What is the recommended itraconazole dosing regimen for different infections in adults and children, including adjustments for hepatic impairment and drug interactions?

Itraconazole Dosing Recommendations

Adults

For dermatophyte onychomycosis, itraconazole 200 mg daily for 12 weeks continuously OR pulse therapy with 400 mg daily for 1 week per month (2 pulses for fingernails, 3 pulses for toenails) is recommended as first-line treatment. 1

Systemic Fungal Infections

• Loading dose: 200 mg three times daily for 3 days for moderately severe to severe infections 2, 3
• Maintenance dose: 200 mg twice daily for most systemic infections 2
• Duration: 6-12 months for blastomycosis; at least 12 months for osteoarticular infections and CNS disease 2

Specific Infections

• Fluconazole-refractory esophageal candidiasis: 200 mg once daily for up to 28 days 2, 3
• Invasive aspergillosis (alternative therapy): Dosing depends on formulation; capsules 200 mg twice daily 1
• Superficial dermatophytoses (tinea corporis/cruris): 100 mg once daily for 15 days 3

Critical Administration Requirements

• Capsules MUST be taken with food to enhance absorption 2, 3
• Capsules and oral solution are NOT interchangeable—capsules have poor bioavailability for esophageal disease 3
• Avoid proton pump inhibitors and H2-blockers with capsules as they markedly reduce absorption 3

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Children

For children with dermatophyte onychomycosis, pulse therapy with itraconazole 5 mg/kg per day for 1 week per month is recommended (2 pulses for fingernails, 3 pulses for toenails). 1

Systemic Infections

• Standard dose: 10 mg/kg/day orally (maximum 400 mg daily) for systemic/disseminated infections 4
• Cutaneous/lymphocutaneous infections: 6-10 mg/kg/day orally (maximum 400 mg daily) 4
• Children >12 years: 200 mg twice daily for most infections 4
• Duration: At least 12 months for systemic/disseminated infections 4

Infants (10 months old)

• Prophylaxis or superficial infections: 5 mg/kg/day divided into two doses 4
• Systemic/invasive infections: 10 mg/kg/day divided into two doses, with loading dose on day 1 4

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Therapeutic Drug Monitoring

Serum itraconazole levels should be measured after at least 2 weeks of therapy to ensure adequate drug exposure. 1, 2, 3

Target Concentrations

• Prophylaxis: Trough ≥0.5-1 μg/mL (combined itraconazole/hydroxy-itraconazole ≥1.5 μg/mL) 1
• Treatment of invasive disease: Trough >3 μg/mL may be associated with increased toxicity 1
• Effective prophylaxis: Plasma concentrations ≥250 μg/mL itraconazole, or 750-1000 μg/mL for combined itraconazole plus hydroxy-itraconazole 5
• Curative effect: Concentrations >500 μg/mL may enhance efficacy 5

When to Monitor

• Populations with increased pharmacokinetic variability (impaired GI function, hepatic disease, pediatric, elderly, critically ill) 1
• Severe or extensive infections 1
• Suspected breakthrough infection or inadequate response 1
• Patients on interacting medications (CYP3A4 inducers, antacids, antiretrovirals) 1
• Diarrhea or malabsorption 3

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Hepatic Impairment

Itraconazole is contraindicated in active liver disease. 3

• Baseline liver function tests are mandatory before initiating therapy 1
• Monitor hepatic function tests in patients with pre-existing abnormalities, those receiving continuous therapy >1 month, and with concomitant hepatotoxic drugs 1
• Patients with pre-existing liver enzyme abnormalities are at higher risk for hepatic damage during treatment 6

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Drug Interactions

Itraconazole is a potent CYP3A4 inhibitor causing significant drug-drug interactions. 1, 2

Critical Interactions

• Immunosuppressants: Cyclosporine, tacrolimus, sirolimus levels increase significantly—dose adjustments required 3, 4
• Anticonvulsants: Phenytoin reduces itraconazole absorption 3
• Rifampin: Markedly reduces itraconazole levels 3
• Antiretrovirals: Protease inhibitors and NNRTIs have significant pharmacokinetic interactions 4

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Contraindications and Cautions

Itraconazole is absolutely contraindicated in heart failure due to negative inotropic effects. 1, 3

Additional Contraindications

• Active hepatic disease 3
• Pregnancy (amphotericin B is preferred) 4

Common Adverse Effects

• Headache and gastrointestinal upset (most frequent) 1
• Diarrhea, particularly with oral solution, can reduce bioavailability and cause breakthrough infections 3

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Management of Diarrhea

• Switch from oral solution to intravenous formulation if severe diarrhea occurs 3
• Consider alternative agents (posaconazole, voriconazole, echinocandin) if diarrhea persists 3
• Mandatory therapeutic drug monitoring to ensure adequate serum concentrations 3

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Special Clinical Scenarios

Severe Life-Threatening Infections

• Initiate with amphotericin B for 1-2 weeks until clinical improvement 2, 4
• Step down to itraconazole 200 mg three times daily for 3 days, then 200 mg twice daily 2

Immunosuppressed Patients

• Lifelong suppressive therapy with 200 mg daily may be required if immunosuppression cannot be reversed 2
• Prophylaxis continues until immune recovery or discontinuation of immunosuppression 4