2 DOSAGE AND ADMINISTRATION Recommended Dosage ( 2.3 ) Infection Loading Dose Maintenance Dose IV IV Oral Invasive Aspergillosis 6 mg/kg q12h for the first 24 hours 4 mg/kg q12h 200 mg q12h Candidemia in non-neutropenics and other deep tissue Candida infections 3 to 4 mg/kg q12h 200 mg q12h Scedosporiosis and Fusariosis 4 mg/kg q12h 200 mg q12h Esophageal Candidiasis not evaluated not evaluated 200 mg q12h • Adult patients weighing less than 40 kg: oral maintenance dose 100 mg or 150 mg q12 hours • See full prescribing information for instructions on reconstitution of oral suspension and important administration instructions ( 2.6 ) 2.1 Instructions for Use in All Patients Voriconazole for oral suspension should be taken at least one hour before or after a meal. 2.3 Recommended Dosing 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 regimen. Intravenous treatment should be continued for at least 7 days. Once the patient has clinically improved and can tolerate medication given by mouth, the oral tablet form or oral suspension form of voriconazole may be utilized. The recommended oral maintenance dose of 200 mg achieves a voriconazole exposure similar to 3 mg/kg IV; a 300 mg oral dose achieves an exposure similar to 4 mg/kg IV. Switching between the intravenous and oral formulations is appropriate because of the high bioavailability of the oral formulation in adults [see Clinical Pharmacology ( 12 )] . Candidemia in non-neutropenic patients and other deep 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 Infection Loading dose Maintenance Dose Increase dose when voriconazole is coadministered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment ( 2.7 ). , In healthy volunteer studies, the 200 mg oral q12h dose provided an exposure (AUC τ ) similar to a 3 mg/kg IV q12h dose; the 300 mg oral q12h dose provided an exposure (AUC τ ) similar to a 4 mg/kg IV q12h dose [see Clinical Pharmacology ( 12 )] . IV IV Oral Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose. Invasive Aspergillosis In a clinical study of invasive aspergillosis, the median duration of IV 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) [see Clinical Studies ( 14.1 )] . 6 mg/kg q12h for the first 24 hours 4 mg/kg q12h 200 mg q12h Candidemia in non-neutropenic patients and other deep tissue Candida infections 6 mg/kg q12h for the first 24 hours 3 to 4 mg/kg q12h In clinical trials, patients with candidemia received 3 mg/kg IV q12h as primary therapy, while patients with other deep tissue Candida infections received 4 mg/kg q12h as salvage therapy. Appropriate dose should be based on the severity and nature of the infection. 200 mg q12h Esophageal Candidiasis Not evaluated in patients with esophageal candidiasis. 200 mg q12h Scedosporiosis and Fusariosis 6 mg/kg q12h for the first 24 hours 4 mg/kg q12h 200 mg q12h 2.4 Dosage Adjustment If patient response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours (similar to 3 mg/kg IV q12h) to 300 mg every 12 hours (similar to 4 mg/kg IV q12h). For adult patients weighing less than 40 kg, the oral maintenance dose may be increased from 100 mg every 12 hours to 150 mg every 12 hours. If patient is unable to tolerate 300 mg orally every 12 hours, reduce the oral maintenance dose by 50 mg steps to a minimum of 200 mg every 12 hours (or to 100 mg every 12 hours for adult patients weighing less than 40 kg). If patient is unable to tolerate 4 mg/kg IV q12h, reduce the intravenous maintenance dose to 3 mg/kg q12h. The maintenance dose of voriconazole should be increased when coadministered with phenytoin or efavirenz [see Drug Interactions ( 7 )] . The maintenance dose of voriconazole should be reduced in patients with mild to moderate hepatic impairment, Child-Pugh Class A and B [see Dosage and Administration ( 2.7 )] . There are no PK data to allow for dosage adjustment recommendations in patients with severe hepatic impairment (Child-Pugh Class C). Duration of therapy should be based on the severity of the patient’s underlying disease, recovery from immunosuppression and clinical response. Duration of therapy should be based on the severity of the patient’s underlying disease, recovery from immunosuppression and clinical response. 2.6 Oral Suspension Reconstitution Tap the bottle to release the powder. Add 46 mL of water to the bottle. Shake the closed bottle vigorously for about one minute. Remove child-resistant cap and push bottle adaptor into the neck of the bottle. Replace the cap. Write the date of expiration of the reconstituted suspension on the bottle label (the shelf life of the reconstituted suspension is 14 days at controlled room temperature 20° to 25°C (68° to 77°F). Instructions for Use Shake the closed bottle of reconstituted suspension for approximately 10 seconds before each use. The reconstituted oral suspension should only be administered using the oral dispenser supplied with each pack. Incompatibilities Voriconazole for oral suspension and the 40 mg/mL reconstituted oral suspension should not be mixed with any other medication or additional flavoring agent. It is not intended that the suspension be further diluted with water or other vehicles. 2.7 Use in Patients with Hepatic Impairment In the clinical program, patients were included who had baseline liver function tests (ALT, AST) up to 5 times the upper limit of normal. No dose adjustment is necessary in patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended [see Warnings and Precautions ( 5.9 )] . It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) [see Clinical Pharmacology ( 12.3 )] . Voriconazole for oral suspension has not been studied in patients with severe hepatic cirrhosis (Child-Pugh Class C) or in patients with chronic hepatitis B or chronic hepatitis C disease. Voriconazole for oral suspension has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice and should only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic insufficiency must be carefully monitored for drug toxicity. 2.8 Use in Patients with Renal Impairment The pharmacokinetics of orally administered voriconazole for oral suspension are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment [see Clinical Pharmacology ( 12.3 )] . In patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral voriconazole therapy [see Warnings and Precautions ( 5.10 )] . Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.