Itraconazole Side Effects
Itraconazole is associated with numerous side effects including gastrointestinal disturbances, hepatotoxicity, cardiovascular effects (including negative inotropic effects and QT prolongation), and significant drug interactions that can lead to serious adverse events. 1, 2
Common Side Effects
Gastrointestinal Effects
- Nausea (11% of patients)
- Diarrhea (11%)
- Vomiting (7%)
- Abdominal pain (6%)
- Constipation (2%)
- Gastrointestinal intolerance (particularly with oral solution) 2
Hepatic Effects
- Hepatotoxicity ranging from mild enzyme elevations to severe hepatic failure
- Rare cases of fatal acute liver failure have been reported
- Transient elevations in liver enzymes (ALT, AST, alkaline phosphatase) 2, 3
- Monitoring of liver function tests is recommended for treatment durations exceeding 1 month 3
Cardiovascular Effects
- Negative inotropic properties that can worsen heart failure
- QT interval prolongation
- Hypertension (particularly resistant hypertension with low renin) 1, 4
- Peripheral edema
- Contraindicated in patients with decreased cardiac ejection fraction or history of congestive heart failure 1
Neurological Effects
- Headache (4%)
- Dizziness (2%)
- Peripheral neuropathy (especially with prolonged therapy and excessive serum concentrations) 1
Metabolic Effects
- Hypertriglyceridemia
- Hypokalemia 5
Dermatologic Effects
- Rash (4%)
- Increased sweating (3%)
- Rare but serious reactions including toxic epidermal necrolysis, Stevens-Johnson syndrome, and acute generalized exanthematous pustulosis 2
Drug Interactions
Itraconazole has extensive drug interaction potential due to its effects on metabolic pathways:
CYP3A4 Inhibition: Itraconazole is both an inhibitor and substrate of CYP3A4, leading to increased plasma concentrations of drugs metabolized by this enzyme 1
P-glycoprotein Inhibition: Inhibits gastric P-glycoprotein, increasing systemic levels of affected drugs 1
High-Risk Interactions:
- Cardiac medications (amiodarone, digoxin) - can lead to cardiac arrest 6
- Chemotherapeutic agents (cyclophosphamide, vincristine) - increased toxicity
- QT-prolonging medications (fluoroquinolones, macrolides, ondansetron) - additive QT effects
- Statins - increased risk of myopathy
- Anticoagulants - enhanced toxicity 1
Special Considerations
Absorption Issues
- Capsule formulation requires high gastric acidity for absorption
- Should be taken with food or cola drinks
- Avoid concurrent use of antacids, H2 blockers, or proton pump inhibitors 1
- Solution formulation has better absorption when taken on an empty stomach 1
Monitoring Recommendations
Liver Function Tests:
- Baseline testing before starting therapy
- Follow-up at 1,2, and 4 weeks, then every 3 months during therapy
- Discontinue if signs of liver disease develop 2
Drug Level Monitoring:
- Consider in immunosuppressed patients
- Recommended for patients with suspected poor absorption
- Useful for those on concomitant enzyme inducers
- Target trough concentrations >250-500 ng/mL for efficacy 7
Cardiac Monitoring:
- Baseline cardiac evaluation in patients with history of heart disease
- Avoid in patients with heart failure or reduced ejection fraction 1
High-Risk Populations
- Patients with pre-existing liver disease
- Patients with heart failure or reduced ejection fraction
- Patients taking multiple medications with potential interactions
- Immunocompromised patients (may require drug level monitoring) 7
Formulation-Specific Considerations
- Pulse therapy (intermittent dosing) appears to have lower hepatotoxicity risk than continuous therapy 3
- Intravenous formulation contains cyclodextrin which can accumulate with renal dysfunction 1
When prescribing itraconazole, carefully weigh the benefits against these potential side effects, especially in patients with pre-existing cardiac or hepatic conditions, and always check for potential drug interactions.