Is itraconazole (antifungal medication) safe to use in a 1-year-old child?

Itraconazole Use in 1-Year-Old Children

Itraconazole is not approved for use in children under 18 years in the EU, though it can be used off-label with caution for serious fungal infections when benefits outweigh risks, requiring therapeutic drug monitoring (TDM) and careful dose adjustment. 1

Regulatory Status and Approval

• Itraconazole is not approved by the European Medicines Agency (EMA) for patients under 18 years of age 1
• The FDA labeling states that efficacy and safety have not been established in pediatric patients 2
• Despite lack of formal approval, itraconazole has been used off-label in children for both superficial and invasive fungal infections 3, 4

Clinical Evidence for Use in Young Children

Invasive Aspergillosis Treatment

• For treatment of invasive aspergillosis in children, itraconazole receives a Grade C recommendation with Level III evidence (weakest recommendation among available antifungals) 1
• The guideline specifically notes sparse pediatric pharmacokinetic and safety data concerning intravenous itraconazole 1
• TDM is strongly recommended with target trough concentration ≥0.5 mg/L 1

Prophylaxis in High-Risk Patients

• For antifungal prophylaxis in high-risk pediatric patients (HSCT, leukemia), itraconazole receives a Grade A recommendation with Level II evidence 1
• However, this comes with the caveat of not being approved in the EU for children under 18 years 1

Dosing Considerations for 1-Year-Olds

Age-Related Pharmacokinetic Challenges

• Children aged 6 months to 2 years have significantly lower drug exposure compared to older children, with lower peak concentrations and areas under the curve after the first dose 5
• Children ≤12 years require substantially higher weight-based doses (median 6.2 mg/kg/day) compared to those >12 years (median 3.9 mg/kg/day) to achieve therapeutic levels 6
• 71.4% of children ≤12 years required doses above the recommended 5 mg/kg/day to achieve therapeutic trough levels 6

Recommended Dosing Regimens

• For superficial fungal infections: 5 mg/kg/day has been used safely 3, 4, 7
• For systemic fungal infections: 10 mg/kg/day has been used in infants 4
• Accumulation occurs over 14 days, with accumulation factors ranging from 3.3 to 8.6 for itraconazole 5

Safety Concerns Specific to Young Children

Bone Growth Effects

• Critical concern: Itraconazole induced bone defects in rat studies at doses as low as 20 mg/kg/day (0.5 times the maximum recommended human dose based on body surface area) 2
• Effects included reduced bone plate activity, thinning of bone, and increased bone fragility 2
• The long-term effects on bone growth in children are unknown 2

Dental Development

• At higher doses, itraconazole induced small tooth pulp with hypocellular appearance in rat studies 2

Hepatotoxicity

• Hepatotoxicity occurred in 6.5% of pediatric courses, though not associated with elevated trough levels 6
• Mild, transient, asymptomatic elevation of liver function tests occurred in 3.4% of children (less than twice upper limit of normal) 7

Gastrointestinal Effects

• Gastrointestinal symptoms occurred in 15.2% of pediatric courses 6
• The oral solution formulation may have somewhat higher potential for gastrointestinal adverse events compared to capsules 3

Therapeutic Drug Monitoring Requirements

• TDM is mandatory when using itraconazole in children 1
• Target trough concentration: ≥0.5 mg/L 1, 8
• 76.8% of pediatric courses had at least one subtherapeutic trough concentration, but only 28.6% had dose adjustments made 6
• Samples should be taken at trough (pre-dose) at steady state (after approximately 14 days of therapy) 6, 5

Preferred Alternatives for 1-Year-Olds

For Invasive Fungal Infections

• Liposomal amphotericin B is the drug of choice for neonates and infants under 2 years (Grade A-III recommendation) 1
• Voriconazole is not approved for patients under 2 years of age 1
• Caspofungin and micafungin are better-studied alternatives with Grade A-I recommendations for empiric therapy 1

For Candida Infections

• Fluconazole, liposomal amphotericin B, or micafungin are preferred for invasive candidiasis in young children 1

Clinical Decision Algorithm

When considering itraconazole for a 1-year-old:

1. First, determine if there are safer, better-studied alternatives (liposomal amphotericin B, fluconazole, echinocandins) 1

2. If itraconazole is being considered, it should only be for:

   • Serious or life-threatening fungal infections where expected benefit exceeds risk 2
   • Situations where other agents have failed or are contraindicated 1

3. Before initiating therapy:

   • Assess liver function (baseline and monitoring) 2, 6
   • Review all concomitant medications for drug interactions 3, 7
   • Counsel family about unknown long-term effects on bone growth 2

4. If proceeding with treatment:

   • Start with 5-10 mg/kg/day depending on infection severity 4, 7, 5
   • Plan for TDM at steady state (day 14) with target trough ≥0.5 mg/L 6, 5
   • Anticipate need for dose escalation above 5 mg/kg/day 6
   • Monitor liver function during therapy 2, 6

Common Pitfalls to Avoid

• Do not assume standard pediatric dosing (5 mg/kg/day) will achieve therapeutic levels in children under 2 years 6, 5
• Do not skip TDM - subtherapeutic levels are common and dose adjustment is frequently needed 6
• Do not ignore the timing of TDM samples - only 82.4% were taken at appropriate times in one study 6
• Do not overlook drug interactions - itraconazole has significant interactions with immunosuppressants and other medications 8, 3, 7
• Do not use for prolonged therapy without considering unknown effects on bone development 2