Voriconazole

CLASS OF DRUG

  • Triazole 
  • Anti-fungal agent

PHARMACEUTICS

  • 50mg or 200mg film-coated tablets
  • 40 mg/mL suspension
  • Dilute to concentration of 0.5 – 5 mg/mL in 0.9% NaCl or 5% glucoseand infuse over 1 – 2 hours at no more than 3 mg/kg/h

DOSING

IV:

  • Loading dose: 6 mg/kg IV every 12 h for 2 doses
  • Maintenance: 3 – 4 mg/kg IV every 12 h

Oral (given 1h before or 1h after meals)

  • If >40kg: 400 mg every 12 h for 2 doses.
  • If <40kg: 200 mg every 12 h for 2 doses

Duration depends on severity and clinical course, and is typically at least 7-14 days

MECHANISM OF ACTION

  • Azoles are fungistatic agents that impair the synthesis of ergosterol in fungal cell membranes leading to their disruption. Cell lysis and death results from the action of the host lytic system.
  • Posaconazole has broad-spectrum potency, including against species resistant to fluconazole (see indications)

INDICATIONS

  • Invasive aspergillosis
  • Serious Candida infections (Iincluding fluconazole resistant C. krusei and resistant strains of C. glabrata and C. albicans)
  • Other serious fungal infections such as Scedosporium (S. prolificans is less susceptible)  and Fusarium spp.
  • Prevention of invasive fungal infections in people at risk, e.g. haemopoietic stem cell recipients 

CONTRA-INDICATIONS / PRECAUTIONS

  • Known hypersensitivity
  • Acute porphyrias
  • QT prolongation

Caution

  • Risk factors for QT prolongation
  • Risk factors for skin cancer (e.g. immunosuppression)
  • Liver disease: Halve the maintenance dose in mild-to-moderate cirrhosis.
  • Oral preparation preferred in renal impairment, as the IV formulation contains SBECD which may accumulate and contribute to nephrotoxicity

PHARMACOKINETICS

  • A: rapid oral absorption with 96% bioavailability (less in children); peak plasma level at 1-2h. High fat meals reduce bioavailability.
  • D: widely distributed with VD 4.6 L/kg, moderate protein binding (58%)
  • M: extensive hepatic metabolism by cytochrome P450 isoenzymes CYP2C19, CYP2C9 and CYP3A4; major N-oxide metabolite (70%) is inactive; CYP2C19 genetic polymorphism results in fast and slow metabolisers (4-fold differences)
  • E: metabolites excreted by kidneys (<2% unchanged in urine); t1/2 = 6h

DRUG-DRUG INTERACTIONS (DDIs)

Numerous potential drug interactions related to:

  • CYP450 enzyme induction
  • QT prolongation (e.g. ciprofloxacin, erythromycin, metoclopramide, ondansetron, amiodarone)

PREGNANCY/ LACTATION

  • category B3 drug (avoid use in pregnancy if possible)
  • Likely enters breast milk (avoid if possible)

ADVERSE EFFECTS

  • Hypersensitivity
  • Anaphylactoid reactions (e.g. at the start of an infusion – slow or stop the infusion if severe)
  • Local injection site reactions
  • GI symptoms: Nausea, vomiting, abdominal pain, diarrhoea, pancreatitis
  • Visual disturbances
    • Affects 30% of people
    • blurred vision, colour changes, photophobia, hallucinations
    • Typically occurs within 30 minutes of dosing.
    • Reactions are dose-related and reversible (resolve within 1h usually)
    • Optic neuritis also reported
  • Skin: urticaria, Stevens-Johnson syndrome / toxic epidermal necrolysis, Photosensitivity reactions (more common in children)
  • Skin cancers (risk from sunlight exposure during longterm treatment, especially in the immunosuppressed): melanoma, squamous cell carcinoma) and accelerated photoageing (e.g. lentigines, actinic keratoses). 
  • QT interval prolongation (risk of Torsades de pointes)
  • Hepatoxicity: dose-related liver function tests abnormalities; rarely hepatic failure
  • Blood dyscrasias: Anaemia, Thrombocytopenia
  • Alopecia (with  prolonged courses)
  • Antimicrobial resistance:  voriconazole-resistant moulds or yeasts may develop

MONITORING

Therapeutic drug monitoring is recommend due to CYP2C19 polymorphisms (fast and slow metabolisers) and risk of drug interactions. Plasma concentrations outside of the therapeutic range are also more common in children, underweight or obese patients, and with hepatic impairment

  • trough concentration between 1 mg/L – 5 mg/L is commonly used therapeutic range
  • ECG monitoring for QT prolongation
  • Baseline and periodic liver function test
  • Monitor visual function if treating for > 28 days
  • Monitor for skin damage and skin cancers during long term treatment 

EVIDENCE

Compared with C-AMB:

  • Superior for invasive aspergillosis (rate of response and survival)
  • Less breakthrough infections than L-AMB in neutropenic fever patients
  • Comparable efficacy and less toxic for esophageal candidiasis

OTHER

Compared with fluconazole, voriconazole has:

  • Increased in vitro activity
  • Extended spectrum of action
  • Poorer aqueous solubility
  • variable metabolism – 20% of Asians are homozygous poor metabolizers of voriconazole, compared with 2% of whites and African Americans.

Posaconazole has similar uses to voriconazole. It lacks voriconazole’s visual side-effects, also has metabolism that is subject to CYP450 polymorphisms, and has much higher volume of distribution and elimination half-life.

REFERENCES

FOAM and web resources

Journal articles and textbooks

  • Brunton, L., Hilal-Dandan, R., Knollman, B. (2017). Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Edition. United States: McGraw-Hill Education. Ch 61.
  • Dockrell, H., Goering, R., Chiodini, P. L., Zuckerman, M. (2018). Mims’ Medical Microbiology and Immunology. United Kingdom: Elsevier. Ch 34.

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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