VORICONAZOLE

Voriconazole, an azole antifungal agent is available as a lyophilized 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 C 16 H 14 F 3 N 5 O and a molecular weight of 349.3. Voriconazole drug substance is a white to light-colored powder. Voriconazole for injection is a white lyophilized powder containing nominally 200 mg voriconazole and 3200 mg sulfobutyl ether beta-cyclodextrin sodium in a 30 mL Type I clear glass vial. Voriconazole for injection is intended for administration by intravenous infusion. It is a single-dose, unpreserved product. Vials containing 200 mg lyophilized voriconazole are intended for reconstitution with Water for Injection to produce a solution containing 10 mg/mL voriconazole and 160 mg/mL of sulfobutyl ether beta-cyclodextrin sodium. The resultant solution is further diluted prior to administration as an intravenous infusion [see Dosage and Administration (2)] . voriconazole-spl-structure

Voriconazole for injection is an azole antifungal indicated for the treatment of adults and pediatric patients 2 years of age and older with: • Invasive aspergillosis ( 1.1 ) • Candidemia in non-neutropenics and other deep tissue Candida infections ( 1.2 ) • Esophageal candidiasis ( 1.3 ) • Serious fungal infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani , in patients intolerant of, or refractory to, other therapy ( 1.4 ) 1.1 Invasive Aspergillosis Voriconazole for injection is indicated in adults and pediatric patients (2 years of age and older) for the treatment of invasive aspergillosis (IA). In clinical trials, the majority of isolates recovered were Aspergillus fumigatus. There was a small number of cases of culture-proven disease due to species of Aspergillus other than A. fumigatus [see Clinical Studies ( 14.1 , 14.5 ) and Microbiology (12.4) ] . 1.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue Candida Infections Voriconazole for injection is indicated in adults and pediatric patients (2 years of age and older) for the treatment of candidemia in non-neutropenic patients and the following Candida infections: disseminated infections in skin and infections in abdomen, kidney, bladder wall, and wounds [see Clinical Studies ( 14.2 , 14.5 ) and Microbiology ( 12.4 )] . 1.3 Esophageal Candidiasis Voriconazole for injection is indicated in adults and pediatric patients (2 years of age and older) for the treatment of esophageal candidiasis (EC) [see Clinical Studies ( 14.3 , 14.5 ) and Microbiology ( 12.4 )] . 1.4 Scedosporiosis and Fusariosis Voriconazole for injection is indicated for the treatment of serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp. including Fusarium solani, in adults and pediatric patients (2 years of age and older) intolerant of, or refractory to, other therapy [see Clinical Studies (14.4) and Microbiology (12.4) ] . 1.5 Usage Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.

• Dosage in Adults ( 2.3) Infection Loading Dose Maintenance Dose Intravenous infusion Intravenous infusion Oral tablets Oral suspension Invasive Aspergillosis 6 mg/kg every 12 hours for the first 24 hours 4 mg/kg every 12 hours 200 mg every 12 hours 5 mL every 12 hours Candidemia in nonneutropenics and other deep tissue Candida infections 3 to 4 mg/kg every 12 hours 200 mg every 12 hours 5 mL every 12 hours Scedosporiosis and Fusariosis 4 mg/kg every 12 hours 200 mg every 12 hours 5 mL every 12 hours Esophageal Candidiasis Not Evaluated Not Evaluated 200 mg every 12 hours 5 mL every 12 hours o Adult patients weighing less than 40 kg: oral maintenance dose 100 mg or 150 mg every 12 hours o Hepatic Impairment: Use half the maintenance dose in adult patients with mild to moderate hepatic impairment (Child-Pugh Class A and B) ( 2.5 ) o Renal Impairment: Avoid intravenous administration in adult patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) ( 2.6 ) • Dosage in Pediatric Patients 2 years of age and older ( 2.4 ) o For pediatric patients 2 to less than 12 years of age and 12 to 14 years of age weighing less than 50 kg see Table below. Infection Loading Dose Maintenance Dose Intravenous infusion Intravenous infusion Oral tablets Oral suspension Invasive Aspergillosis 9 mg/kg every12 hours for the first 24 hours 8 mg/kg every 12 hours after the first 24 hours 9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours) 0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours] Candidemia in nonneutropenics and other deep tissue Candida infections Scedosporiosis and Fusariosis Esophageal Candidiasis Not Evaluated 4 mg/kg every 12 hours 9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours) 0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours] o 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 ) o 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 and important administration instructions ( 2.1 , 2.6 , 2.7 ) 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. 2.2 Use of Voriconazole for Injection With Other Parenteral Drug Products 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 )] . Intravenous solutions containing (non-concentrated) electrolytes Voriconazole for injection can be infused at the same time as other intravenous solutions containing (non-concentrated) electrolytes, but must be infused through a separate line. Total parenteral nutrition (TPN) Voriconazole for injection can be infused at the same time as total parenteral nutrition, but must be infused in a separate line. If infused through a multiple-lumen catheter, TPN needs to be administered using a different port from the one used for voriconazole for injection. 2.3 Recommended Dosing Regimen in Adults Invasive aspergillosis and serious fungal infections due to Fusarium spp. and Scedosporium apiospermum See Table 1. Therapy must be initiated with the specified loading dose regimen of intravenous voriconazole on Day 1 followed by the recommended maintenance dose (RMD) regimen. Intravenous treatment should be continued for at least 7 days. Once the patient has clinically improved and can tolerate medication given by mouth, the oral tablet form or oral suspension form of voriconazole may be utilized. The recommended oral maintenance dose of 200 mg achieves a voriconazole exposure similar to 3 mg/kg intravenously; a 300 mg oral dose achieves an exposure similar to 4 mg/kg intravenously [see Clinical Pharmacology ( 12.3 )] . Candidemia in non-neutropenic patients and other deep tissue Candida infections See Table 1. Patients should be treated for at least 14 days following resolution of symptoms or following last positive culture, whichever is longer. Esophageal Candidiasis See Table 1. Patients should be treated for a minimum of 14 days and for at least 7 days following resolution of symptoms. Table 1: Recommended Dosing Regimen (Adults) Infection Loading Dose Maintenance Dose a,b Intravenous infusion Intravenous infusion Oral tablets c Oral suspension Invasive Aspergillosis d 6 mg/kg every 12 hours for the first 24 hours 4 mg/kg every 12 hours 200 mg every 12 hours 5 mL every 12 hours Candidemia in nonneutropenic patients and other deep tissue Candida infections 6 mg/kg every 12 hours for the first 24 hours 3 to 4 mg/kg every 12 hours e 200 mg every 12 hours 5 mL every 12 hours Esophageal Candidiasis Not Evaluated f Not Evaluated f 200 mg every 12 hours 5 mL every 12 hours Scedosporiosis and Fusariosis 6 mg/kg every 12 hours for the first 24 hours 4 mg/kg every 12 hours 200 mg every 12 hours 5 mL every 12 hours a Increase dose when voriconazole is co-administered with phenytoin or efavirenz ( 7 ); Decrease dose in patients with hepatic impairment ( 2.5 ) b In healthy volunteer studies, the 200 mg oral every 12 hours dose provided an exposure (AUC τ ) similar to a 3 mg/kg intravenous infusion every 12 hours dose; the 300 mg oral every 12 hours dose provided an exposure (AUC τ ) similar to a 4 mg/kg intravenous infusion every 12 hours dose ( 12 ). c Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose. d In a clinical study of IA, the median duration of intravenous voriconazole therapy was 10 days (range 2 to 85 days). The median duration of oral voriconazole therapy was 76 days (range 2 to 232 days) ( 14.1 ). e In clinical trials, patients with candidemia received 3 mg/kg intravenous infusion every 12 hours as primary therapy, while patients with other deep tissue Candida infections received 4 mg/kg every 12 hours as salvage therapy. Appropriate dose should be based on the severity and nature of the infection. f Not evaluated in patients with EC. Method for Adjusting the Dosing Regimen in Adults If the patient’s response is inadequate, the oral maintenance dose for voriconazole tablets or oral suspension may be increased from 200 mg (or 5 mL) every 12 hours to 300 mg (or 7.5 mL) every 12 hours. For adult patients weighing less than 40 kg, the oral maintenance dose for voriconazole tablets or oral suspension may be increased from 100 mg (or 2.5 mL) every 12 hours to 150 mg (or 3.75 mL) every 12 hours. If the patient is unable to tolerate 300 mg (or 7.5 mL) orally every 12 hours, reduce the oral maintenance dose of voriconazole tablets or oral suspension by 50 mg (or 1.25 mL) steps to a minimum of 200 mg (or 5 mL) every 12 hours for adult patients weighing more than 40 kg or to 100 mg (or 2.5 mL) every 12 hours for adult patients weighing less than 40 kg. If the patient is unable to tolerate 4 mg/kg intravenously every 12 hours, reduce the intravenous maintenance dose to 3 mg/kg every 12 hours. 2.4 Recommended Dosing Regimen in Pediatric Patients The recommended dosing regimen for pediatric patients 2 to less than 12 years of age and 12 to 14 years of age with body weight less than 50 kg is shown in Table 2. For pediatric patients 12 to 14 years of age with a body weight greater than or equal to 50 kg and those 15 years of age and above regardless of body weight, administer the adult dosing regimen of voriconazole [see Dosage and Administration ( 2.3 )] . Table 2: Recommended Dosing Regimen for Pediatric Patients 2 to less than 12 years of age and 12 to 14 years of age with body weight less than 50 kg^ Loading Dose Maintenance Dose Intravenous infusion Intravenous infusion Oral tablets Oral suspension Invasive Aspergillosis* 9 mg/kg every 12 hours for the first 24 hours 8 mg/kg every 12 hours after the first 24 hours 9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours) 0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours] Candidemia in nonneutropenics and other deep tissue Candida infections † Scedosporiosis and Fusariosis Esophageal Candidiasis † Not Evaluated 4 mg/kg every 12 hours 9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours) 0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours] ^ Based on a population pharmacokinetic analysis in 112 immunocompromised pediatric patients aged 2 to less than 12 years of age and 26 immunocompromised pediatric patients aged 12 to less than 17 years of age. * In the Phase 3 clinical trials, patients with IA received intravenous (IV) treatment for at least 6 weeks and up to a maximum of 12 weeks. Patients received IV treatment for at least the first 7 days of therapy and then could be switched to oral voriconazole therapy. † Study treatment for primary or salvage invasive candidiasis and candidemia (ICC) or EC consisted of intravenous voriconazole, with an option to switch to oral therapy after at least 5 days of IV therapy, based on subjects meeting switch criteria. For subjects with primary or salvage ICC, voriconazole was administered for at least 14 days after the last positive culture. A maximum of 42 days of treatment was permitted. Patients with primary or salvage EC were treated for at least 7 days after the resolution of clinical signs and symptoms. A maximum of 42 days of treatment was permitted. Initiate therapy with an intravenous infusion regimen. Consider an oral regimen only after there is a significant clinical improvement. Note that an 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose. The oral dose recommendation for children is based on studies in which voriconazole was administered as the powder for oral suspension formulation. Bioequivalence between the voriconazole powder for oral suspension and voriconazole tablets has not been investigated in a pediatric population. Oral bioavailability may be limited in pediatric patients 2 to 12 years with malabsorption and very low body weight for age. In that case, intravenous voriconazole administration is recommended. Method for Adjusting the Dosing Regimen in Pediatric Patients Pediatric Patients 2 to less than 12 years of age and 12 to 14 years of age with body weight less than 50 kg If patient response is inadequate and the patient is able to tolerate the initial intravenous maintenance dose, the maintenance dose may be increased by 1 mg/kg steps. If patient response is inadequate and the patient is able to tolerate the oral maintenance dose, the dose may be increased by 1 mg/kg (0.025 mL/kg) steps or 50 mg (1.25 mL) steps to a maximum of 350 mg (8.75 mL) every 12 hours. If patients are unable to tolerate the initial intravenous maintenance dose, reduce the dose by 1 mg/kg steps. If patients are unable to tolerate the oral maintenance dose, reduce the dose by 1 mg/kg (0.025 mL/kg) or 50 mg (1.25 mL) steps. Pediatric patients 12 to 14 years of age weighing greater than or equal to 50 kg and 15 years of age and older regardless of body weight: Use the optimal method for titrating dosage recommended for adults [see Dosage and Administration ( 2.3 )] . 2.5 Dosage Modifications in Patients With Hepatic Impairment Adults The maintenance dose of voriconazole should be reduced in adult patients with mild to moderate hepatic impairment, Child-Pugh Class A and B. There are no PK data to allow for dosage adjustment recommendations in patients with severe hepatic impairment (Child-Pugh Class C). Duration of therapy should be based on the severity of the patient’s underlying disease, recovery from immunosuppression, and clinical response. Adult patients with baseline liver function tests (ALT, AST) of up to 5 times the upper limit of normal (ULN) were included in the clinical program. Dose adjustments are not necessary for adult patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended [see Warnings and Precautions ( 5.1 )] . It is recommended that the recommended voriconazole loading dose regimens be used, but that the maintenance dose be halved in adult patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) [see Clinical Pharmacology ( 12.3 )] . Voriconazole has not been studied in adult patients with severe hepatic cirrhosis (Child-Pugh Class C) or in patients with chronic hepatitis B or chronic hepatitis C disease. Voriconazole has been associated with elevations in liver function tests and with clinical signs of liver damage, such as jaundice. Voriconazole should only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic impairment must be carefully monitored for drug toxicity. Pediatric Patients Dosage adjustment of voriconazole in pediatric patients with hepatic impairment has not been established [see Use in Specific Populations ( 8.4 )] . 2.6 Dosage Modifications in Patients With Renal Impairment Adult Patients The pharmacokinetics of orally administered voriconazole are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment [see Clinical Pharmacology ( 12.3 )] . In patients with moderate or severe renal impairment (creatinine clearance <50 mL/min) who are receiving an intravenous infusion of voriconazole, accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral voriconazole therapy [see Warnings and Precautions ( 5.7 )] . Voriconazole and the intravenous vehicle, SBECD, are dialyzable. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment [see Clinical Pharmacology ( 12.3 )] . Pediatric Patients Dosage adjustment of voriconazole in pediatric patients with renal impairment has not been established [see Use in Specific Populations ( 8.4 )] . 2.7 Dosage Adjustment When Co-Administered With Phenytoin or Efavirenz The maintenance dose of voriconazole should be increased when co-administered with phenytoin or efavirenz. Use the optimal method for titrating dosage [see Drug Interactions ( 7 ) and Dosage and Administration ( 2.3 )] . 2.8 Preparation and Intravenous Administration of Voriconazole for Injection Reconstitution The powder is reconstituted with 19 mL of Water For Injection to obtain an extractable volume of 20 mL of clear concentrate containing 10 mg/mL of voriconazole. It is recommended that a standard 20 mL (non-automated) syringe be used to ensure that the exact amount (19.0 mL) of Water for Injection is dispensed. Discard the vial if a vacuum does not pull the diluent into the vial. Shake the vial until all the powder is dissolved. Dilution Voriconazole for injection must be infused over 1 to 3 hours, at a concentration of 5 mg/mL or less. Therefore, the required volume of the 10 mg/mL voriconazole for injection concentrate should be further diluted as follows (appropriate diluents listed below): 1. Calculate the volume of 10 mg/mL voriconazole for injection concentrate required based on the patient’s weight (see Table 3). 2. In order to allow the required volume of voriconazole for injection concentrate to be added, withdraw and discard at least an equal volume of diluent from the infusion bag or bottle to be used. The volume of diluent remaining in the bag or bottle should be such that when the 10 mg/mL voriconazole for injection concentrate is added, the final concentration is not less than 0.5 mg/mL nor greater than 5 mg/mL. 3. Using a suitable size syringe and aseptic technique, withdraw the required volume of voriconazole for injection concentrate from the appropriate number of vials and add to the infusion bag or bottle. Discard Partially Used Vials . The final voriconazole for injection solution must be infused over 1 to 3 hours at a maximum rate of 3 mg/kg per hour. Table 3: Required Volumes of 10 mg/mL Voriconazole for Injection Concentrate Body Weight (kg) Volume of Voriconazole for Injection Concentrate (10 mg/mL) required for: 3 mg/kg dose (number of vials) 4 mg/kg dose (number of vials) 6 mg/kg dose (number of vials) 8 mg/kg dose (number of vials) 9 mg/kg dose (number of vials) 10 - 4 mL (1) - 8 mL (1) 9 mL (1) 15 - 6 mL (1) - 12 mL (1) 13.5 mL (1) 20 - 8 mL (1) - 16 mL (1) 18 mL (1) 25 - 10 mL (1) - 20 mL (1) 22.5 mL (2) 30 9 mL (1) 12 mL (1) 18 mL (1) 24 mL (2) 27 mL (2) 35 10.5 mL (1) 14 mL (1) 21 mL (2) 28 mL (2) 31.5 mL (2) 40 12 mL (1) 16 mL (1) 24 mL (2) 32 mL (2) 36 mL (2) 45 13.5 mL (1) 18 mL (1) 27 mL (2) 36 mL (2) 40.5 mL (3) 50 15 mL (1) 20 mL (1) 30 mL (2) 40 mL (2) 45 mL (3) 55 16.5 mL (1) 22 mL (2) 33 mL (2) 44 mL (3) 49.5 mL (3) 60 18 mL (1) 24 mL (2) 36 mL (2) 48 mL (3) 54 mL (3) 65 19.5 mL (1) 26 mL (2) 39 mL (2) 52 mL (3) 58.5 mL (3) 70 21 mL (2) 28 mL (2) 42 mL (3) - - 75 22.5 mL (2) 30 mL (2) 45 mL (3) - - 80 24 mL (2) 32 mL (2) 48 mL (3) - - 85 25.5 mL (2) 34 mL (2) 51 mL (3) - - 90 27 mL (2) 36 mL (2) 54 mL (3) - - 95 28.5 mL (2) 38 mL (2) 57 mL (3) - - 100 30 mL (2) 40 mL (2) 60 mL (3) - - Voriconazole for injection is a single-dose unpreserved sterile lyophile. Therefore, from a microbiological point of view, once reconstituted, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2°C to 8°C (36°F to 46°F). This medicinal product is for single use only and any unused solution should be discarded. Only clear solutions without particles should be used. The reconstituted solution can be diluted with: 0.9% Sodium Chloride USP Lactated Ringers USP 5% Dextrose and Lactated Ringers USP 5% Dextrose and 0.45% Sodium Chloride USP 5% Dextrose USP 5% Dextrose and 20 mEq Potassium Chloride USP 0.45% Sodium Chloride USP 5% Dextrose and 0.9% Sodium Chloride USP The compatibility of voriconazole for injection with diluents other than those described above is unknown (see Incompatibilities below). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Incompatibilities Voriconazole for injection must not be diluted with 4.2% Sodium Bicarbonate Infusion. The mildly alkaline nature of this diluent caused slight degradation of voriconazole after 24 hours storage at room temperature. Although refrigerated storage is recommended following reconstitution, use of this diluent is not recommended as a precautionary measure. Compatibility with other concentrations is unknown.

• Voriconazole is contraindicated in patients with known hypersensitivity to voriconazole or its excipients. There is no information regarding cross-sensitivity between voriconazole and other azole antifungal agents. Caution should be used when prescribing voriconazole to patients with hypersensitivity to other azoles. • Coadministration of pimozide, quinidine or ivabradine with voriconazole is contraindicated because increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of torsade de pointes [see Drug Interactions (7)] . • Coadministration of voriconazole with sirolimus is contraindicated because voriconazole for injection significantly increases sirolimus concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3)] . • Coadministration of voriconazole with rifampin, carbamazepine, long-acting barbiturates or 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 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 with rifabutin is contraindicated since voriconazole significantly increases rifabutin plasma concentrations and rifabutin also significantly decreases voriconazole plasma concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3)] . • Coadministration of voriconazole with ergot alkaloids (ergotamine and dihydroergotamine) is contraindicated because voriconazole may increase the plasma concentration of ergot alkaloids, which may lead to ergotism [see Drug Interactions (7)] . • Coadministration of voriconazole with naloxegol is contraindicated because voriconazole may increase plasma concentrations of naloxegol which may precipitate opioid withdrawal symptoms [see Drug Interactions (7)] . • Coadministration of voriconazole with tolvaptan is contraindicated because voriconazole may increase tolvaptan plasma concentrations and increase risk of adverse reactions [see Drug Interactions (7)] . • Coadministration of voriconazole 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 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)] . • Coadministration of voriconazole with finerenone is contraindicated since it may result in significant increases in finerenone exposure and the potential for serious adverse reactions [see Drug Interactions (7)] . Hypersensitivity to voriconazole or its excipients ( 4 ) Coadministration with pimozide, quinidine, sirolimus or ivabradine due to risk of serious adverse reactions ( 4 , 7 ) Coadministration with rifampin, carbamazepine, long-acting barbiturates, efavirenz, ritonavir, rifabutin, ergot alkaloids or St. John’s Wort due to risk of loss of efficacy ( 4 , 7 ) Coadministration with naloxegol, tolvaptan, lurasidone or finerenone due to risk of adverse reactions ( 4 , 7 ) Coadministration of voriconazole with venetoclax at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to increased risk of adverse reactions ( 4 , 7 )

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) ] • Adult Patients: The most common adverse reactions (incidence ≥2%) were visual disturbances, fever, nausea, rash, vomiting, chills, headache, liver function test abnormal, tachycardia, hallucinations ( 6 ) • Pediatric Patients: The most common adverse reactions (incidence ≥5%) were visual disturbances, pyrexia, vomiting, epistaxis, nausea, rash, abdominal pain, diarrhea, hypertension, hypokalemia, cough, headache, thrombocytopenia, ALT abnormal, hypotension, peripheral edema, hyperglycemia, tachycardia, dyspnea, hypocalcemia, hypophosphatemia, LFT abnormal, mucosal inflammation, photophobia, abdominal distention, constipation, dizziness, hallucinations, hemoptysis, hypoalbuminemia, hypomagnesemia, renal impairment, upper respiratory tract infection ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Fosun Pharma USA Inc. at 1-866-611-3762 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in Adults Overview The most frequently reported adverse reactions (see Table 4) in the adult therapeutic trials were visual disturbances (18.7%), fever (5.7%), nausea (5.4%), rash (5.3%), vomiting (4.4%), chills (3.7%), headache (3.0%), liver function test increased (2.7%), tachycardia (2.4%), hallucinations (2.4%). The adverse reactions which most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances [see Warnings and Precautions (5.1 , 5.4 ) and Adverse Reactions (6.1) ] . The data described in Table 4 reflect exposure to voriconazole in 1655 patients in nine therapeutic studies. This represents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy or HIV and non-neutropenic patients. This subgroup does not include healthy subjects and patients treated in the compassionate use and non- therapeutic studies. This patient population was 62% male, had a mean age of 46 years (range 11 to 90, including 51 patients aged 12 to 18 years), and was 78% White and 10% Black. Five hundred sixty one patients had a duration of voriconazole therapy of greater than 12 weeks, with 136 patients receiving voriconazole for over six months. Table 4 includes all adverse reactions which were reported at an incidence of ≥2% during voriconazole therapy in the all therapeutic studies population, studies 307/602 and 608 combined, or study 305, as well as events of concern which occurred at an incidence of <2%. In study 307/602, 381 patients (196 on voriconazole, 185 on amphotericin B) were treated to compare voriconazole to amphotericin B followed by other licensed antifungal therapy (OLAT) in the primary treatment of patients with acute IA. The rate of discontinuation from voriconazole study medication due to adverse reactions was 21.4% (42/196 patients). In study 608, 403 patients with candidemia were treated to compare voriconazole (272 patients) to the regimen of amphotericin B followed by fluconazole (131 patients). The rate of discontinuation from voriconazole study medication due to adverse reactions was 19.5% out of 272 patients. Study 305 evaluated the effects of oral voriconazole (200 patients) and oral fluconazole (191 patients) in the treatment of EC. The rate of discontinuation from voriconazole study medication in Study 305 due to adverse reactions was 7% (14/200 patients). Laboratory test abnormalities for these studies are discussed under Clinical Laboratory Values below. Table 4: Adverse Reactions Rate ≥2% on Voriconazole or Adverse Reactions of Concern in Therapeutic Studies Population, Studies 307/602 to 608 Combined, or Study 305. Possibly Related to Therapy or Causality Unknown † Therapeutic Studies* Studies 307/602 and 608 (IV/oral therapy) Study 305 (oral therapy) Voriconazole N=1655 Voriconazole N=468 A m ph o B**N=185 A m pho B→ Fluconazole N=131 Voriconazole N=200 Fluconazole N=191 N (%) N (%) N (%) N (%) N (%) N (%) Special Senses*** Abnormal vision 310 (18.7) 63 (13.5) 1 (0.5) 0 31 (15.5) 8 (4.2) Photophobia 37 (2.2) 8 (1.7) 0 0 5 (2.5) 2 (1.0) Chromatopsia 20 (1.2) 2 (0.4) 0 0 2 (1.0) 0 Body as a Whole Fever 94 (5.7) 8 (1.7) 25 (13.5) 5 (3.8) 0 0 Chills 61 (3.7) 1 (0.2) 36 (19.5) 8 (6.1) 1 (0.5) 0 Headache 49 (3.0) 9 (1.9) 8 (4.3) 1 (0.8) 0 1 (0.5) Cardiovascular System Tachycardia 39 (2.4) 6 (1.3) 5 (2.7) 0 0 0 Digestive System Nausea 89 (5.4) 18 (3.8) 29 (15.7) 2 (1.5) 2 (1.0) 3 (1.6) Vomiting 72 (4.4) 15 (3.2) 18 (9.7) 1 (0.8) 2 (1.0) 1 (0.5) Liver function tests abnormal 45 (2.7) 15 (3.2) 4 (2.2) 1 (0.8) 6 (3.0) 2 (1.0) Cholestatic jaundice 17 (1.0) 8 (1.7) 0 1 (0.8) 3 (1.5) 0 Metabolic and Nutritional Systems Alkaline phosphatase increased 59 (3.6) 19 (4.1) 4 (2.2) 3 (2.3) 10 (5.0) 3 (1.6) Hepatic enzymes increased 30 (1.8) 11 (2.4) 5 (2.7) 1 (0.8) 3 (1.5) 0 SGOT increased 31 (1.9) 9 (1.9) 0 1 (0.8) 8 (4.0) 2 (1.0) SGPT increased 29 (1.8) 9 (1.9) 1 (0.5) 2 (1.5) 6 (3.0) 2 (1.0) Hypokalemia 26 (1.6) 3 (0.6) 36 (19.5) 16 (12.2) 0 0 Bilirubinemia 15 (0.9) 5 (1.1) 3 (1.6) 2 (1.5) 1 (0.5) 0 Creatinine increased 4 (0.2) 0 59 (31.9) 10 (7.6) 1 (0.5) 0 Nervous System Hallucinations 39 (2.4) 13 (2.8) 1 (0.5) 0 0 0 Skin and Appendages Rash 88 (5.3) 20 (4.3) 7 (3.8) 1 (0.8) 3 (1.5) 1 (0.5) Uro g enital Kidney function abnormal 10 (0.6) 6 (1.3) 40 (21.6) 9 (6.9) 1 (0.5) 1 (0.5) Acute kidney failure 7 (0.4) 2 (0.4) 11 (5.9) 7 (5.3) 0 0 † Study 307/602: IA; Study 608: candidemia; Study 305: EC * Studies 303, 304, 305, 307, 309, 602, 603, 604, 608 ** Amphotericin B followed by other licensed antifungal therapy *** See Warnings and Precautions (5.4) Visual Disturbances Voriconazole treatment-related visual disturbances are common. In therapeutic trials, approximately 21% of patients experienced abnormal vision, color vision change and/or photophobia. Visual disturbances may be associated with higher plasma concentrations and/or doses. The mechanism of action of the visual disturbance is unknown, although the site of action is most likely to be within the retina. In a study in healthy subjects investigating the effect of 28-day treatment with voriconazole on retinal function, voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude, a decrease in the visual field, and an alteration in color perception. The ERG measures electrical currents in the retina. These effects were noted early in administration of voriconazole and continued through the course of study drug treatment. Fourteen days after the end of dosing, ERG, visual fields and color perception returned to normal [see Warnings and Precautions (5.4) ] . Dermatological Reactions Dermatological reactions were common in patients treated with voriconazole. The mechanism underlying these dermatologic adverse reactions remains unknown. Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported during treatment with voriconazole. Erythema multiforme has also been reported during treatment with voriconazole [see Warnings and Precautions (5.5) and Adverse Reactions (6.2) ] . Voriconazole has also been associated with additional photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus [see Warnings and Precautions (5.6) and Adverse Reactions (6.2) ] . Less Common Adverse Reactions The following adverse reactions occurred in <2% of all voriconazole-treated patients in all therapeutic studies (N=1655). This listing includes events where a causal relationship to voriconazole cannot be ruled out or those which may help the physician in managing the risks to the patients. The list does not include events included in Table 4 above and does not include every event reported in the voriconazole clinical program. Body as a Whole: abdominal pain, abdomen enlarged, allergic reaction, anaphylactoid reaction [see Warnings and Precautions ( 5.3 )] , ascites, asthenia, back pain, chest pain, cellulitis, edema, face edema, flank pain, flu syndrome, graft versus host reaction, granuloma, infection, bacterial infection, fungal infection, injection site pain, injection site infection/inflammation, mucous membrane disorder, multi-organ failure, pain, pelvic pain, peritonitis, sepsis, substernal chest pain. Cardiovascular: atrial arrhythmia, atrial fibrillation, AV block complete, bigeminy, bradycardia, bundle branch block, cardiomegaly, cardiomyopathy, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, congestive heart failure, deep thrombophlebitis, endocarditis, extrasystoles, heart arrest, hypertension, hypotension, myocardial infarction, nodal arrhythmia, palpitation, phlebitis, postural hypotension, pulmonary embolus, QT interval prolonged, supraventricular extrasystoles, supraventricular tachycardia, syncope, thrombophlebitis, vasodilatation, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia (including torsade de pointes) [see Warnings and Precautions (5.2) ] . Digestive: anorexia, cheilitis, cholecystitis, cholelithiasis, constipation, diarrhea, duodenal ulcer perforation, duodenitis, dyspepsia, dysphagia, dry mouth, esophageal ulcer, esophagitis, flatulence, gastroenteritis, gastrointestinal hemorrhage, GGT/LDH elevated, gingivitis, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hepatic coma, hepatic failure, hepatitis, intestinal perforation, intestinal ulcer, jaundice, enlarged liver, melena, mouth ulceration, pancreatitis, parotid gland enlargement, periodontitis, proctitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, stomach ulcer, stomatitis, tongue edema. Endocrine: adrenal cortex insufficiency, diabetes insipidus, hyperthyroidism, hypothyroidism. Hemic and Lymphatic: agranulocytosis, anemia (macrocytic, megaloblastic, microcytic, normocytic), aplastic anemia, hemolytic anemia, bleeding time increased, cyanosis, DIC, ecchymosis, eosinophilia, hypervolemia, leukopenia, lymphadenopathy, lymphangitis, marrow depression, pancytopenia, petechia, purpura, enlarged spleen, thrombocytopenia, thrombotic thrombocytopenic purpura. Metabolic and Nutritional: albuminuria, BUN increased, creatine phosphokinase increased, edema, glucose tolerance decreased, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperuricemia, hypocalcemia, hypoglycemia, hypomagnesemia, hyponatremia, hypophosphatemia, peripheral edema, uremia. Musculoskeletal: arthralgia, arthritis, bone necrosis, bone pain, leg cramps, myalgia, myasthenia, myopathy, osteomalacia, osteoporosis. Nervous System: abnormal dreams, acute brain syndrome, agitation, akathisia, amnesia, anxiety, ataxia, brain edema, coma, confusion, convulsion, delirium, dementia, depersonalization, depression, diplopia, dizziness, encephalitis, encephalopathy, euphoria, Extrapyramidal Syndrome, grand mal convulsion, Guillain-Barré syndrome, hypertonia, hypesthesia, insomnia, intracranial hypertension, libido decreased, neuralgia, neuropathy, nystagmus, oculogyric crisis, paresthesia, psychosis, somnolence, suicidal ideation, tremor, vertigo. Respiratory System: cough increased, dyspnea, epistaxis, hemoptysis, hypoxia, lung edema, pharyngitis, pleural effusion, pneumonia, respiratory disorder, respiratory distress syndrome, respiratory tract infection, rhinitis, sinusitis, voice alteration. Skin and Appendages: alopecia, angioedema, contact dermatitis, discoid lupus erythematosis, eczema, erythema multiforme, exfoliative dermatitis, fixed drug eruption, furunculosis, herpes simplex, maculopapular rash, melanoma, melanosis, photosensitivity skin reaction, pruritus, pseudoporphyria, psoriasis, skin discoloration, skin disorder, skin dry, Stevens-Johnson syndrome, squamous cell carcinoma (including cutaneous SCC in situ, or Bowen’s disease), sweating, toxic epidermal necrolysis, urticaria. Special Senses: abnormality of accommodation, blepharitis, color blindness, conjunctivitis, corneal opacity, deafness, ear pain, eye pain, eye hemorrhage, dry eyes, hypoacusis, keratitis, keratoconjunctivitis, mydriasis, night blindness, optic atrophy, optic neuritis, otitis externa, papilledema, retinal hemorrhage, retinitis, scleritis, taste loss, taste perversion, tinnitus, uveitis, visual field defect. Urogenital: anuria, blighted ovum, creatinine clearance decreased, dysmenorrhea, dysuria, epididymitis, glycosuria, hemorrhagic cystitis, hematuria, hydronephrosis, impotence, kidney pain, kidney tubular necrosis, metrorrhagia, nephritis, nephrosis, oliguria, scrotal edema, urinary incontinence, urinary retention, urinary tract infection, uterine hemorrhage, vaginal hemorrhage. Clinical Laboratory Values in Adults The overall incidence of transaminase increases >3x upper limit of normal (not necessarily comprising an adverse reaction) was 17.7% (268/1514) in adult subjects treated with voriconazole for therapeutic use in pooled clinical trials. Increased incidence of liver function test abnormalities may be associated with higher plasma concentrations and/or doses. The majority of abnormal liver function tests either resolved during treatment without dose adjustment or resolved following dose adjustment, including discontinuation of therapy. Voriconazole has been infrequently associated with cases of serious hepatic toxicity including cases of jaundice and rare cases of hepatitis and hepatic failure leading to death. Most of these patients had other serious underlying conditions. Liver function tests should be evaluated at the start of and during the course of voriconazole therapy. Patients who develop abnormal liver function tests during voriconazole therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of voriconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to voriconazole [see Warnings and Precautions (5.1) ] . Acute renal failure has been observed in severely ill patients undergoing treatment with voriconazole. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and may have concurrent conditions that can result in decreased renal function. It is recommended that patients are monitored for the development of abnormal renal function. This should include laboratory evaluation of serum creatinine. Tables 5 to 7 show the number of patients with hypokalemia and clinically significant changes in renal and liver function tests in three randomized, comparative multicenter studies. In study 305, patients with EC were randomized to either oral voriconazole or oral fluconazole. In study 307/602, patients with definite or probable IA were randomized to either voriconazole or amphotericin B therapy. In study 608, patients with candidemia were randomized to either voriconazole or the regimen of amphotericin B followed by fluconazole. Table 5: Protocol 305 – Patients with Esophageal Candidiasis Clinically Significant Laboratory Test Abnormalities Criteria* Voriconazole Fluconazole n/N (%) n / N (%) T. Bilirubin >1.5x ULN 8/185 (4.3) 7/186 (3.8) AST >3.0x ULN 38/187 (20.3) 15/186 (8.1) ALT >3.0x ULN 20/187 (10.7) 12/186 (6.5) Alkaline Phosphatase >3.0x ULN 19/187 (10.2) 14/186 (7.5) * Without regard to baseline value n = number of patients with a clinically significant abnormality while on study therapy N = total number of patients with at least one observation of the given lab test while on study therapy AST = Aspartate aminotransferase; ALT= alanine aminotransferase ULN = upper limit of normal Table 6: Protocol 307/602 – Primary Treatment of Invasive Aspergillosis Clinically Significant Laboratory Test Abnormalities Criteria* Voriconazole Amphotericin B** n/N (%) n / N (%) T. Bilirubin >1.5x ULN 35/180 (19.4) 46/173 (26.6) AST >3.0x ULN 21/180 (11.7) 18/174 (10.3) ALT >3.0x ULN 34/180 (18.9) 40/173 (23.1) Alkaline Phosphatase >3.0x ULN 29/181 (16.0) 38/173 (22.0) Creatinine >1.3x ULN 39/182 (21.4) 102/177 (57.6) Potassium <0.9x LLN 30/181 (16.6) 70/178 (39.3) * Without regard to baseline value **Amphotericin B followed by other licensed antifungal therapy n = number of patients with a clinically significant abnormality while on study therapy N = total number of patients with at least one observation of the given lab test while on study therapy AST = Aspartate aminotransferase; ALT = alanine aminotransferase ULN = upper limit of normal LLN = lower limit of normalTable 7: Protocol 608 – Treatment of Candidemia Clinically Significant Laboratory Test Abnormalities Criteria* Voriconazole A m photericin B followed by Fluconazole n/N (%) n / N (%) T. Bilirubin >1.5x ULN 50/261 (19.2) 31/115 (27.0) AST >3.0x ULN 40/261 (15.3) 16/116 (13.8) ALT >3.0x ULN 22/261 (8.4) 15/116 (12.9) Alkaline Phosphatase >3.0x ULN 59/261 (22.6) 26/115 (22.6) Creatinine >1.3x ULN 39/260 (15.0) 32/118 (27.1) Potassium <0.9x LLN 43/258 (16.7) 35/118 (29.7) *Without regard to baseline value n = number of patients with a clinically significant abnormality while on study therapy N = total number of patients with at least one observation of the given lab test while on study therapy AST = Aspartate aminotransferase; ALT = alanine aminotransferase ULN = upper limit of normal LLN = lower limit of normal Clinical Trials Experience in Pediatric Patients The safety of voriconazole was investigated in 105 pediatric patients aged 2 to less than 18 years, including 52 pediatric patients less than 18 years of age who were enrolled in the adult therapeutic studies. Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In clinical studies, serious adverse reactions occurred in 46% (48/105) of voriconazole treated pediatric patients. Treatment discontinuations due to adverse reactions occurred in 12/105 (11%) of all patients. Hepatic adverse reactions (i.e. ALT increased; liver function test abnormal; jaundice) 6% (6/105) accounted for the majority of voriconazole treatment discontinuations. Most Common Adverse Reactions The most common adverse reactions occurring in ≥5% of pediatric patients receiving voriconazole in the pooled pediatric clinical trials are displayed by body system, in Table 8. Table 8: Adverse Reactions Occurring in ≥5% of Pediatric Patients Receiving Voriconazole in the Pooled Pediatric Clinical Trials Body System Adverse Reaction Pooled Pediatric Data a N=105 n (%) Blood and Lymphatic Systems Disorders Thrombocytopenia 10 (10) Cardiac Disorders Tachycardia 7 (7) Eye Disorders Visual Disturbances b 27 (26) Photophobia 6 (6) Gastrointestinal Disorders Vomiting 21 (20) Nausea 14 (13) Abdominal pain c 13 (12) Diarrhea 12 (11) Abdominal distention 5 (5) Constipation 5 (5) General Disorders and Administration Site Conditions Pyrexia 25 (25) Peripheral edema 9 (9) Mucosal inflammation 6 (6) Infections and Infestations Upper respiratory tract infection 5 (5) Investigations ALT abnormal d 9 (9) LFT abnormal 6 (6) Metabolism and Nutrition Disorders Hypokalemia 11 (11) Hyperglycemia 7 (7) Hypocalcemia 6 (6) Hypophosphotemia 6 (6) Hypoalbuminemia 5 (5) Hypomagnesemia 5 (5) Nervous System Disorders Headache 10 (10) Dizziness 5 (5) Psychiatric Disorders Hallucinations e 5 (5) Renal and Urinary Disorders Renal impairment f 5 (5) Respiratory Disorders Epistaxis 17 (16) Cough 10 (10) Dyspnea 6 (6) Hemoptysis 5 (5) Skin and Subcutaneous Tissue Disorders Rash g 14 (13) Vascular Disorders Hypertension 12 (11) Hypotension 9 (9) a Reflects all adverse reactions and not treatment-related only. b Pooled reports include such terms as: amaurosis (partial or total blindness without visible change in the eye); asthenopia (eye strain); chromatopsia (abnormally colored vision); color blindness; diplopia; photopsia; retinal disorder; vision blurred, visual acuity decreased, visual brightness; visual impairment. Several patients had more than one visual disturbance. c Pooled reports include such terms as: abdominal pain and abdominal pain, upper. d Pooled reports include such terms as: ALT abnormal and ALT increased. e Pooled reports include such terms as: hallucination; hallucination, auditory; hallucination, visual. Several patients had both visual and auditory hallucinations. f Pooled reports include such terms as: renal failure and a single patient with renal impairment. g Pooled reports include such terms as: rash; rash generalized; rash macular; rash maculopapular; rash pruritic. Abbreviations: ALT = alanine aminotransferase; LFT = liver function test The following adverse reactions with incidence less than 5% were reported in 105 pediatric patients treated with voriconazole: Blood and Lymphatic System Disorders: anemia, leukopenia, pancytopenia Cardiac Disorders : bradycardia, palpitations, supraventricular tachycardia Eye Disorders: dry eye, keratitis Ear and Labyrinth Disorders : tinnitus, vertigo Gastrointestinal Disorders : abdominal tenderness, dyspepsia General Disorders and Administration Site Conditions : asthenia, catheter site pain, chills, hypothermia, lethargy Hepatobiliary Disorders : cholestasis, hyperbilirubinemia, jaundice Immune System Disorders : hypersensitivity, urticaria Infections and Infestations : conjunctivitis Laboratory Investigations: AST increased, blood creatinine increased, gamma-glutamyl transferase increased Metabolism and Nutrition Disorders : hypercalcemia, hypermagnesemia, hyperphosphatemia, hypoglycemia Musculoskeletal and Connective Tissue Disorders : arthralgia, myalgia Nervous System Disorders: ataxia, convulsion, dizziness, nystagmus, paresthesia, syncope Psychiatric Disorders: affect lability, agitation, anxiety, depression, insomnia Respiratory Disorders : bronchospasm, nasal congestion, respiratory failure, tachypnea Skin and Subcutaneous Tissue Disorders : alopecia, dermatitis (allergic, contact, and exfoliative), pruritus Vascular Disorders : flushing, phlebitis Hepatic-Related Adverse Reactions in Pediatric Patients The frequency of hepatic-related adverse reactions in pediatric patients exposed to voriconazole in therapeutic studies was numerically higher than that of adults (28.6% compared to 24.1%, respectively). The higher frequency of hepatic adverse reactions in the pediatric population was mainly due to an increased frequency of liver enzyme elevations (21.9% in pediatric patients compared to 16.1% in adults), including transaminase elevations (ALT and AST combined) 7.6% in the pediatric patients compared to 5.1% in adults. Clinical Laboratory Values in Pediatric Patients The overall incidence of transaminase increases >3x upper limit of normal was 27.2% (28/103) in pediatric and 17.7% (268/1514) in adult patients treated with voriconazole in pooled clinical trials. The majority of abnormal liver function tests either resolved on treatment with or without dose adjustment or after voriconazole discontinuation. A higher frequency of clinically significant liver laboratory abnormalities, irrespective of baseline laboratory values (>3x ULN ALT or AST), was consistently observed in the combined therapeutic pediatric population (15.5% AST and 22.5% ALT) when compared to adults (12.9% AST and 11.6% ALT). The incidence of bilirubin elevation was comparable between adult and pediatric patients. The incidence of hepatic abnormalities in pediatric patients is shown in Table 9. Table 9: Incidence of Hepatic Abnormalities among Pediatric Subjects Criteria n/N (%) Total bilirubin >1.5x ULN 19/102 (19) AST >3.0x ULN 16/103 (16) ALT >3.0x ULN 23/102 (23) Alkaline Phosphatase >3.0x ULN 8/97 (8) n = number of patients with a clinically significant abnormality while on study therapy N = total number of patients with at least one observation of the given lab test while on study therapy AST = Aspartate aminotransferase; ALT = alanine aminotransferase ULN = upper limit of normal 6.2 Postmarketing Experience in Adult and Pediatric Patients The following adverse reactions have been identified during post-approval use of voriconazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Dermatological Reactions Increased risk of skin toxicity with concomitant use of methotrexate, a drug associated with UV reactivation, was observed in postmarketing reports [see Warnings and Precautions (5.6) and Adverse Reactions (6.1) ]. Adults Skeletal: fluorosis and periostitis have been reported during long-term voriconazole therapy [see Warnings and Precautions ( 5.12 )]. Eye disorders: prolonged visual adverse reactions, including optic neuritis and papilledema [see Warnings and Precautions ( 5.4 )]. Skin and Appendages: drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported [see Warnings and Precautions ( 5.5 ) and Adverse Reactions ( 6.1 )]. Endocrine disorders: adrenal insufficiency, Cushing’s syndrome (when voriconazole has been used concomitantly with corticosteroids) [see Warnings and Precautions ( 5.8 )]. Pediatric Patients There have been postmarketing reports of pancreatitis in pediatric patients.

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 10 and 11 provide the clinically significant interactions between voriconazole and other medical products. Table 10: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)] Drug/Drug Class (Mechanism of Interaction by the Drug) VoriconazolePlasma Exposure (C max and AUC t 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) Efavirenz (300 mg every 24 hours)** (CYP450 Induction) Significantly Reduced Slight Decrease in AUC t Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours. High-dose Ritonavir (400 mg every 12 hours)** (CYP450 Induction) Low-dose Ritonavir (100 mg every 12 hours)** (CYP450 Induction) Significantly Reduced Reduced Contraindicated Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. 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 every 12 hours or from 200 mg to 400 mg orally every 12 hours (100 mg to 200 mg orally every 12 hours in patients weighing less than 40 kg). 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 In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir. Frequent monitoring for adverse reactions and toxicity related to voriconazole when coadministered with other HIV protease inhibitors. Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction) In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to voriconazole. Careful assessment of voriconazole effectiveness. * Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjects ** Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects *** Non-Nucleoside Reverse Transcriptase Inhibitors Table 11: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)] Drug/Drug Class (Mechanism of Interaction by Voriconazole) Drug Plasma Exposure (C max and AUC t ) Recommendations for Drug Dosage Adjustment/ Comments Sirolimus* (CYP3A4 Inhibition) Significantly Increased Contraindicated Rifabutin* (CYP3A4 Inhibition) Significantly Increased Contraindicated Efavirenz (400 mg every 24 hours)** (CYP3A4 Inhibition) Efavirenz (300 mg every 24 hours)** (CYP3A4 Inhibition) Significantly Increased Slight Increase in AUCt Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours. High-dose Ritonavir (400 mg every 12hours)** (CYP3A4 Inhibition) Low-dose Ritonavir (100 mg every 12 hours)** No Significant Effect of Voriconazole on Ritonavir Cmax or AUC t Slight Decrease in Ritonavir C m a x and AUC t Contraindicated because of significant reduction of voriconazole C max and AUC t . Coadministration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole C m ax and AUCt) 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 Lurasidone (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone Contraindicated Finerenone (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Finerenone 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 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. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product. Cyclosporine* (CYP3A4 Inhibition) AUC t Significantly Increased; No Significant Effect on Cmax When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. Methadone*** (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. 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. 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. Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary . NSAIDs**** 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 in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. Phenytoin* (CYP2C9 Inhibition) Significantly 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 on Prednisolone Exposure Not Studied In vitro or In vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased No dosage adjustment for prednisolone when coadministered with voriconazole [see Clinical Pharmacology (12.3)]. Monitor for potential adrenal dysfunction when voriconazole is administered with other corticosteroids [See Warnings and Precautions (5.8)]. Warfarin* (CYP2C9 Inhibition) Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition) Prothrombin Time Significantly Increased Not Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be 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. 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 in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects on Indinavir Exposure In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) No dosage adjustment for indinavir when coadministered with voriconazole. Frequent monitoring for adverse reactions and toxicity related to other HIV protease inhibitors. Other NNRTIs***** (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) Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition) Significantly Increased In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines. 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 patients receiving a vinca alkaloid who have no alternative antifungal treatment options. Everolimus (CYP3A4 Inhibition) Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased Concomitant administration of voriconazole and everolimus is not recommended. * Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects ** Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects *** Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects receiving a methadone maintenance dose (30 to 100 mg every 24 hours) **** Non-Steroidal Anti-Inflammatory Drug ***** Non-Nucleoside Reverse Transcriptase Inhibitors • CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers: Adjust voriconazole dosage and monitor for adverse reactions or lack of efficacy ( 4 , 7 ) • Voriconazole may increase the concentrations and activity of drugs that are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce dosage of these other drugs and monitor for adverse reactions ( 4 , 7 ) • Phenytoin or Efavirenz: With co-administration, increase maintenance oral and intravenous dosage of voriconazole ( 2.3 , 2.7 , 7 )