2 DOSAGE AND ADMINISTRATION Dosage in Adults (2.3) Infection Loading Dose Maintenance Dose Intravenous infusion Intravenous infusion Oral Invasive Aspergillosis 6 mg/kg every 12 hours for the first 24 hours 4 mg/kg every 12 hours 200 mg every 12 hours Candidemia in nonneutropenics and other deep tissue Candida infections 3-4 mg/kg every 12 hours 200 mg every 12 hours Scedosporiosis and Fusariosis 4 mg/kg every 12 hours 200 mg every 12 hours Esophageal Candidiasis Not Evaluated Not Evaluated 200 mg every 12 hours Adult patients weighing less than 40 kg: oral maintenance dose 100 mg or 150 mg 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 years of age and older (2.4) 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 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) 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) 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 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 lyophilized powder for intravenous use and important administration instructions (2.1, 2.8) 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 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 Increase dose when voriconazole is co-administered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment (2.5) , 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). Intravenous infusion Intravenous infusion Oral Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose. Invasive Aspergillosis 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). 6 mg/kg every 12 hours for the first 24 hours 4 mg/kg every 12 hours 200 mg 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 mg/kg to 4 mg/kg every 12 hours 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. 200 mg every 12 hours Esophageal Candidiasis Not Evaluated Not evaluated in patients with EC. Not Evaluated # 200 mg 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 Method for Adjusting the Dosing Regimen in Adults If the patient’s response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours (similar to 3 mg/kg intravenously every 12 hours) to 300 mg every 12 hours (similar to 4 mg/kg intravenously every 12 hours). For adult patients weighing less than 40 kg, the oral maintenance dose may be increased from 100 mg every 12 hours to 150 mg every 12 hours. If patient is unable to tolerate 300 mg orally every 12 hours, reduce the oral maintenance dose by 50 mg steps to a minimum of 200 mg every 12 hours (or to 100 mg every 12 hours for adult patients weighing less than 40 kg). If 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 ^ 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. 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) 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) 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 steps or 50 mg steps to a maximum of 350 mg 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 or 50 mg 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 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 for injection after 24 hours storage at room temperature. Although refrigerated storage is recommended following reconstitution, use of this diluent is not recommended as a precautionary measure. Compatibility with other concentrations is unknown.