Up Time Point By Baseline Pathogen

A few patients had more than one pathogen at baseline.

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

Baseline Pathogen	Clinical and Mycological Success (%)
	Voriconazole	Amphotericin B --> Fluconazole
C. albicans	46/107 (43%)	30/63 (48%)
C. tropicalis	17/53 (32%)	1/16 (6%)
C. parapsilosis	24/45 (53%)	10/19 (53%)
C. glabrata	12/36 (33%)	7/21 (33%)
C. krusei	1/4	0/1

Advanced Ingredient Data

[{"name": "VORICONAZOLE", "unii": "JFU09I87TR", "classCode": "ACTIB", "strengthNumerator": "10", "strengthDenominator": "1", "strengthNumeratorUnit": "mg", "strengthDenominatorUnit": "mL"}, {"name": "HYDROXYPROPYL BETADEX", "unii": "1I96OHX6EK", "classCode": "IACT", "strengthNumerator": "", "strengthDenominator": "", "strengthNumeratorUnit": "", "strengthDenominatorUnit": ""}]

Raw Label Data

All Sections (JSON)

{"42229-5": "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 for injection therapy [see Warnings and Precautions (5.10) ] .", "43683-2": "Contraindications ( 4 ) 1/2023 Warnings and Precautions, Photosensitivity ( 5.6 ) 1/2023", "1.4 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) for injection. However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information.", "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, HPβCD, is hemodialyzed with clearance of 37.5±24 mL/min. In an overdose, hemodialysis may assist in the removal of voriconazole and HPβCD from the body.", "11 DESCRIPTION": "Voriconazole for injection, an azole antifungal is available as a sterile lyophilized cake or powder for solution for intravenous infusion. 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 16 H 14 F 3 N 5 O and a molecular weight of 349.3. Voriconazole drug substance is a white or almost white powder. Voriconazole for injection is a white to off white lyophilized cake or powder containing nominally 200 mg voriconazole and 3200 mg hydroxypropyl β-cyclodextrin (HPβCD) in a 30 mL Type I clear glass vial. Voriconazole for injection is intended for administration by intravenous infusion. It is an unpreserved product in a single dose vial. 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 hydroxypropyl β-cyclodextrin (HPβCD). The resultant solution is further diluted prior to administration as an intravenous infusion [see Dosage and Administration (2) ] .", "16.1 How Supplied": "Voriconazole for injection is supplied in a single dose-vial as a sterile white to off white lyophilized cake or powder equivalent to 200 mg voriconazole and 3,200 mg hydroxypropyl β-cyclodextrin (HPβCD). It does not contain preservatives and is not made with natural rubber latex. Individually packaged vials of Voriconazole for injection, 200 mg, NDC 70594-067-01.", "5.11 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.", "8.4 Pediatric Use": "The safety and effectiveness of voriconazole 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 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 cell carcinoma has been reported in patients who experience photosensitivity reactions. Stringent measures for photoprotection are warranted. Sun avoidance and dermatologic follow-up are recommended in pediatric patients experiencing photoaging 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 , 5.10) ] . Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole) for injection. 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 (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) ] .", "5.7 Renal Toxicity": "Hydroxypropyl-β-cyclodextrin (HPβCD), the intravenous vehicle of Voriconazole for injection, is eliminated through glomerular filtration. Therefore, in patients with moderate to severe renal dysfunction (creatinine clearance <50 mL/min), accumulation of HPβCD occurs. Serum creatinine (Scr) levels should be closely monitored in patients with renal impairment. If increases in Scr occur, consideration should be given to changing to alternate antifungal therapy with similar coverage, unless an assessment of the benefit/risk to the patient justifies the continued use of intravenous Voriconazole for injection [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3) ] . 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) ] .", "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.", "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 for injection (voriconazole) and other azole antifungal agents. Caution should be used when prescribing Voriconazole for injection to patients with hypersensitivity to other azoles. Coadministration of pimozide, quinidine or ivabradine 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) ] . 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, long-acting barbiturates and St. John's Wort 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) ] . Coadministration of Voriconazole for injection with naloxegol is contraindicated because Voriconazole for injection may increase plasma concentrations of naloxegol which may precipitate opioid withdrawal symptoms [see Drug Interactions (7) ]. Coadministration of Voriconazole for injection with tolvaptan is contraindicated because Voriconazole for injection may increase tolvaptan plasma concentrations and increase risk of adverse reactions [see Drug Interactions (7) ]. Coadministration of Voriconazole for injection with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome [see Drug Interactions (7) ]. Coadministration of Voriconazole for injection with lurasidone is contraindicated since it may result in significant increases in lurasidone exposure and the potential for serious adverse reactions [see 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) ] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5) ] Photosensitivity [see Warnings and Precautions (5.6) ] Renal Toxicity [see Warnings and Precautions (5.7) ]", "7 DRUG INTERACTIONS": "Voriconazole is metabolized by cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Therefore, inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively. Voriconazole is a strong inhibitor of CYP3A4, and also inhibits CYP2C19 and CYP2C9. Therefore, voriconazole may increase the plasma concentrations of substances metabolized by these CYP450 isoenzymes. Tables 6 and 7 provide the clinically significant interactions between voriconazole and other medical products. Table 6: 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 every 12 hours) Recommendations for Voriconazole Dosage Adjustment/Comments Rifampin and Rifabutin (CYP450 Induction) Significantly Reduced Contraindicated Efavirenz (400 mg every 24 hours) (CYP450 Induction) Significantly Reduced Contraindicated High-dose Ritonavir (400 mg every 12 hours) (CYP450 Induction) Significantly Reduced Contraindicated Low-dose Ritonavir (100 mg every 12 hours) (CYP450 Induction) Reduced 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 Carbamazepine (CYP450 Induction) Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction Contraindicated Long Acting Barbiturates (e.g., phenobarbital, mephobarbital) (CYP450 Induction) Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction Contraindicated Phenytoin (CYP450 Induction) Significantly Reduced Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every12 hours Letermovir (CYP2C9/2C19 Induction) Reduced If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole. St. John's Wort (CYP450 inducer; P-gp inducer) Significantly Reduced Contraindicated Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) Increased Monitoring for adverse reactions and toxicity related to voriconazole is recommended when coadministered with oral contraceptives Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions 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 No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir. In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to voriconazole when coadministered with other HIV protease inhibitors Other 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). Frequent monitoring for adverse reactions and toxicity related to voriconazole 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) Careful assessment of voriconazole effectiveness Table 7: 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 τ ) Recommendations for Drug Dosage Adjustment/Comments Sirolimus (CYP3A4 Inhibition) Significantly Increased Contraindicated Rifabutin (CYP3A4 Inhibition) Significantly Increased Contraindicated Efavirenz (400 mg every 24 hours) (CYP3A4 Inhibition) Significantly Increased Contraindicated High-dose Ritonavir (400 mg every 12 hours) (CYP3A4 Inhibition) No Significant Effect of Voriconazole on Ritonavir C max or AUC τ Contraindicated because of significant reduction of voriconazole C max and AUC τ Low-dose Ritonavir (100 mg every 12 hours) Slight Decrease in Ritonavir C max and AUC τ Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) 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 Pimozide, Quinidine, Ivabradine (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 pointes Ergot Alkaloids (CYP450 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Contraindicated Naloxegol (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions Contraindicated Tolvaptan (CYP3A4 Inhibition) Although Not Studied Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Tolvaptan Contraindicated Venetoclax (CYP3A4 Inhibition) Not studied In Vivo or In Vitro , but Venetoclax Plasma Exposure Likely to be Significantly Increased Coadministration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering Voriconazole for injection with venetoclax. Refer to the venetoclax prescribing information for dosing instructions. Lemborexant (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Avoid concomitant use of Voriconazole for injection with lemborexant. Glasdegib (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Consider alternative therapies. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions including QTc interval prolongation. Tyrosine kinase inhibitors (including but not limited to axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Avoid concomitant use of Voriconazole for injection. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product. Lurasidone (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone Contraindicated Cyclosporine (CYP3A4 Inhibition) AUC τ Significantly Increased; No Significant Effect on C max When initiating therapy with Voriconazole for injection 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 for injection is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. Methadone (CYP3A4 Inhibition) Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse reactions and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed. Fentanyl (CYP3A4 Inhibition) Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with Voriconazole for injection. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary. Alfentanil (CYP3A4 Inhibition) Significantly Increased An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when coadministered with Voriconazole for injection. Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with Voriconazole for injection. A longer period for monitoring respiratory and other opiate-associated adverse reactions may be necessary. Oxycodone (CYP3A4 Inhibition) Significantly Increased Increased visual effects (heterophoria and miosis) of oxycodone were observed when coadministered with Voriconazole for injection. Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with Voriconazole for injection. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary. NSAIDs Non-Steroidal Anti-Inflammatory Drug including ibuprofen and diclofenac (CYP2C9 Inhibition) Increased Frequent monitoring for adverse reactions and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. Tacrolimus (CYP3A4 Inhibition) Significantly Increased When initiating therapy with Voriconazole for injection 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 for injection is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. Phenytoin (CYP2C9 Inhibition) Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) Increased Monitoring for adverse reactions related to oral contraceptives is recommended during coadministration. Prednisolone and other corticosteroids (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects of Voriconazole for injection on Prednisolone Exposure No dosage adjustment for prednisolone when coadministered with Voriconazole for injection [see Clinical Pharmacology (12.3) ] . Not Studied In vitro or In vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased Monitor for potential adrenal dysfunction when Voriconazole for injection is administered with other corticosteroids [see Warnings and Precautions (5.8) ] . Warfarin (CYP2C9 Inhibition) Prothrombin Time Significantly Increased 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. Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition) Not Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be Increased Ivacaftor (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions Dose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor Eszopiclone (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased which may Increase the Sedative Effect of Eszopiclone Dose reduction of eszopiclone is recommended. Refer to the prescribing information for eszopiclone. Omeprazole (CYP2C19/3A4 Inhibition) Significantly Increased When initiating therapy with Voriconazole for injection 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 No dosage adjustment for indinavir when coadministered with Voriconazole for injection In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to other HIV protease inhibitors Other 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 reactions and toxicity related to NNRTI. Tretinoin (CYP3A4 Inhibition) Although Not Studied, Voriconazole may Increase Tretinoin Concentrations and Increase the Risk of Adverse Reactions Frequent monitoring for signs and symptoms of pseudotumor cerebri or hypercalcemia. Midazolam (CYP3A4 Inhibition) Significantly Increased Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines. Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Refer to drug-specific labeling for details. HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse reactions 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 reactions 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 reactions and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including Voriconazole for injection, 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 for injection and everolimus is not recommended.", "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) ] .", "5.6 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 (including cutaneous SCC in situ , or Bowen's disease) 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, as well as increased risk of skin toxicity with concomitant use of methotrexate, a drug associated with ultraviolet (UV) reactivation. There is the potential for this risk to be observed with other drugs associated with UV reactivation. 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.", "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 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 8). Table 8: Geometric Mean (%CV) Plasma Voriconazole Pharmacokinetic Parameters in Adults Receiving Different Dosing Regimens 6 mg/kg IV (loading dose) 3 mg/kg IV every 12 hours 4 mg/kg IV every 12 hours 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. N 35 23 40 AUC 12 (μg∙h/mL) 13.9 (32) 13.7 (53) 33.9 (54) C max (μg/mL) 3.13 (20) 3.03 (25) 4.77 (36) C min (μg/mL) -- 0.46 (97) 1.73 (74) 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.", "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) ] .", "5.10 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).", "14.4 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 4 mg/kg every 12 hours. Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole) for injection. However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information.", "1 INDICATIONS AND USAGE": "Voriconazole for injection is an azole antifungal indicated for use in the treatment of 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 with: Invasive aspergillosis ( 1.1 ) Candidemia in non-neutropenics and other deep tissue Candida infections ( 1.2 ) Serious fungal infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani , in patients intolerant of, or refractory to, other therapy ( 1.3 )", "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 reactions, 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) ] .", "5.8 Adrenal Dysfunction": "Reversible cases of azole-induced adrenal insufficiency have been reported in patients receiving azoles, including Voriconazole for injection. Adrenal insufficiency has been reported in patients receiving azoles with or without concomitant corticosteroids. In patients receiving azoles without corticosteroids adrenal insufficiency is related to direct inhibition of steroidogenesis by azoles. In patients taking corticosteroids, voriconazole associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] . Cushing's syndrome with and without subsequent adrenal insufficiency has also been reported in patients receiving Voriconazole for injection concomitantly with corticosteroids. Patients receiving Voriconazole for injection and corticosteroids (via all routes of administration) should be carefully monitored for adrenal dysfunction both during and after Voriconazole for injection treatment. Patients should be instructed to seek immediate medical care if they develop signs and symptoms of Cushing's syndrome or adrenal insufficiency.", "12.1 Mechanism of Action": "Voriconazole is an antifungal drug [see Microbiology (12.4) ] .", "5.9 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) ] .", "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) and Microbiology (12.4) ].", "5 WARNINGS AND PRECAUTIONS": "Hepatic Toxicity : Serious hepatic reactions reported. Evaluate liver function tests at start of and during Voriconazole for injection therapy ( 5.1 ) Arrhythmias and QT Prolongation : Correct potassium, magnesium and calcium prior to use; caution patients with proarrhythmic conditions ( 5.2 ) Infusion Related Reactions (including anaphylaxis) : Stop the infusion ( 5.3 ) Visual Disturbances (including optic neuritis and papilledema): Monitor visual function if treatment continues beyond 28 days ( 5.4 ) Severe Cutaneous Adverse Reactions : Discontinue for exfoliative cutaneous reactions ( 5.5 ) Photosensitivity : Avoid sunlight due to risk of photosensitivity ( 5.6 ) Adrenal Dysfunction : Carefully monitor patients receiving Voriconazole for injection and corticosteroids (via all routes of administration) for adrenal dysfunction both during and after Voriconazole for injection treatment. Instruct patients to seek immediate medical care if they develop signs and symptoms of Cushing's syndrome or adrenal insufficiency ( 5.8 ) Embryo-Fetal Toxicity : Voriconazole can cause fetal harm when administered to a pregnant woman. Inform pregnant patients of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with Voriconazole for injection ( 5.9 , 8.1 , 8.3 ) Skeletal Adverse Reactions : Fluorosis and periostitis with long-term voriconazole therapy. Discontinue if these adverse reactions occur ( 5.12 ) Clinically Significant Drug Interactions : Review patient's concomitant medications ( 5.13 , 7 )", "2 DOSAGE AND ADMINISTRATION": "Dosage in Adults ( 2.3 ) Infection Loading dose Maintenance Dose Intravenous infusion Intravenous infusion Invasive Aspergillosis 6 mg/kg every 12 hours for the first 24 hours 4 mg/kg every 12 hours Candidemia in nonneutropenics and other deep tissue Candida infections 3–4 mg/kg every 12 hours Scedosporiosis and Fusariosis 4 mg/kg every 12 hours Hepatic Impairment : Use half the maintenance dose in adult patients with mild to moderate hepatic impairment (Child-Pugh Class A and B) ( 2.5 ) Renal Impairment : Avoid intravenous administration in adult patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) ( 2.6 ) Dosage in Pediatric Patients ( 2.4 ) For pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight use adult dosage. ( 2.4 ) Dosage adjustment of Voriconazole for injection in pediatric patients with renal or hepatic impairment has not been established. ( 2.5 , 2.6 ) See full prescribing information for instructions on reconstitution of Voriconazole for injection lyophilized powder for intravenous use ( 2.8 )", "3 DOSAGE FORMS AND STRENGTHS": "For Injection : Lyophilized white to off white cake or powder containing 200 mg voriconazole and 3,200 mg of hydroxypropyl β-cyclodextrin (HPβCD); after reconstitution 10 mg/mL of voriconazole and 160 mg/mL of HPβCD ( 3 )", "8 USE IN SPECIFIC POPULATIONS": "Pediatrics : Safety and effectiveness in patients younger than 2 years has not been established ( 8.4 ) Additional pediatric use information is approved for PF PRISM C.V.'s VFEND (voriconazole) for injection. However, due to PF PRISM C.V.'s marketing exclusivity rights, this drug product is not labeled with that information .", "5.3 Infusion Related Reactions": "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.", "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.", "5.12 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) ] .", "14.1 Invasive Aspergillosis (IA)": "Voriconazole was studied in patients for primary therapy of IA (randomized, controlled study 307/602), for primary and salvage therapy of aspergillosis (non-comparative study 304) and for treatment of patients with IA who were refractory to, or intolerant of, other antifungal therapy (non-comparative study 309/604).", "1.3 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 adult 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 (14.3) and Microbiology (12.4) ] .", "14.3 Other Serious Fungal Pathogens": "In pooled analyses of patients, voriconazole was shown to be effective against the following additional fungal pathogens:", "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 for injection. 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) ].", "5.5 Severe Cutaneous Adverse Reactions": "Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with Voriconazole for injection. If a patient develops a severe cutaneous adverse reaction, Voriconazole for injection should be discontinued [see Adverse Reactions (6.1 , 6.2) ].", "PRINCIPAL DISPLAY PANEL - 200 MG Vial Label": "NDC 70594-067-01 Rx Only Voriconazole for Injection 200 MG* per vial Not made with natural rubber latex No Preservatives Sterile Single Dose Vial Must be reconstituted then diluted For Intravenous Infusion Only Discard Unused Portion", "5.13 Clinically Significant Drug Interactions": "See Table 6 for a listing of drugs that may significantly alter voriconazole concentrations. Also, see Table 7 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) ].", "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.", "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 RMD on a body surface area 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 body surface area 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.", "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.", "2.1 Important Administration 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 3 hours. Administer diluted Voriconazole for injection by intravenous infusion over 1 to 3 hours only. Do not administer as an IV bolus injection.", "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) ].", "1.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue Candida": "Voriconazole for injection is indicated in adult 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) and Microbiology (12.4) ].", "14.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue Candida": "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 11. Table 11: Overall Success Rates Sustained From EOT To The Fixed 12-Week Follow-Up Time Point By Baseline Pathogen A few patients had more than one pathogen at baseline. , Patients who did not have a 12-week assessment for any reason were considered a treatment failure. Baseline Pathogen Clinical and Mycological Success (%) Voriconazole Amphotericin B --> Fluconazole C. albicans 46/107 (43%) 30/63 (48%) C. tropicalis 17/53 (32%) 1/16 (6%) C. parapsilosis 24/45 (53%) 10/19 (53%) C. glabrata 12/36 (33%) 7/21 (33%) C. krusei 1/4 0/1 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."}

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Source: dailymed · Ingested: 2026-02-15T11:40:37.536618 · Updated: 2026-03-14T22:03:35.886530