Voriconazole Dosing and Administration

Introduction to Voriconazole

• The Infectious Diseases Society of America recommends a loading dose of 400 mg (6 mg/kg) twice daily for 2 doses on day 1, followed by a maintenance dose of 200-300 mg (3-4 mg/kg) twice daily for a 70 kg male 1, 2

Intravenous Administration

• The recommended loading dose is 6 mg/kg every 12 hours for the first 24 hours (420 mg IV every 12 hours for a 70 kg patient) 2
• The maintenance dose is 3-4 mg/kg every 12 hours (210-280 mg IV every 12 hours for a 70 kg patient) 2

Oral Administration

• The loading dose is 400 mg (6 mg/kg) twice daily for 2 doses 2
• The maintenance dose is 200-300 mg (3-4 mg/kg) twice daily 2
• Oral bioavailability is excellent (>90%) and allows for easy transition between IV and oral formulations 2

Dosing Considerations

Renal Function

• Intravenous voriconazole is not recommended for patients with creatinine clearance <50 mL/minute due to potential cyclodextrin accumulation 2
• Oral voriconazole does not require dosage adjustment for renal insufficiency 2, 3

Hepatic Function

• Voriconazole requires dosage reduction for patients with mild to moderate hepatic impairment 2

Drug Interactions

• Common polymorphisms in metabolic enzymes result in wide variability of serum levels 2
• Drug-drug interactions are common with voriconazole and should be carefully considered 2

Therapeutic Considerations

Indications

• Voriconazole is effective for both mucosal and invasive candidiasis 2
• It is particularly useful for step-down oral therapy in patients with infections due to C. krusei and fluconazole-resistant, voriconazole-susceptible C. glabrata 2
• Voriconazole achieves good CSF and vitreous concentrations (>50% of serum concentration) 2

Monitoring

• Common side effects include hepatic injury, visual side effects, photosensitivity, periostitis, and CNS side effects 2

Duration of Therapy

• For candidemia without obvious metastatic complications, treat for 2 weeks after documented clearance of Candida from the bloodstream and resolution of symptoms 4
• For invasive aspergillosis, the median duration in clinical trials was 10 days IV followed by 76 days oral therapy 2

Special Considerations

• Voriconazole should not be used for urinary candidiasis as it does not accumulate in active form in the urine 2
• For CNS aspergillosis, voriconazole is the primary recommended agent 5

Voriconazole Dosing and Administration

Adult Dosing

• The recommended oral voriconazole dosing is a loading dose of 400 mg (6 mg/kg) twice daily for 2 doses on day 1, followed by a maintenance dose of 200-300 mg (3-4 mg/kg) twice daily, with no dosage adjustment necessary for patients with renal impairment 6
• For patients with mild to moderate hepatic impairment, the maintenance dose should be halved 6

Pediatric Dosing

• Higher doses may be required in pediatric patients due to accelerated metabolic clearance, with the European Medicines Agency recommending a maintenance dosage of 7 mg/kg twice daily in pediatric patients to attain plasma levels comparable to those of adults 7

Administration Considerations

• Bioavailability of voriconazole decreases when administered with food, and for optimal absorption, it should be taken at least 1 hour before or after a meal 6

Clinical Considerations

• Due to high interpatient variability in voriconazole exposure, therapeutic drug monitoring may be beneficial, especially with oral therapy, and common polymorphisms in CYP2C19 can result in wide variability of serum levels 6, 7
• Voriconazole should not be used for urinary candidiasis as it does not accumulate in active form in the urine, and drug-drug interactions are common with voriconazole and should be carefully evaluated before initiating therapy 6
• Oral voriconazole is preferred over IV formulation in patients with renal dysfunction, and voriconazole is the only triazole that requires dosage reduction for patients with mild to moderate hepatic impairment 6

Voriconazole Dosing Considerations in ICU Patients

Dosing Adjustments for Renal and Hepatic Impairment

• For ICU patients with creatinine clearance <50 mL/min, the Infectious Diseases Society of America recommends avoiding intravenous voriconazole and using oral formulation instead at standard doses without adjustment, due to the risk of nephrotoxicity associated with the IV formulation's vehicle, sulfobutylether-β-cyclodextrin (SBECD) 8
• In patients with mild to moderate hepatic impairment (Child-Pugh Class A or B), the Clinical Infectious Diseases guideline suggests reducing the maintenance dose by 50% while keeping the loading dose unchanged, as voriconazole is the only triazole requiring dose reduction in hepatic impairment 8

Adverse Effects and Monitoring

• Visual disturbances occur in approximately 30% of patients and are dose-related but typically reversible, according to the Clinical Infectious Diseases journal 8
• The Infectious Diseases Society of America recommends monitoring for hepatotoxicity, photosensitivity, periostitis, and CNS effects, which are more common with higher concentrations 8

Voriconazole Administration Considerations

Drug Interactions and Monitoring

• The American College of Cardiology recommends cautious monitoring of drug interactions, particularly with medications metabolized by CYP3A4, CYP2C19, and CYP2C9, in elderly patients taking voriconazole 9, 10
• The National Comprehensive Cancer Network recommends monitoring for QTc prolongation, especially when combining voriconazole with other QT-prolonging drugs, in elderly patients 10
• The American College of Cardiology suggests reducing warfarin dose by 50% due to CYP2C9 inhibition when co-administered with voriconazole 9
• The National Comprehensive Cancer Network and Clinical Microbiology and Infection recommend significant dose reductions of immunosuppressants, such as cyclosporine and tacrolimus, when co-administered with voriconazole 10, 11

Dose Adjustments and Route Selection

• The American College of Cardiology and National Comprehensive Cancer Network suggest avoiding IV formulation in patients with creatinine clearance <50 mL/min due to SBECD accumulation and nephrotoxicity risk, and instead using the oral formulation 9, 10

Special Considerations

• The National Comprehensive Cancer Network recommends monitoring for photosensitivity and skin cancers, which increase with prolonged voriconazole use 10
• The American College of Cardiology and National Comprehensive Cancer Network emphasize the importance of therapeutic drug monitoring in elderly patients due to high interpatient variability from CYP2C19 polymorphisms 9, 10