Antifungal prophylaxis for children with cancer or undergoing haematopoietic stem cell transplant


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    This guideline has been adapted for statewide use with the support of the Victorian Paediatric Clinical Network

  • See also

    Fever and suspected or confirmed neutropenia

    In this guideline

    Background
    Prophylaxis regimens based on risk groups
    Drug information
    Dose adjustment based on TDM
    Timing and duration of prophylaxis
    Secondary prophylaxis
    Important drug interactions

    Key points

    1. Appropriate antifungal prophylaxis is an important component of cancer care
    2. Antifungal prophylaxis has been shown to reduce the risk of invasive fungal infection (IFI) in selected high-risk children.
    3. Where possible, an azole agent is preferred and therapeutic drug monitoring should be done for posaconazole, voriconazole and itraconazole.

    Background

    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 neutropenia, 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 (i.e. against Aspergillus spp.) and non-mould active (i.e. 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. 

    Assessment

    • Prophylaxis recommendations are based on underlying risk of IFI.
    • The type of prophylaxis (mould versus non-mould active) varies according to cancer diagnosis associated complications and/or treatment phases.
    • Children at high and intermediate risk for IFI should receive appropriate prophylaxis.  

    Table 1: Stratification of risk of IFI in children with cancer/Haematopoietic Stem Cell Transplant (HSCT)

    Risk Stratum Risk of IFI with Patient Population
    High Risk (≥10%)   Mould > Yeast  

    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

    Yeast > Mould  

    Non-relapse AML

    Allogeneic HSCT (pre-engraftment 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

    Management

    Investigations

    Nil

    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.   

    Primary prophylaxis

    Note: Refer to Table 3 for dose and monitoring recommendations.

    Drug information 

    Table 3: Antifungal prophylaxis dose, therapeutic drug monitoring (TDM) targets, important food-drug interactions and monitoring recommendations

    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

     
    Posaconazole    

    Oral suspension:

    ≥13 years: 200 mg oral TDS

     

    Oral tablets:

    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.

     

    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

       

    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.

     

    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 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 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 pre/concurrent hydration with 10ml/kg normal saline.

     

    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)  

    *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 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

    Therapeutic drug monitoring (TDM)

    Itraconazole, voriconazole and posaconazole require TDM.

    • All children 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 

    Dose adjustments should be discussed with oncology pharmacy and/or local infectious diseases unit.

    • 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

    Prior to any dose adjustment, repeat drug level and ensure the following:

    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.
     

       

    Secondary prophylaxis

    In children with a documented history of proven or probableIFI, 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.

    Important drug interactions for azole antifungal agents

    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. 

    Table IV: Important drug interactions for azole antifungal agents and management recommendations.

    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 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.

    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 children 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 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)

    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 children 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 children with additional cardiac risk factors including reduced left ventricular fraction and electrolyte disturbances.

    Consider consultation with local paediatric team when:

    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. 

    Consider transfer when:

    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.

    Last Updated January 2019