Voriconazole

Background

• Azole antifungal derived from fluconazole to improve mold coverage
• Indications include Acanthamoeba, Alternaria, Blastomyces dermatitidis, Coccidioides immitis, Exophiala, Exserohilum, Fungal endocarditis, Histoplasma capsulatum, Rasamsonia

Mechanism of Action

• Like all azoles, inhibits Erg11/Cyp51p lanosterol 14-α-demethylase in the ergosterol synthesis pathway

Pharmacokinetics and Pharmacodynamics

• Non-linear pharmacokinetics
• 58% protein-bound
• CSF 50% of plasma concentration
• Less than 5% excreted unchanged in the urine

Spectrum of Activity

• Active against Aspergillus (including Aspergillus terreus), Scedosporium, Fusarium, and Candida
• Possibly active against Cryptococcus, Blastomyces dermatitidis, Coccidioides immitis, and Histoplasma capsulatum
• Less active against Sporothrix schenckii

Breakpoints

Species	ECV (μg/mL)	Breakpoints (μg/mL)				Breakpoints (mm)
		S	I	SDD	R	S	I	SDD	R
Candida albicans	0.3	≤0.12	0.25-0.5	—	≥1	≥17	15-16	—	≤14
Candida glabrata	0.25	—	—	—	—	—	—	—	—
Candida krusei	0.5	≤0.5	1	—	≥2	≥15	13-14	—	≤12
Candida parapsilosis	0.03	≤0.12	0.25-0.5	—	≥1	≥17	15-16	—	≤14
Candida tropicalis	0.12	≤0.12	0.25-0.5	—	≥1	≥17	15-16	—	≤14
Cryptococcus neoformans	0.25
Cryptococcus gattii	0.5
Aspergillus flavus	2	—			—
Aspergillus fumigatus	1	≤1			>1
Aspergillus niger	1	≤1			>1
Aspergillus niger	2	—			—
Aspergillus terreus	2	—			—

Dosing

• Voriconazole 6 mg/kg IV q12h x2 followed by 4 mg/kg PO/IV q12h
• Voriconazole 200 mg PO q12h if weight >40 kg, or 100 mg PO q12h if weight <40 kg
  • Give at least 1 hour before or after a meal
  • Can be preceded by a loading dose of twice the maintenance for 24 hours

Therapeutic Drug Monitoring

• Measure trough within 5 to 7 days of starting or following dose adjustment, and at regular intervals
• Target trough > 1 mg/L for prophylaxis and treatment

Trough (mcg/mL)	Recommendation
0.0 to 0.6	Increase dose by 100 mg and recheck trough on day 5 of new regimen
0.7 to 0.9	Increase dose by 50 mg and recheck trough on day 5 of new regimen
1.0 to 4.0	At target, no dose adjustment needed
4.1 to 5.5	Decrease dose by 50 mg and recheck trough on day 5 of new regimen
5.6 to 7.9	Hold dose. Follow trough levels every 2 days, then restart when trough is ≤2.5 at a dose decreased by 100 mg. Recheck trough on day 5 of new regimen.
≥8.0	Hold dose. Follow trough levels every 2 days, then restart when trough is ≤2.5 at a dose decreased by 50%. Recheck trough level on day 5 of new regimen.

Monitoring

• Weekly liver enzymes for first month, then monthly thereafter

Renal Dysfunction

• No dosage adjustment necessary, though for the IV formulation there is a risk of accumulation of sulfobutylether-beta-cyclodextrin (SBECD), which has been associated with renal injury in animal models

Liver Dysfunction

• For Child-Pugh A and B, consider reducing the maintenance dose to half the usual dose, while keeping the same loading dose

Safety

• Elevated levels predict neurotoxicity, but not hepatotoxicity

Adverse Drug Reactions

• Visual, which tend to improve after the first week of therapy and are reversible
  • Floaters (photopsia) that usually improves with time (30%)
  • Visual hallucinations (5%)
  • Colour vision loss, blurred vision, photophobia
• Dermatologic
  • Rashes, usually mild
  • Stevens-Johnson syndrome and toxic epidermal necrolysis (rare)
  • Photosensitivity
• Hepatotoxicity1
  • Risk factors include higher trough (though can occur at any level), other hepatotoxic medications (and specifically tigecycline and TMP-SMX), and septic shock2
  • In critically ill patients, mostly occurs within 7 days of starting
  • Primarily cholestasis, but can be hepatocellular damage or mixed
  • Resolves with discontinuation, but can take 1 to 3 months
  • See also LiverTox
• QTc prolongation
• Headache, nausea and vomiting, diarrhea, abdominal pain
• Periostitis is a rare reaction3
  • Onset average 6 months after starting voriconazole (range 45 days to 8 years)
  • Likely more often with high doses
  • Characterized by widespread skeletal pain involving, in order from most common to least: ribs, femurs, scapulae, humerus, clavicle, tibias, phalanges, radius, ulna, acetabulum, metacarpals, carpals, and other
    • On occasion can affect a single site
  • All have elevated plasma fluoride levels and ALP
  • Managed with discontinuation, which is followed by complete resolution of symptoms usually within a week or two

Drug-Drug Interactions

• Voriconazole is metabolised by CYP450 enzymes
• Voriconazole also inhibits CYP3A4 and CYP2C9

Drug	Recommendation
Decreases voriconazole levels
carbamazepine	contraindicated
long-acting barbiturates	contraindicated
rifampin	contraindicated
Levels increased by voriconazole
astemizole	contraindicated
cisapride	contraindicated
cyclosporine	reduce cyclosporine dosage 50% and monitor levels
ergot alkaloids	contraindicated
omeprazole	reduce omeprazole by 50%
quinidine	contraindicated
sirolimus	contraindicated
tacrolimus	reduce tacrolimus levels to 33% and monitor levels
terfenadine	contraindicated
warfarin	monitor INR
Decreases voriconazole levels, and levels increased by voriconazole
rifabutin	contraindicated
phenytoin	double voriconazole, and monitor phenytoin levels
Levels likely increased by voriconazole
sulfonylureas	monitor for side effects of drug and consider decreasing dosage
statins
vinca alkaloids
calcium channel blockers
benzodiazepines

Further Reading

• Voriconazole Dose Modification Guideline to Optimize Therapeutic Levels in Patients With Hematologic Malignancies. Open Forum Infect Dis. 2015;2(S1):810. doi: 10.1093/ofid/ofv133.527