In this section
Fever and suspected or confirmed neutropenia
Prophylaxis regimens based on risk groups
Dose adjustment based on TDM
Timing and duration of prophylaxis
Important drug interactions
Children with cancer are at varying risk of invasive fungal infection (IFI). Factors that influence this risk include type of cancer, chemotherapy protocol, depth and duration of neutropaenia, steroid exposure and previous history of IFI. Antifungal prophylaxis has been shown to reduce the
risk of developing an IFI and can be broadly divided into mould-active (ie against Aspergillus spp.) and non-mould active (ie against Candida spp.) prophylaxis.
Primary antifungal prophylaxis is recommended when the underlying incidence of IFI exceeds 10%. When implementing prophylaxis regimens, consideration must also be given to institutional epidemiology and relevant adjustments made.
1: Stratification of risk of IFI in children with cancer/Haematopoietic Stem Cell Transplant (HSCT)
Relapsed acute leukaemia
High risk/very high risk ALL (intensive treatment phases)
Allogeneic HSCT with acute Grade II-IV GvHD
Allogeneic HSCT chronic extensive GvHD
Severe aplastic anaemia
Allogeneic HSCT (pre-engraftment phase)
Non-relapse ALL (excluding very-high risk ALL in induction phase)
Lymphoma (excluding autologous HSCT)
Solid tumours (excluding autologous HSCT)
Paediatric solid tumours
If a child has a suspected IFI (i.e. prolonged or recurrent fever), evaluation and empiric treatment should follow the
Fever and suspected or confirmed neutropenia recommendations.
Recommended prophylaxis regimens according to patient population
Note: Refer to Table 3 for dose and monitoring recommendations.
3: Antifungal prophylaxis dose, therapeutic drug monitoring (TDM) targets, important food-drug interactions and monitoring recommendations
Administer with or without food
Monitor for rash (rare) and hepatotoxicity (rare)
Monitor for QT prolongation if other risk factors or pro-arrhythmic drugs
≥13 years: 200 mg oral TDS
7-12 years: 200 mg oral TDS
≥13 years: 300 mg oral daily
Trough level >0.7 µg/mL
Take trough level 5-7 days after starting drug or changing dose
Administer with food.
(absorption ↑with high fat meal)
Safety and efficacy in children below the age of 13 years has not been well established.
Monitor for rash (rare), hepatotoxicity (rare), neurotoxicity and GI upset.
2 years to
<12 years or 12-14 years and weighing <50 kg: 9 mg/kg (max 350 mg) oral BD
≥15 years or aged 12-14 years and weighing ≥50 kg: 200 mg oral BD
2 years to
<12 years or 12-14 years and weighing <50 kg: 8 mg/kg (day 1, 9 mg/kg) IV BD
≥15 years or aged 12-14 years and weighing ≥50 kg: 4 mg/kg (day 1, 6 mg/kg) IV BD
Trough level 1-2 µg/mL**
Take trough level 2-5 days after starting drug or changing dose
Dose should not be altered if level is 4-6 mg/L and clinical signs of toxicity are not present
Oral: administer 1 h before or after food (absorption ↓ with high fat meals)
Council on avoidance sun exposure. Reports of skin cancer with prolonged (>1yr) use.
Caution in renal impairment as solubilizer may accumulate. Significance is not known, consult pharmacy.
Monitor for rash, hepatotoxicity, neurotoxicity and visual disturbances (NB. a trough level >5-6 is associated with an increased probability of neurological and ocular toxicity). Visual disturbances are dose related, self-limiting and rarely require cessation of treatment.
(Sporonox®): 2.5 mg/kg oral BD (max 200 mg daily)
and capsules are not interchangeable. The oral solution is preferred due to improved bioavailability and as there is limited experience with capsules in children. If conversion is required, consult pharmacy.
Trough level >0.5 µg/mL
Take trough level 10-15 days after starting drug or changing dose
Liquid (Sporanox®): administer on an empty stomach at least 1h before food. Absorption not affected by H2-anagonists
Capsules (Sporanox®): administer with or after food. For children on gastric acid suppressant medications, separate administration by at least 2 hours and administer with an acidic beverage (e.g. cola).
Monitor for rash, hepatotoxicity, neurotoxicity and GI upset.
Monitor for renal toxicity, electrolyte disturbances (esp. hypokalaemia and hypomagnesaemia) and hepatotoxicity.
Consider pre/concurrent hydration with 10 mL/kg normal saline.
Consider premedication if infusion related adverse effects (inc. fever, chills, rigors)
1 to 3 months: 25 mg/m2 (max 50mg) IV daily
≥3 months: 50 mg/m2 (max 50mg) IV daily
*Trough levels for voriconazole, itraconazole and posaconazole are sent to the Alfred hospital and run on a Monday, Tuesday and Thursday (must arrive at The Alfred by 11am). Samples require minimum 1 mL in an EDTA tube.
**A voriconazole trough level >5–6 mg/L is associated with an increased probability of neurological toxicity, including visual disturbances, hallucinations and encephalopathy
Itraconazole, voriconazole and posaconazole require TDM.
Dose adjustments should be discussed with oncology pharmacy and/or local infectious diseases unit.
Prior to any dose adjustment, repeat drug level and ensure the following:
In children with a documented history of proven or probable IFI, secondary prophylaxis is required for further cycles of chemotherapy.
The azole class of antifungal agents are metabolised by the cytochrome P450 (CYP450) system. The potential for drug-drug interactions is higher for itraconazole and voriconazole than posaconazole and, in particular, fluconazole.
IV: Important drug interactions for azole antifungal agents and management recommendations.
(vincristine and vinblastine)
Vinca alkaloid metabolism reduced leading to excess vinca alkaloid exposure.
Cases of neurotoxicity (peripheral neuropathy, autonomic neuropathy and seizures) have been reported with vincristine and vinblastine and itraconazole, voriconazole and posaconazole. Concurrent use with itraconazole leads to earlier and more severe toxicity.
Electrolyte abnormalities, hyponatraemia associated with SIADH and GI upset have also been reported.
Fluconazole is a weaker CYP3A4 inhibitor so toxicity is rare.
Concurrent use of itraconazole is strictly contraindicated.
For weekly IV vinca alkaloid: non-azole agent is preferred
For monthly IV vinca alkaloid: consider withholding voriconazole or posaconazole the day before, the day of and the day after vinca alkaloid dose. Monitor for toxicity.
TKI metabolism reduced, increasing risk of toxicity including QT prolongation and cardiac arrhythmias.
Refer to chemotherapy protocols for detailed management.
Concurrent use of itraconazole, voriconazole and posaconazole is not recommended in most protocols.
Fluconazole can be used in most instances except in combination with sorafenib. A non-azole agent is mandated for all children receiving sorafenib.
Bortezomib metabolism reduced.
Cases of new or worsening peripheral neurotoxicity have been reported with itraconazole and voriconazole.
All azoles should be stopped 72 hours prior to bortezomib dosing and recommenced 72 hours (24 hours for fluconazole) after final dose in course. A non-azole agent should be substituted during this period.
For example, in children with AML receiving bortezomib on D1 and D8 in a 28-day curse, substitute fluconazole for an echinocandin on D(-3) to D(+12)
Metabolism reduced, leading to significant increases in levels of these drugs.
Reports of significantly increased trough concentrations despite dose reduction, due to combination of itraconazole and sirolimus.
Monitor sirolimus, tacrolimus or cyclosporine levels. Dose reduction usually required.
Itraconazole should be used with extreme caution in children on sirolimus.
Use combination in caution. Obtain an ECG prior to starting treatment and weekly thereafter.
Azoles should not be used in children with additional cardiac risk factors including reduced left ventricular fraction and electrolyte disturbances.
All decisions to start and stop antifungal prophylaxis as well as issues with tolerability or side effects should be discussed with the child’s primary treating team.
All suspected or confirmed fungal infections should be discussed with the child’s primary treating team and consideration given to transfer to a tertiary paediatric cancer centre for investigation and management.
For emergency advice and paediatric or neonatal ICU transfers, call the Paediatric Infant Perinatal Emergency Retrieval (PIPER) Service: 1300 137 650.