Posaconazole
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Candida, Aspergillus sp.
some Zygomycete sp and some of the rarer moulds
Dimorphic fungi and C.neoformans
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Oral
Noxafil® modified-release tablets 300 mg twice a day on day 1 (loading dose) followed by 300 mg once daily from day 2. Swallowed whole, with or without food.
Noxafil® oral liquid: 200 mg orally, 8-hourly. Taken with or immediately after food (full meal or nutritional supplement or an acidic beverage) - avoid PPI or H2 antagonists.
Intravenous (IV) infusion
Noxafil® 300 mg IV twice a day (loading dose) on day 1 followed by 300 mg once daily from day 2.
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TDM recommended.
Timing of first sample 5-7 days.
Aim for a target trough level > 0.7 mg/L for prophylaxis (C).
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If possible avoid IV formulation if CrCl < 50 ml/min as the injection solvent (a cyclodextrin) accumulates.
Hepatic impairment may increase half-life, consider dose adjustment. Monitor liver function; manufacturer advises caution.
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Oral administration is first line.
Oral preparations are not bioequivalent; appropriate dosing and administration depends on the preparation.
Where possible, posaconazole tablets should be used in preference to the suspension because the tablets have a higher bioavailability. Only consider intravenous administration if oral route is unavailable or absorption may be impaired and benefits outweigh risks.
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Voriconazole |
Candida, Aspergillus species and some of the rarer moulds
Dimorphic fungi and C. neoformans
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Oral
400 mg orally, 12-hourly for 2 doses then 200 mg orally, 12- hourly
Oral: take at least one hour before, or one hour after a meal
Intravenous (IV) infusion
6mg/kg IV 12-hourly for 2 doses then 4 mg/kg IV 12-hourlyr
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TDM recommended in patients with leukaemia and BMT recipients (B).
Consider monitoring, in other patients with haematological malignancy who require prophylaxis (D), particularly if poor absorption is likely (e.g. in patients with severe mucositis or diarrhoea).
First sample 2-5 days and repeat sample should be collected to ensure stability.
Aim for a target trough level between 1 and 5 mg/L – commonly recommended for clinical efficacy (C).
Trough levels > 5-6 mg/L associated with increased toxicity i.e. ocular toxicity and encephalopathy (C).
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If possible avoid IV formulation if CrCl < 50 ml/min as the injection solvent (a cyclodextrin) accumulates.
For mild to moderate hepatic impairment: follow standard loading dose, but reduce maintenance dose by 50%. No data for sever hepatic impairment – monitor for toxicity.
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Oral formulation has a bioavailability of > 90%, which is reduced by ~ 30% when taken with a high fat meal.
Long term complications resulting from metabolic irregularities may include increased risk of squamous cell carcinoma and hyperphosphataemia.r
With prolonged use, fluoride in drug can cause a painful periostitis. Correlates with elevated serum fluoride levels. Resolves with discontinuation of drug.r
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Fluconazole |
Candida
Cryptococcus.neoformans
Coccidioidomycosis
Inactive against moulds |
200 mg – 400 mg orally or IV, daily
Tablets: taken with or without food |
TDM not recommended.
Routine monitoring is not indicated in most patients. Consider in those that have severely compromised renal function, for those who are undergoing dialysis, or for those where absorption may be impacted. |
Predominantly renally cleared. For CrCl less than 50 mL/min increase dosage interval or reduce doser (seek expert advice and/or consider TDM). |
Oral bioavailability is reported to be over 90%.r |
Itraconazole |
Candida, Aspergillus species and some of the rarer moulds
Dimorphic fungi and C.neoformans
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Conventional itraconazole capsules 200 mg orally, 12-hourly. To be taken with food (but not a rice meal) and acidic beverage for best absorption. Avoid PPI or H2 antagonists within 2 hours of conventional itraconazole capsules as they will interfere with its absorption.
Itraconazole liquid 200 mg orally, 12-hourly. To be taken on an empty stomach, at least 1 hour before food.
SUBA-itraconazole capsules (Lozanoc®) 200 mg orally, 12-hourly. Can be taken with or without foodr
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TDM recommended to ensure adequate absorption, as absorption is unpredictable. Timing of first sample 7-15 days. Aim for target trough level > 0.5 - 1.0 mg/L.
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No dose adjustment required for renal impairment with oral formulation.
Predominately hepatically cleared. May require dose adjustment, limited data.
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Brands and formulations of oral itraconazole are NOT interchangeable.r
Bioavailability of Sporanox® oral liquid taken in the fasting state is ~ 60% higher than from a conventional itraconazole capsule taken with a meal,r i.e. conventional 100 mg capsule is roughly equivalent to 50 mg Sporanox® oral liquid.
One 50 mg Lozanoc® capsule (SUBA-itraconazole) is therapeutically equivalent to one 100 mg conventional itraconazole capsule,r with less inter-patient variability, however starting dose should remain the same for rapid attainment of therapeutic levels.r
Itraconazole IV is not marketed in Australia but may be available via Special Access Scheme.
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Isavuconazole (Isavuconazonium sulfate) |
Invasive Aspergillosis sp.
Mucormycosis
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Oral
Initial: 372 mg (isavuconazole 200 mg) 8-hourly for 6 doses;
Maintenance: 372 mg (isavuconazole 200 mg) once daily. Start maintenance dose 12 to 24 hours after the last loading dose. Given with or without food.
Intravenous (IV) infusion
Initial: 372 mg (isavuconazole 200 mg) 8-hourly for 6 doses;
Maintenance: 372 mg (isavuconazole 200 mg) once daily. Start maintenance dose 12 to 24 hours after the last loading dose.
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TDM may not be accessible in Australia
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No dose adjustment required for renal impairment with oral formulation.
Predominately hepatically cleared. May require dose adjustment, limited data.
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Can be considered in patients intolerant or refractory to first-line anti-mould therapy.
May shorten QTc.
Duration of therapy: 6 to 12 weeks (minimum), although duration is highly dependent on degree/duration of immunosuppression, disease site, and evidence of disease improvement.r
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Amphotericin B |
Candida Aspergillus sp. (excluding Aspergillus terreus)
Zygomycetes
Dimorphic fungi and C.neoformans
Rarer moulds
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Various dosing schedules have been used:
- 100 mg IV three times a weekr
- 50 mg IV on alternate daysr
- 3 mg/kg IV three times a weekr
- 5 mg/kg IV twice a weekr
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TDM not recommended |
Manufacturer recommends close monitoring of patients with renal or hepatic dysfunction. |
Although the level of evidence for liposomal amphotericin B prophylaxis is weak and an azole should be used if possible in high risk patients, it is often used for prophylaxis in settings where an azole cannot be used due to drug interactions.
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Echinocandins |
Primary therapy for candidemia and invasive candidiasis
C. auris may be resistant to echinocandins
May be used as part of second-line or subsequent regimen for invasive aspergillosis
Not reliable or effective against other fungal pathogens
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- Caspofungin 50 mg IV daily
- Micafungin 50 mg IV daily
- Anidulafungin 100 mg IV dailyr
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TDM not recommended |
Caspofungin:
For moderate hepatic impairment: reduce dose to 35mg IV dailyr
Micafungin and anidulafungin:
No dose adjustment is required for renal or hepatic impairment
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Good safety profile.
Echinocandins have poor CNS penetration.
Lack broad spectrum anti-mould activity.r
Only available as IV.
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Read more about the National Health and Medical Research Council (NHMRC) evidence hierarchy and grades of recommendations.
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