Voriconazole
Dosing in kidney impairment
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 ] . 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 ] .
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 ] . Pediatric Patients Dosage adjustment of voriconazole in pediatric patients with renal impairment has not been established [see Use in Specific Populations ] .
Dosing in liver impairment
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 ] .
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 ] . 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 ] .
| Infection | Loading Dose | Maintenance DoseIncrease dose when voriconazole is coadministered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment (2.4),In healthy volunteer studies, the 200 mg oral every 12 hours dose provided an exposure (AUCτ) similar to a 3 mg/kg intravenous infusion every 12 hours dose; the 300 mg oral every 12 hours dose provided an exposure (AUCτ) similar to a 4 mg/kg intravenous infusion every 12 hours dose (12). | |
| Intravenous infusion | Intravenous infusion | Oral suspensionAdult patients who weigh less than 40 kg should receive half of the oral maintenance dose. | |
| Invasive AspergillosisIn 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 | 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 | 3–4 mg/kg every 12 hoursIn 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. | 5 mL every 12 hours |
| Esophageal Candidiasis | Not EvaluatedNot evaluated in patients with EC. | Not Evaluated | 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 | 5 mL every 12 hours |
Preparation and administration
Important Administration Instructions for Use in All Patients Administer Voriconazole Oral Suspension at least one hour before or after a meal.
Preparation and Administration of Voriconazole 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 1 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 15°C to 30°C [59 to 86°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.
| Infection | Loading Dose | Maintenance Dose | |
| Intravenous infusion | Intravenous infusion | Oralsuspension | |
| Invasive Aspergillosis | 6 mg/kg every 12 hours for the first 24 hours | 4 mg/kg every 12 hours | 5 mL every 12 hours |
| Candidemia in nonneutropenics and other deep tissue Candida infections | 3–4 mg/kg every 12 hours | 5 mL every 12 hours | |
| Scedosporiosis and Fusariosis | 4 mg/kg every 12 hours | 5 mL every 12 hours | |
| Esophageal Candidiasis | Not Evaluated | Not Evaluated | 5 mL every 12 hours |
| Infection | Loading Dose | Maintenance Dose | |
| Intravenous infusion | Intravenous infusion | Oralsuspension | |
| Invasive Aspergillosis | 9 mg/kg every 12 hours for the first 24 hours | 8 mg/kg every 12 hours after the first 24 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 | 0.225 mL/kg every 12 hours[maximum dose of 8.75 mL (350 mg) every 12 hours] |
| Infection | Loading Dose | Maintenance DoseIncrease dose when voriconazole is coadministered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment (2.4),In healthy volunteer studies, the 200 mg oral every 12 hours dose provided an exposure (AUCτ) similar to a 3 mg/kg intravenous infusion every 12 hours dose; the 300 mg oral every 12 hours dose provided an exposure (AUCτ) similar to a 4 mg/kg intravenous infusion every 12 hours dose (12). | |
| Intravenous infusion | Intravenous infusion | Oral suspensionAdult patients who weigh less than 40 kg should receive half of the oral maintenance dose. | |
| Invasive AspergillosisIn 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 | 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 | 3–4 mg/kg every 12 hoursIn 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. | 5 mL every 12 hours |
| Esophageal Candidiasis | Not EvaluatedNot evaluated in patients with EC. | Not Evaluated | 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 | 5 mL every 12 hours |