Voriconazole: Difference between revisions
From IDWiki
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
== |
==Background== |
||
*Azole antifungal |
*Azole antifungal derived from [[fluconazole]] to improve mold coverage |
||
*Indications include {{#ask: [[Is treated by::voriconazole]]}} |
*Indications include {{#ask: [[Is treated by::voriconazole]]}} |
||
=== |
=== 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=== |
|||
{| class="wikitable" |
{| class="wikitable" |
||
! rowspan="2" |Species |
! rowspan="2" |Species |
||
| Line 95: | Line 112: | ||
|} |
|} |
||
== Dosing == |
|||
==Therapeutic Drug Monitoring== |
|||
* Voriconazole 6 mg/kg IV q12h x2 followed by 3-4 mg/kg PO/IV q12h |
|||
===Therapeutic Drug Monitoring=== |
|||
*Measure trough within 7 days of starting, and at regular intervals or following dose adjustment |
*Measure trough within 7 days of starting, and at regular intervals or following dose adjustment |
||
| Line 116: | Line 137: | ||
|} |
|} |
||
== |
== Safety == |
||
*Elevated levels predict neurotoxicity, but ''not'' hepatotoxicity |
*Elevated levels predict neurotoxicity, but ''not'' hepatotoxicity |
||
==Adverse Drug Reactions== |
===Adverse Drug Reactions=== |
||
*Visual, which tend to improve after the first week of therapy and are reversible |
|||
*Visual |
|||
**[[Adverse drug reaction::Floaters]] |
**[[Adverse drug reaction::Floaters]] (photopsia) that usually improves with time (30%) |
||
**[[Adverse drug reaction::Visual hallucinations]] |
**[[Adverse drug reaction::Visual hallucinations]] (5%) |
||
**[[Adverse drug reaction::Colour vision loss]] |
**[[Adverse drug reaction::Colour vision loss]], [[Adverse drug reaction::blurred vision]], [[Adverse drug reaction::photophobia]] |
||
*Dermatologic |
|||
*[[Adverse drug reaction::Photosensitivity]] |
|||
**Rashes, usually mild |
|||
*[[Adverse drug reaction::Hepatotoxicity]] |
|||
**[[Stevens-Johnson syndrome]] and [[toxic epidermal necrolysis]] (rare) |
|||
**[[Adverse drug reaction::Photosensitivity]] |
|||
*[[Adverse drug reaction::Hepatotoxicity]], proportional to serum levels |
|||
*[[Adverse drug reaction::QTc prolongation]] |
*[[Adverse drug reaction::QTc prolongation]] |
||
*Headache, nausea and vomiting, diarrhea, abdominal pain |
|||
=== Drug-Drug Interactions === |
|||
* Voriconazole is metabolised by CYP450 enzymes |
|||
* Voriconazole also inhibits CYP3A4 and CYP2C9 |
|||
{| class="wikitable" |
|||
!Drug |
|||
!Recommendation |
|||
|- |
|||
! colspan="2" |Decreases voriconazole levels |
|||
|- |
|||
|[[carbamazepine]] |
|||
|contraindicated |
|||
|- |
|||
|long-acting [[Barbiturate|barbiturates]] |
|||
|contraindicated |
|||
|- |
|||
|[[rifampin]] |
|||
|contraindicated |
|||
|- |
|||
! colspan="2" |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 |
|||
|- |
|||
! colspan="2" |Decreases voriconazole levels, and levels increased by voriconazole |
|||
|- |
|||
|[[rifabutin]] |
|||
|contraindicated |
|||
|- |
|||
|[[phenytoin]] |
|||
|double voriconazole, and monitor phenytoin levels |
|||
|- |
|||
! colspan="2" |Levels likely increased by voriconazole |
|||
|- |
|||
|sulfonylureas |
|||
| rowspan="5" |monitor for side effects of drug and consider decreasing dosage |
|||
|- |
|||
|statins |
|||
|- |
|||
|vinca alkaloids |
|||
|- |
|||
|calcium channel blockers |
|||
|- |
|||
|benzodiazepines |
|||
|} |
|||
==Further Reading== |
==Further Reading== |
||
Revision as of 00:33, 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 3-4 mg/kg PO/IV q12h
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.
- ^ 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.
