Voriconazole: Difference between revisions

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== Background ==
==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]]}}


=== Breakpoints ===
=== 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
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|}
|}


== 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
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|}
|}


===Safety===
== 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]] etc that may improve with time
**[[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

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

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

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
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