Background
- Azole antifungal derived from fluconazole to improve mold coverage
- Indications include 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 | ||||||||
| 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 7 days of starting, and at regular intervals or following dose adjustment
- 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 daily trough levels, 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 daily trough levels, 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
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
References
- ^ Romeo-Gabriel Mihăilă. Voriconazole and the liver. World Journal of Hepatology. 2015;7(13):1828. doi:10.4254/wjh.v7.i14.1828.
- ^ Taotao Wang, Liyan Miao, Hua Shao, Xiaohua Wei, Miao Yan, Xiaocong Zuo, Jun Zhang, Xin Hai, Guangjun Fan, Wei Wang, Linlin Hu, Jian Zhou, Yichang Zhao, Yueliang Xie, Jingjing Wang, Sixun Guo, Liu Jin, Hao Li, Hui Liu, Quanfang Wang, Jiaojiao Chen, Sihan Li, Yalin Dong. Voriconazole therapeutic drug monitoring and hepatotoxicity in critically ill patients: A nationwide multi-centre retrospective study. International Journal of Antimicrobial Agents. 2022;60(5-6):106692. doi:10.1016/j.ijantimicag.2022.106692.
