Voriconazole: Difference between revisions

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==Background==
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* Azole antifungal
  
−
* Indications include {{#ask: [[Is treated by::voriconazole]]}}
  
   
  +
*Azole antifungal derived from [[fluconazole]] to improve mold coverage
−
== Therapeutic Drug Monitoring ==
  
  +
*Indications include {{#ask: [[Is treated by::voriconazole]]}}
−
* Measure trough within 7 days of starting, and at regular intervals or following dose adjustment
  
−
* Target trough > 1 mg/L for prophylaxis and treatment
  
   
  +
===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]]
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*Possibly active against [[Cryptococcus]], [[Blastomyces dermatitidis]], [[Coccidioides immitis]], and [[Histoplasma capsulatum]]
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*Less active against [[Sporothrix schenckii]]
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  +
===Breakpoints===
 
{| class="wikitable"
  
{| class="wikitable"
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! rowspan="2" |Species
−
! Trough (mcg/mL) !! Recommendation
  
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! rowspan="2" |ECV (μg/mL)
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! colspan="4" |Breakpoints (μg/mL)
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! colspan="4" |Breakpoints (mm)
 
|-
  
|-
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!S
−
| 0.0 to 0.6 || Increase dose by 100 mg and recheck trough on day 5 of new regimen
  
  +
!I
  +
!SDD
  +
!R
  +
!S
  +
!I
  +
!SDD
  +
!R
 
|-
  
|-
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|[[Candida albicans]]
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| 0.7 to 0.9 || Increase dose by 50 mg and recheck trough on day 5 of new regimen
  
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|0.3
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|≤0.12
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|0.25-0.5
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|—
  +
|≥1
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|≥17
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|15-16
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|—
  +
|≤14
 
|-
  
|-
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|[[Candida glabrata]]
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| 1.0 to 4.0 || At target, no dose adjustment needed
  
  +
|0.25
  +
|—
  +
|—
  +
|—
  +
|—
  +
|—
  +
|—
  +
|—
  +
|—
 
|-
  
|-
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|[[Candida krusei]]
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| 4.1 to 5.5 || Decrease dose by 50 mg and recheck trough on day 5 of new regimen
  
  +
|0.5
  +
|≤0.5
  +
|1
  +
|—
  +
|≥2
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|≥15
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|13-14
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|—
  +
|≤12
 
|-
  
|-
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|[[Candida parapsilosis]]
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| 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.
  
  +
|0.03
  +
|≤0.12
  +
|0.25-0.5
  +
|—
  +
|≥1
  +
|≥17
  +
|15-16
  +
|—
  +
|≤14
 
|-
  
|-
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|[[Candida tropicalis]]
−
| ≥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.
  
  +
|0.12
  +
|≤0.12
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|0.25-0.5
  +
|—
  +
|≥1
  +
|≥17
  +
|15-16
  +
|—
  +
|≤14
  +
|-
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|[[Cryptococcus neoformans]]
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|0.25
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| colspan="8" rowspan="6" |
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|-
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|[[Cryptococcus gattii]]
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|0.5
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|-
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|[[Aspergillus flavus]]
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|2
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|-
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|[[Aspergillus fumigatus]]
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|1
  +
|-
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|[[Aspergillus niger]]
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|2
  +
|-
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|[[Aspergillus terreus]]
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|2
 
|}
  
|}
   
−
=== Safety ===
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==Dosing==
  +
−
* Elevated levels predict neurotoxicity, but ''not'' hepatotoxicity
  
  +
*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
  +
  +
{| class="wikitable"
  +
!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
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**[[Adverse drug reaction::Floaters]] (photopsia) that usually improves with time (30%)
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**[[Adverse drug reaction::Visual hallucinations]] (5%)
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**[[Adverse drug reaction::Colour vision loss]], [[Adverse drug reaction::blurred vision]], [[Adverse drug reaction::photophobia]]
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*Dermatologic
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**Rashes, usually mild
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**[[Stevens-Johnson syndrome]] and [[toxic epidermal necrolysis]] (rare)
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**[[Adverse drug reaction::Photosensitivity]]
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*[[Adverse drug reaction::Hepatotoxicity]][[CiteRef::mihăilă2015vo]]
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**Risk factors include higher trough (though can occur at any level), other hepatotoxic medications (and specifically [[tigecycline]] and [[TMP-SMX]]), and septic shock<ref>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 Multicenter Retrospective Study. ''International Journal of Antimicrobial Agents'', 2022, Page 106692. doi: https://doi.org/10.1016/j.ijantimicag.2022.106692</ref>
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**In critically ill patients, mostly occurs within 7 days of starting
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**Primarily cholestasis, but can be hepatocellular damage or mixed
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**Resolves with discontinuation, but can take 1 to 3 months
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**See also [https://www.ncbi.nlm.nih.gov/books/NBK547891/ LiverTox]
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*[[Adverse drug reaction::QTc prolongation]]
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*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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  +
{| class="wikitable"
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!Drug
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!Recommendation
  +
|-
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! colspan="2" |Decreases voriconazole levels
  +
|-
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|[[carbamazepine]]
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|contraindicated
  +
|-
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|long-acting [[Barbiturate|barbiturates]]
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|contraindicated
  +
|-
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|[[rifampin]]
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|contraindicated
  +
|-
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! colspan="2" |Levels increased by voriconazole
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|-
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|[[astemizole]]
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|contraindicated
  +
|-
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|[[cisapride]]
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|contraindicated
  +
|-
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|[[cyclosporine]]
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|reduce cyclosporine dosage 50% and monitor levels
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|-
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|ergot alkaloids
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|contraindicated
  +
|-
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|[[omeprazole]]
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|reduce omeprazole by 50%
  +
|-
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|[[quinidine]]
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|contraindicated
  +
|-
  +
|[[sirolimus]]
  +
|contraindicated
  +
|-
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|[[tacrolimus]]
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|reduce tacrolimus levels to 33% and monitor levels
  +
|-
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|[[terfenadine]]
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|contraindicated
  +
|-
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|[[warfarin]]
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|monitor INR
  +
|-
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! colspan="2" |Decreases voriconazole levels, and levels increased by voriconazole
  +
|-
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|[[rifabutin]]
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|contraindicated
  +
|-
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|[[phenytoin]]
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|double voriconazole, and monitor phenytoin levels
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|-
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! colspan="2" |Levels likely increased by voriconazole
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|-
  +
|sulfonylureas
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| rowspan="5" |monitor for side effects of drug and consider decreasing dosage
  +
|-
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|statins
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|-
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|vinca alkaloids
  +
|-
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|calcium channel blockers
  +
|-
  +
|benzodiazepines
  +
|}
   
  +
==Further Reading==
−
== Adverse Drug Reactions ==
  
−
* Visual
  
−
** [[Adverse drug reaction::Floaters]] etc that may improve with time
  
−
** [[Adverse drug reaction::Visual hallucinations]]
  
−
** [[Adverse drug reaction::Colour vision loss]]
  
−
* [[Adverse drug reaction::Photosensitivity]]
  
−
* [[Adverse drug reaction::Hepatotoxicity]]
  
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* [[Adverse drug reaction::QTc prolongation]]
  
   
  +
*Voriconazole Dose Modification Guideline to Optimize Therapeutic Levels in Patients With Hematologic Malignancies. ''Open Forum Infect Dis''. 2015;2(S1):810. doi: [https://doi.org/10.1093/ofid/ofv133.527 10.1093/ofid/ofv133.527]
−
== Further Reading ==
  
−
* Voriconazole Dose Modification Guideline to Optimize Therapeutic Levels in Patients With Hematologic Malignancies. ''Open Forum Infect Dis''. 2015;2(S1):810. doi: [https://doi.org/10.1093/ofid/ofv133.527 10.1093/ofid/ofv133.527]
  
   
−
[[Category:Antifungals]]
 +
[[Category:Triazoles]]

Latest revision as of 10:07, 13 November 2022

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 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

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
  1. ↑ 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 Multicenter Retrospective Study. International Journal of Antimicrobial Agents, 2022, Page 106692. doi: https://doi.org/10.1016/j.ijantimicag.2022.106692

References

  1. ^  Romeo-Gabriel Mihăilă. Voriconazole and the liver. World Journal of Hepatology. 2015;7(13):1828. doi:10.4254/wjh.v7.i14.1828.

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