Voriconazole: Difference between revisions
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*Indications include {{#ask: [[Is treated by::voriconazole]]}} |
*Indications include {{#ask: [[Is treated by::voriconazole]]}} |
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===Mechanism of Action=== |
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*Like all azoles, inhibits Erg11/Cyp51p lanosterol 14-α-demethylase in the ergosterol synthesis pathway |
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===Pharmacokinetics and Pharmacodynamics=== |
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*Non-linear pharmacokinetics |
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*58% protein-bound |
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*CSF 50% of plasma concentration |
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*Less than 5% excreted unchanged in the urine |
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===Spectrum of Activity=== |
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*Active against [[Aspergillus]] (including [[Aspergillus terreus]]), [[Scedosporium species]], [[Fusarium species]], and [[Candida species]] |
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*Possibly active against [[Cryptococcus species]], [[Blastomyces dermatitidis]], [[Coccidioides immitis]], and [[Histoplasma capsulatum]] |
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*Less active against [[Sporothrix schenckii]] |
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===Breakpoints=== |
===Breakpoints=== |
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==Dosing== |
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*Voriconazole 6 mg/kg IV q12h x2 followed by 4 mg/kg PO/IV q12h |
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*Voriconazole 200 mg PO q12h if weight >40 kg, or 100 mg PO q12h if weight <40 kg |
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**Give at least 1 hour before or after a meal |
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**Can be preceded by a loading dose of twice the maintenance for 24 hours |
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===Therapeutic Drug Monitoring=== |
===Therapeutic Drug Monitoring=== |
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==Safety== |
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*Elevated levels predict neurotoxicity, but ''not'' hepatotoxicity |
*Elevated levels predict neurotoxicity, but ''not'' hepatotoxicity |
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*Headache, nausea and vomiting, diarrhea, abdominal pain |
*Headache, nausea and vomiting, diarrhea, abdominal pain |
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===Drug-Drug Interactions=== |
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*Voriconazole is metabolised by CYP450 enzymes |
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*Voriconazole also inhibits CYP3A4 and CYP2C9 |
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Revision as of 00:36, 6 September 2020
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 species, Fusarium species, and Candida species
- Possibly active against Cryptococcus species, 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. |
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
- Hepatotoxicity, proportional to serum levels
- 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.
