Antimicrobials

Active against:

• Candida species: albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei
• Aspergillus species
• Fusarium species

Not active against:

• Zygomycetes

Appropriate Uses:

• Treatment of systemic candidiasis (typically reserved for fluconazole non-susceptible isolates)
• Treatment of severe mucocutaneous candidiasis (typically reserved for fluconazole non-susceptible isolates)
• Treatment of aspergillosis
• Antifungal prophylaxis for complex hematologic malignancies (where applicable)

Inappropriate Uses

• Treatment of fungal infections for which there are narrower options (e.g., fluconazole)

Adapted from: CID. 2003;36:633

• For use in Pregnancy and Breastfeeding, see Safe Use of Antibacterial Agents: Pregnancy & Breastfeeding
• Use with caution in patients with prolonged QT interval
• Oral voriconazole does not require dose adjustment in patients with renal insufficiency, however IV voriconazole should be used with caution in patients with renal insufficiency (see Dosing Guidelines)
• Use with caution in patients with severe hepatic impairment (Child Pugh Class C)

• Common: transaminitis, QT prolongation, photosensitivity, visual disturbances (blurred vision, colour changes, enhanced vision)*, hallucinations**
• Uncommon: rash, nausea, vomiting, abdominal pain, hepatoxicity

* typically self-limiting and do not require discontinuation of therapy
** associated with elevated trough levels (>5 mg/L)

Usual Dosage:

• Candidiasis (fluconazole-resistant isolates):
  • Candidemia: 6 mg/kg (~400 mg) PO Q12H x 2 doses then 4 mg/kg (~200-300 mg) PO Q12H
  • Esophageal candidiasis: 200 mg PO Q12H
• Aspergillosis: 6 mg/kg (~400 mg) PO Q12H x 2 doses then 4 mg/kg (~200-300 mg) PO Q12H
• Antifungal Prophylaxis in acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) patients receiving induction or consolidation chemotherapy:
  • 200mg PO Q12H until neutropenia resolves

Renal Dosage:

• dose adjustment not required for oral therapy;
• use IV voriconazole with caution in patients with CrCl < 50 mL/min due to potential concern regarding accumulation of diluent with theoretical associated toxicity due to vacuolation in kidneys and liver, that have only been seen in animal studies to date.

Dosage in Hepatic Impairment:

• Child-Pugh Class A & B: 6 mg/kg q12h x2, then 2 mg/kg IV q12h; monitor serum concentrations (see Voriconazole Therapeutic Drug Monitoring Guidelines below)
• Child-Pugh class C: use with caution (not studied)

• IV voriconazole: for preparation/administration, see IV drug monograph
• Oral voriconazole: for optimal absorption of oral voriconazole, administer on an empty stomach either 1 hour before or 2 hours after a meal

• Voriconazole levels (see Voriconazole Therapeutic Drug Monitoring Guidelines)
• Transaminases – several times weekly
• QTc- several times weekly, particularly if patient has prolonged QTc at baseline
• Consider ophthalmology consult for visual function, including visual acuity, visual field, and colour perception monitoring with prolonged therapy or if patient describes persistent visual changes

Voriconazole therapeutic monitoring guideline

Rationale

CYP 2C19, the major isoenzyme involved in voriconazole’s metabolism, is subject to several genetic polymorphisms. These result in several distinct and well-described phenotypes: ultraslow metabolizers, intermediate metabolizers, and extensive metabolizers. It has been demonstrated that, among these phenotypes, there are extensive variations in drug exposure, leading to concerns regarding toxicity and treatment failure secondary to subtherapeutic levels. In addition, voriconazole’s non-linear pharmacokinetics and propensity for drug interactions further complicate initial dosing and subsequent dose adjustments.

Because of voriconazole’s complicated and non-predictable pharmacokinetics, there is ongoing research on the benefits of therapeutic drug monitoring (TDM). Clinical data suggests that the efficacy of treatment of invasive fungal infections with voriconazole is optimized and the risk of voriconazole-related toxicities may be mitigated when TDM is performed.

Indications for TDM of Voriconazole

1. Treatment of invasive mycoses associated with high morbidity and mortality (e.g. Aspergillosis)
2. Suspected breakthrough Aspergillus infection in patients receiving voriconazole prophylaxis
3. Poor response to voriconazole therapy
4. Suspected voriconazole-related toxicities:
   • Hepatotoxicity [ALT ≥ 5 x ULN without an alternative etiology OR elevated bilirubin ≥ 2-3 x ULN
   • Persistent and/or distressing visual changes (altered color sensation, photophobia, and blurred vision)
   • Unexplained hallucinations or encephalopathy
   • Unexplained hyponatremia
5. The presence of clinically-significant drug interactions: it is highly recommended to screen for drug interactions. Please contact Infectious Diseases if there is an addition or discontinuation of any strong inducers or inhibitors of voriconazole’s metabolism while a patient is on therapy.

Targets for TDM: 1.0 mg/L – 5 mg/L

How to draw levels