Risk Stratum

Risk of IFI with

Patient Population

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

Intermediate Risk

Yeast > Mould

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)

Sporadic occurrence

Paediatric solid tumours
Brain tumours
Hodgkin’s lymphoma

Antifungal

Dose

Target trough* for prophylaxis

Notes

Fluconazole

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

Itraconazole

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

Voriconazole

Oral tablets/suspension:
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

Intravenous solution:
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.

Monitor for QT prolongation if other risk factors or pro-arrhythmic drugs

Posaconazole

Oral suspension:
≥13 years: 200 mg oral TDS

Oral tablets:
≥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.

Monitor for QT prolongation if other risk factors or pro-arrhythmic drugs

Liposomal amphotericin (Ambisome®)

3mg/kg IV three times per week

Not required

Monitor for renal toxicity, electrolyte disturbances (esp hypokalaemia and hypomagnesaemia) and hepatotoxicity.

Consider premedication if infusion related adverse effects (inc. fever, chills, rigors)

Caspofungin

1 to 3 months: 25mg/m2 (max 50mg) IV daily

≥3 months: 50mg/m2 (max 50mg) IV daily

Not required

May cause histamine induced reaction (rash, facial swelling, pruritus and/or bronchospasm)

Micafungin

1mg/kg (max 50mg) IV daily

Not required

May cause histamine induced reaction (rash, facial swelling, pruritus and/or bronchospasm)

Low azole levels

High azole levels

• Confirm true trough sample was taken
• Confirm adherence
• Exclude poor absorption (absorption reduced with severe mucositis and diarrhoea). Depending on agent, diet may also affect absorption (see Table III)
• Investigate potential drug-drug interactions (see below and discuss with pharmacy)
  

• Confirm a true trough sample was taken
• Investigate potential drug-drug interactions (see below and discuss with pharmacy)
• If clinical signs of toxicity are not present, consider leaving dose regimen unchanged and monitor potential toxicity carefully.

Medication

Interaction

Management

Decreased plasma concentration of azoles

Rifampicin, rifabutin

Induces azole metabolism.

Avoid combination where possible. An increase in azole dose may be required

Carbamazepine

Induces azole metabolism (fluconazole, itraconazole, voriconazole)

Phenobarbitone

Phenytoin

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

Vinca alkaloids
(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

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.

Diazepam, midazolam

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.