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 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.
Table 1: Stratification of risk of IFI in paediatric cancer/HSCT patients
Risk of IFI with
High Risk (≥10%)
Mould > Yeast
Relapsed acute leukaemia
Allogeneic HSCT with acute Grade II-IV GvHD
Allogeneic HSCT chronic extensive GvHD
Severe aplastic anaemia
Yeast > Mould
Non-relapse Acute Myeloid Leukaemia (AML)
Allogeneic HSCT (pre-engraftment phase)
Very high-risk Acute Lymphoblastic Leukaemia (ALL) induction phase
Autologous HSCT (neutropenic phase)
Low Risk (≤5%)
Non-relapse ALL (excluding very-high risk ALL in induction phase)
Lymphoma (excluding autologous HSCT)
Solid tumours (excluding autologous HSCT)
Paediatric solid tumours
*Very high-risk ALL includes T-cell, age >13y and high MRD, Philadelphia positive
Recommended prophylaxis regimens according to patient population.
See Table 3 for dose and monitoring recommendations.
Table 3: Antifungal prophylaxis dose, therapeutic drug monitoring (TDM) targets, important food-drug interactions and monitoring recommendations
Target trough* for prophylaxis
6-12 mg/kg (max 400 mg) oral/IV daily
Not routinely required
Administer with or without food
Monitor for rash (rare) and hepatotoxicity (rare)
Monitor for QT prolongation if other risk factors or pro-arrhythmic drugs
Oral solution (Sporonox®): 2.5 mg/kg oral BD (max 200 mg daily)
Oral solution 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 7-15 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 patients 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 QT prolongation if other risk factors or pro-arrhythmic drugs
2 years to
<12 years or 12-14 years and weighing <50kg: 9mg/kg (max 350mg) oral BD
≥15 years or aged 12-14 years and weighing ≥ 50kg: 200mg oral BD
2 years to
<12 years or 12-14 years and weighing <50kg: 8mg/kg (day 1, 9mg/kg) IV BD
≥15 years or aged 12-14 years and weighing ≥ 50kg: 4mg/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
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 therapy.
≥13 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 paediatric patients below the age of 13 years has not been well established.
Monitor for rash (rare), hepatotoxicity (rare), neurotoxicity and GI upset.
Liposomal amphotericin (Ambisome®)
3mg/kg IV three times per week
Monitor for renal toxicity, electrolyte disturbances (esp hypokalaemia and hypomagnesaemia) and hepatotoxicity.
Consider premedication if infusion related adverse effects (inc. fever, chills, rigors)
1 to 3 months: 25mg/m2 (max 50mg) IV daily
≥3 months: 50mg/m2 (max 50mg) IV daily
May cause histamine induced reaction (rash, facial swelling, pruritus and/or bronchospasm)
1mg/kg (max 50mg) IV daily
*Trough levels for voriconazole, itraconazole and posaconazole are sent to the Alfred hospital and run on a Tuesday and Thursday (must arrive at The Alfred by 11am). Samples require minimum 1ml 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. All patients should have one repeat TDM to confirm stability. Once target trough levels are confirmed, repeat TDM is not routinely required. Indications for repeat TDM include (i) dose adjustment or iv/oral switch; (ii) introduction of new drug with potential interactions (iii) suspected toxicity (always do level before withholding or adjusting dose); or (iv) diagnosis of a proven, probable or possible IFI.
Depending on the age of the child, azoles may exhibit nonlinear or linear pharmacokinetics. There is also significant INTER- and INTRA- patient variability with these agents. 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:
Low azole levels
High azole levels
In patients with a documented history of proven or probable IFI, secondary prophylaxis is required for further cycles of chemotherapy. The agent that was used to treat the initial infection may be used for prophylaxis, provided it was well tolerated and effective. Discuss with local infectious diseases unit.
Table 4: Important drug interactions for azole antifungal agents and management recommendations.
Decreased plasma concentration of azoles
Induces azole metabolism.
Avoid combination where possible. An increase in azole dose may be required
Induces azole metabolism (fluconazole, itraconazole, voriconazole)
Induces azole metabolism (itraconazole, voriconazole and posaconazole). Phenytoin metabolism reduced.
Avoid combination where possible. Monitoring of phenytoin and azole levels recommended. An increase in azole dose may be required
Increased plasma concentration of co-administered drug
(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 monthlyIV vinca alkaloid: consider withholding voriconazole or posaconazole the day before, the day of and the day after vinca alkaloid dose. Monitor for toxicity.
Tyrosine kinase inhibitors (TKI): (sorafenib, imatinib, dasatinib, nioltinib, ceritinib, carfizomib)
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 patients 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 patients with AML receiving bortezomib on D1 and D8 in a 28-day curse, substitute fluconazole for an echinocandin on D(-3) to D(+12)
Sirolimus, Tacrolimus Cyclosporin
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 patients on sirolimus.
Metabolism reduced, increasing risk of toxicity including respiratory depression
Monitor for signs of toxicity
Prolonged QT interval
Macrolide & quinolone antibiotics, conventional antipsychotics
Additive risk of QT prolongation in setting of azole prophylaxis
Use combination in caution. Obtain an ECG prior to starting treatment and weekly thereafter.
Azoles should not be used in patients with additional cardiac risk factors including reduced left ventricular fraction and electrolyte disturbances.
Chau MM et al. Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy, 2014. Intern Med J. 2014; v44
Fleming S. et al. Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation, 2014. Intern Med J. 2014; v44