BLACK BOX WARNING
- drug interactions — potentially fatal if certain drugs co-administered
- congestive heart failure — itraconazole has negative inotropic effect; avoid in CHF or ventricular dysfunction
itraconazole
Brand: Sporanox, Onmel
⚠ BBW Beers Criteria TDM Required Prototype: fluconazole
Drug Class: triazole antifungal
Drug Family: antifungal
Subclass: first-generation triazole with broad spectrum
Organ Systems: infectious-disease
Mechanism of Action
Inhibits fungal CYP51, blocking ergosterol synthesis and disrupting fungal cell membrane integrity; broader spectrum than fluconazole, including Aspergillus; also a potent CYP3A4 and P-gp inhibitor.
fungal CYP51 (lanosterol 14-alpha-demethylase)
Indications
- aspergillosis (prophylaxis and treatment)
- histoplasmosis
- blastomycosis
- sporotrichosis
- onychomycosis
- paracoccidioidomycosis
Contraindications
- itraconazole hypersensitivity
- concomitant use of CYP3A4-cleared drugs with narrow therapeutic index (pimozide, cisapride, lovastatin, simvastatin, ergotamine, quinidine)
- negative inotropic effect — avoid in ventricular dysfunction
Adverse Effects
Common
- nausea
- vomiting
- abdominal pain
- headache
Serious
- hepatotoxicity
- negative inotropy/heart failure exacerbation
- severe drug interactions via CYP3A4 and P-gp inhibition
- peripheral neuropathy (prolonged use)
Pharmacokinetics (ADME)
| Absorption | highly variable; capsules require food and gastric acid; solution taken on empty stomach for better systemic absorption; avoid with acid-suppressing drugs |
| Distribution | large Vd; extensively distributed to tissues; plasma levels may not reflect tissue concentrations |
| Metabolism | extensive CYP3A4 metabolism; active metabolite hydroxyitraconazole (equal antifungal potency); also a strong CYP3A4 and P-gp inhibitor |
| Excretion | primarily fecal (54% as metabolites); renal <1% unchanged |
| Half-life | 40 hours (multiple dose) |
| Onset | variable |
| Peak | 1–5 hours (capsules with food) |
| Duration | 24 hours |
| Protein Binding | 99.8% |
| Vd | very large (11 L/kg) |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| simvastatin/lovastatin | CYP3A4 inhibition raises statin levels dramatically; rhabdomyolysis risk — contraindicated | major |
| warfarin | CYP3A4 inhibition increases INR; monitor closely | major |
| tacrolimus/cyclosporine | CYP3A4 inhibition markedly increases immunosuppressant levels; require dose adjustment | major |
| calcium channel blockers | CYP3A4 inhibition plus additive negative inotropy; monitor for edema and hypotension | major |
Nursing Considerations
- Capsules must be taken with food and in an acidic environment; do not administer capsules with antacids or acid-suppressing drugs — instruct patient to take with a cola beverage if on acid suppression.
- Itraconazole oral solution should be taken on an empty stomach for better systemic absorption (opposite of capsules).
- Screen all medications for CYP3A4-based drug interactions before initiating; the interaction list is extensive.
- Monitor LFTs monthly; hepatotoxicity can be severe — stop drug and notify prescriber if LFTs rise >3× ULN.
Clinical Pearls
- Itraconazole's active metabolite (hydroxyitraconazole) has antifungal activity equal to the parent drug, contributing to its efficacy, but both strongly inhibit CYP3A4 and P-gp, creating a vast drug interaction burden.
- For histoplasmosis and blastomycosis, itraconazole is the drug of choice for non-severe disease; the solution formulation achieves more reliable bioavailability than capsules.
Safety Profile
Pregnancy contraindicated
Lactation avoid
Renal Adjustment Not required
Hepatic Adjustment Required
TDM Required
Concordance Terms
Cross-referenced clinical concepts — click any term to see all content where it appears.