Itraconazole (Sporanox)
itraconazole
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Blastomycosis (pulmonary and extrapulmonary) | Adults | Monotherapy | FDA Approved |
| Histoplasmosis (chronic cavitary pulmonary; disseminated, non-meningeal) | Adults | Monotherapy | FDA Approved |
| Aspergillosis (pulmonary and extrapulmonary; patients intolerant of or refractory to amphotericin B) | Adults | Second-line | FDA Approved |
| Onychomycosis of the toenail (± fingernail) due to dermatophytes | Adults, non-immunocompromised | Monotherapy | FDA Approved |
| Onychomycosis of the fingernail due to dermatophytes | Adults, non-immunocompromised | Monotherapy | FDA Approved |
| Oropharyngeal candidiasis (oral solution only) | Adults | Monotherapy | FDA Approved |
| Esophageal candidiasis (oral solution only) | Adults | Monotherapy | FDA Approved |
Itraconazole is a broad-spectrum triazole antifungal with particularly strong activity against dimorphic fungi (Blastomyces, Histoplasma) and Aspergillus species, distinguishing it from fluconazole. Its extensive tissue distribution (especially into lung, skin, and keratinous tissues) makes it well-suited for both systemic mycoses and dermatophyte infections. However, it has virtually no CNS penetration, making it unsuitable for fungal meningitis. Clinicians should note that capsules and oral solution are not interchangeable — they differ in bioavailability, and only the oral solution is approved for oropharyngeal and esophageal candidiasis.
Coccidioidomycosis — non-meningeal disease; alternative to fluconazole for non-CNS manifestations. Evidence quality: Moderate
Paracoccidioidomycosis — treatment of mild-to-moderate disease. Evidence quality: Moderate
Sporotrichosis — lymphocutaneous and osteoarticular forms; IDSA-recommended first-line agent. Evidence quality: High
Seborrheic dermatitis — moderate-to-severe cases refractory to topical therapy; administered as pulse therapy. Evidence quality: Moderate
Fungal prophylaxis — in neutropenic patients or post-transplant; oral solution has better bioavailability for prophylaxis. Evidence quality: High
Allergic bronchopulmonary aspergillosis (ABPA) — adjunctive to corticosteroids in patients with asthma or cystic fibrosis. Evidence quality: Moderate
Dosing
Adult Dosing by Clinical Scenario (Capsules Unless Noted)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Blastomycosis / Histoplasmosis — mild-to-moderate | 200 mg once daily | 200 mg once daily | 400 mg/day | Increase by 100 mg increments if no improvement; doses >200 mg/day given in 2 divided doses Treat ≥3 months minimum until clinical and lab resolution |
| Blastomycosis / Histoplasmosis — life-threatening | 200 mg TID (600 mg/day) × 3 days loading | 200 mg BID (400 mg/day) | 600 mg/day (loading only) | Loading dose based on PK data to approach steady state faster; typically step-down from IV amphotericin B IDSA recommends itraconazole step-down after induction with amphotericin B for moderately severe to severe disease |
| Aspergillosis — second-line (intolerant/refractory to amphotericin B) | 200 mg TID × 3 days loading | 200–400 mg/day | 400 mg/day | Median treatment duration ~3 months in clinical trials; doses >200 mg/day in 2 divided doses |
| Onychomycosis — toenail (± fingernail) | 200 mg once daily | 200 mg once daily × 12 weeks | 200 mg/day | Continuous dosing for 12 consecutive weeks; nail clearance may take 6–12 months after therapy ends (drug persists in nail keratin) Confirm diagnosis with KOH/culture before starting |
| Onychomycosis — fingernail only | 200 mg BID × 1 week | Pulse: 200 mg BID × 1 week on, 3 weeks off × 2 pulses | 400 mg/day (during pulse week) | Two pulse cycles total; mycologic cure ~61% in clinical trials Mean time to overall success ~5 months |
| Oropharyngeal candidiasis (oral solution only) | 200 mg (20 mL) daily | 100–200 mg daily | 200 mg/day | Swish and swallow; take on empty stomach for optimal absorption Do NOT use capsules for this indication |
| Esophageal candidiasis (oral solution only) | 100 mg (10 mL) daily | 100–200 mg daily | 200 mg/day | Minimum 3 weeks treatment; increase to 200 mg if no response Oral solution only |
The capsule and oral solution formulations are not interchangeable. Capsule absorption requires gastric acidity and food (take immediately after a full meal). Oral solution contains hydroxypropyl-beta-cyclodextrin, has higher bioavailability, and should be taken on an empty stomach. Patients on proton pump inhibitors or H2 blockers will have markedly reduced capsule absorption — consider the oral solution or administer capsules with an acidic beverage (e.g., non-diet cola). For oropharyngeal and esophageal candidiasis, only the oral solution is approved and effective.
For systemic fungal infections, itraconazole trough concentrations should be measured after at least 2 weeks of therapy at steady state. Target trough: ≥0.5 mcg/mL for prophylaxis, ≥1.0 mcg/mL for treatment of invasive infections. Trough levels should be measured by HPLC (which measures itraconazole only) or bioassay (which measures both itraconazole and hydroxy-itraconazole combined). Note that the bioassay result is typically higher than the HPLC result.
Pharmacology
Mechanism of Action
Itraconazole is a synthetic triazole antifungal that inhibits the fungal cytochrome P450 enzyme lanosterol 14α-demethylase (CYP51), blocking the conversion of lanosterol to ergosterol. Ergosterol is an essential structural component of fungal cell membranes, and its depletion leads to increased membrane permeability, impaired function of membrane-bound enzymes, and inhibition of fungal growth. Itraconazole has broader antifungal spectrum than fluconazole, with clinically meaningful activity against Aspergillus species, dimorphic fungi (Blastomyces, Histoplasma, Coccidioides, Paracoccidioides), dermatophytes, and many Candida species. Additionally, itraconazole uniquely inhibits the hedgehog signaling pathway and angiogenesis, properties being explored in oncology research. Its principal active metabolite, hydroxy-itraconazole, achieves trough plasma concentrations approximately twice those of the parent compound and contributes comparable antifungal activity.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | ~55% bioavailability (capsules with food); Tmax 2–5 h; non-linear pharmacokinetics; capsule absorption requires gastric acidity | Must take capsules with a full meal; reduced absorption with PPIs/H2 blockers (use acidic beverage as workaround); oral solution has higher and more reliable absorption |
| Distribution | Vd >700 L; protein binding 99.8% (albumin); tissue:plasma ratios of 2–4× in lung, liver, kidney, bone, skin; CSF penetration negligible | Excellent for pulmonary, cutaneous, and keratinous tissue infections; not suitable for CNS fungal infections; persists in nail keratin for ≥6 months after 3-month course |
| Metabolism | Extensive hepatic metabolism via CYP3A4; primary metabolite hydroxy-itraconazole (active, ~2× parent trough levels); >30 metabolites identified | Strong CYP3A4 inhibitor and substrate — extensive drug-drug interaction profile; saturable metabolism leads to non-linear kinetics at higher doses |
| Elimination | t½ 16–28 h (single dose), 34–42 h (steady state); urine 35%, feces 54% (within 1 week); <1% unchanged in urine; not removed by dialysis | Steady state reached in ~15 days without loading; loading dose (600 mg/day × 3 days) recommended for life-threatening infections; no dose adjustment needed for renal impairment |
Side Effects
Adverse event data below are derived primarily from 602 patients treated for systemic fungal infections in U.S. clinical trials (immunocompromised or receiving multiple concomitant medications) and from onychomycosis trials. Incidence rates reflect the systemic infection trials unless otherwise noted.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nausea | 11% | Most common GI complaint; may improve with dose reduction or taking capsules with food |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Rash | 9% | More frequent in immunocompromised patients receiving immunosuppressive medications; monitor for progression |
| Vomiting | 5% | May require anti-emetics or formulation change if persistent |
| Headache | 4% | Generally mild; manage with simple analgesics |
| Edema | 4% | Peripheral edema; assess for fluid retention especially in patients with cardiac risk factors |
| Hypertension | 3% | Monitor blood pressure, especially with concurrent calcium channel blockers |
| Diarrhea | 3% | More common with oral solution formulation (cyclodextrin-related osmotic effect) |
| Fatigue | 3% | Consider adrenal function assessment if unexplained or persistent |
| Fever | 3% | Distinguish from underlying infection |
| Pruritus | 3% | May respond to topical treatment; discontinue if accompanied by rash progression |
| Abnormal hepatic function | 3% | Transaminase elevations occur in 1–5% of patients; usually mild and reversible |
| Abdominal pain | 2% | Self-limiting in most cases |
| Hypokalemia | 2% | Monitor potassium, especially with concurrent diuretics or amphotericin B |
| Dizziness | 2% | Advise caution with driving |
| Anorexia | 2% | May contribute to weight loss on prolonged courses |
| Decreased libido / Impotence | 1–2% | Likely related to adrenal hormone suppression at higher doses; usually reversible |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Hepatotoxicity (hepatitis, cholestasis, fulminant hepatic failure) | Rare; fatal cases reported | 1 week to 6 months; some within first week | Discontinue immediately if clinical signs of liver disease develop; do not reinitiate unless life-threatening situation |
| Congestive heart failure / Negative inotropy | Rare (post-marketing) | Variable; can occur during or after treatment | Contraindicated for onychomycosis in patients with CHF or history of CHF; discontinue immediately if signs/symptoms of CHF appear |
| QT prolongation / Torsades de pointes | Rare | Any time during therapy | Avoid concurrent QT-prolonging agents (contraindicated with cisapride, pimozide, quinidine, methadone); ECG monitoring in high-risk patients |
| Peripheral neuropathy | Rare | Weeks to months | Discontinue itraconazole if neuropathic symptoms develop (paresthesia, numbness, burning) |
| Hearing loss (transient or permanent) | Rare | Variable | Discontinue treatment if hearing loss occurs; may be reversible upon discontinuation but permanent cases reported |
| Stevens-Johnson syndrome / Anaphylaxis | Very rare | 1–4 weeks (SJS); minutes to hours (anaphylaxis) | Permanent discontinuation; emergency management for anaphylaxis |
Itraconazole has been associated with rare but serious hepatotoxicity, including liver failure and death. Notably, some cases occurred in patients without pre-existing liver disease and within the first week of treatment. Liver function testing should be performed in all patients before starting treatment courses exceeding 1 month. Treatment should be discontinued immediately if clinical signs or symptoms suggestive of hepatic dysfunction develop (fatigue, anorexia, nausea, jaundice, dark urine, pale stools). Reinitiation of itraconazole is strongly discouraged unless the infection is life-threatening and no suitable alternatives exist.
Drug Interactions
Itraconazole is both a strong CYP3A4 inhibitor and a CYP3A4 substrate, and also inhibits P-glycoprotein (P-gp) and BCRP drug transporters. This dual role as inhibitor and substrate creates a particularly complex interaction profile. Drugs that induce CYP3A4 can reduce itraconazole to sub-therapeutic levels, while itraconazole raises levels of many co-administered CYP3A4 substrates to potentially dangerous concentrations. The contraindicated drug list is extensive — always check before prescribing.
Monitoring
-
Hepatic Function (AST, ALT, ALP, bilirubin)
Baseline; monthly during treatment
Routine Obtain baseline before courses exceeding 1 month. Liver function monitoring is recommended in all patients receiving itraconazole. Discontinue if clinical signs of liver disease develop. Strong caution in patients with pre-existing liver disease or prior hepatotoxicity from other drugs. -
Itraconazole Trough Level
After ≥2 weeks of therapy; repeat if dose changes
Routine Target trough ≥0.5 mcg/mL (prophylaxis) or ≥1.0 mcg/mL (treatment). Bioassay measures itraconazole + hydroxy-itraconazole combined. HPLC measures itraconazole alone. Especially important in immunocompromised patients, those on acid-suppressing therapy, and when treatment failure is suspected. -
Signs/Symptoms of CHF
Each visit during therapy
Routine Assess for dyspnea, weight gain, peripheral edema, and exercise intolerance. Itraconazole has demonstrated negative inotropic effects. Contraindicated for onychomycosis in patients with CHF or history of CHF. -
Electrolytes (K+)
Baseline and periodically
Trigger-based Hypokalemia reported; correct before starting itraconazole. Particularly important with concurrent diuretics, corticosteroids, or amphotericin B. -
Hearing Assessment
As needed if symptoms arise
Trigger-based Both transient and permanent hearing loss have been reported. Discontinue treatment if hearing changes occur. -
Neuropathy Assessment
As needed
Trigger-based Peripheral neuropathy has been reported; discontinue if paresthesias or numbness develop and are attributable to itraconazole.
Contraindications & Cautions
Absolute Contraindications
- Hypersensitivity to itraconazole or any other azole antifungal
- CHF or history of CHF when treating onychomycosis (boxed warning)
- Pregnancy — for onychomycosis treatment (teratogenic in animal studies; effective contraception required during treatment and for 2 months after stopping)
- Coadministration with contraindicated CYP3A4 substrates — including but not limited to: cisapride, pimozide, quinidine, dofetilide, dronedarone, methadone, oral midazolam, triazolam, lovastatin, simvastatin, ergot alkaloids, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, naloxegol, lomitapide, avanafil, ticagrelor, finerenone, voclosporin, lurasidone, isavuconazole
Relative Contraindications (Specialist Input Recommended)
- Ventricular dysfunction (non-onychomycosis indications) — use only if benefit clearly outweighs risk; monitor closely for CHF signs
- Active liver disease or elevated liver enzymes — treatment strongly discouraged unless life-threatening infection with no alternative
- Pregnancy (systemic fungal infections) — use only if benefit outweighs risk to fetus; documented informed consent recommended
Use with Caution
- Hepatic impairment — elimination half-life doubled in cirrhosis (37 vs 16 hours); monitor LFTs closely
- Concurrent acid-suppressing therapy — markedly reduces capsule absorption; use oral solution or acidic beverage workaround
- Elderly patients — increased risk of hearing loss, renal/hepatic/cardiac comorbidities
- Patients on multiple CYP3A4-metabolized drugs — extensive interaction potential requires careful medication review
- Immunocompromised patients — may have reduced and variable oral bioavailability; therapeutic drug monitoring recommended
Itraconazole has demonstrated a negative inotropic effect and should not be administered for onychomycosis treatment in patients with evidence of ventricular dysfunction such as CHF or a history of CHF. If signs or symptoms of CHF appear during administration, itraconazole must be discontinued. Coadministration with numerous CYP3A4 substrates is contraindicated due to the risk of elevated drug levels leading to QT prolongation, ventricular tachyarrhythmias including Torsades de pointes, and sudden cardiac death. The contraindicated drug list is extensive — prescribers must review all concomitant medications before initiating therapy.
Patient Counselling
Purpose of Therapy
Itraconazole is an antifungal medication used to treat a range of fungal infections, from toenail fungus to serious lung and body-wide infections. Depending on the type of infection, treatment can last from a few weeks (pulse therapy for nail infections) to several months (systemic infections). The medication works by disrupting the cell membranes of fungi. Even after completing treatment for nail infections, it may take several months for nails to appear fully clear, as the drug remains in the nail tissue long after the course ends.
How to Take
Capsules must be taken immediately after a full meal to ensure adequate absorption — taking on an empty stomach significantly reduces the drug’s effectiveness. Do not crush or chew capsules. If you are taking antacids or stomach acid medications (such as omeprazole or famotidine), take itraconazole capsules with a glass of non-diet cola to help with absorption, or ask your prescriber about switching to the liquid formulation. The oral solution, conversely, should be taken on an empty stomach (1 hour before or 2 hours after eating). Capsules and liquid are not interchangeable even at the same dose. Do not switch between formulations without consulting your prescriber.
Sources
- Janssen Pharmaceuticals. SPORANOX (itraconazole) Capsules Prescribing Information (revised 2024). U.S. Food and Drug Administration. accessdata.fda.gov Primary source for all FDA-approved capsule indications, boxed warning, dosing, adverse reactions (602-patient systemic infections trial), drug interactions, and contraindications.
- Janssen Pharmaceuticals. SPORANOX (itraconazole) Oral Solution Prescribing Information. U.S. Food and Drug Administration. accessdata.fda.gov Prescribing information specific to the oral solution formulation, covering oropharyngeal/esophageal candidiasis indications and the distinct absorption profile.
- Mayne Pharma. TOLSURA (itraconazole) Capsules Prescribing Information (revised 2024). U.S. Food and Drug Administration. accessdata.fda.gov Prescribing information for the super-bioavailable capsule formulation (Tolsura), including modified dosing and comparable adverse event profile.
- Chapman SW, Dismukes WE, Proia LA, et al. Clinical Practice Guidelines for the Management of Blastomycosis: 2008 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(12):1801-1812. doi:10.1086/588300 IDSA guideline establishing itraconazole as preferred agent for mild-to-moderate blastomycosis with step-down from amphotericin B for severe disease.
- Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical Practice Guidelines for the Management of Patients with Histoplasmosis: 2007 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2007;45(7):807-825. doi:10.1086/521259 IDSA guideline recommending itraconazole for mild-to-moderate histoplasmosis treatment and maintenance suppression in immunocompromised patients.
- Patterson TF, Thompson GR 3rd, Denning DW, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63(4):e1-e60. doi:10.1093/cid/ciw326 IDSA aspergillosis guideline positioning itraconazole as an alternative agent and its role in ABPA management.
- Kauffman CA, Bustamante B, Chapman SW, Pappas PG. Clinical Practice Guidelines for the Management of Sporotrichosis: 2007 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2007;45(10):1255-1265. doi:10.1086/522765 IDSA guideline recommending itraconazole as first-line treatment for lymphocutaneous and osteoarticular sporotrichosis.
- Kim J, Tang JY, Gong R, et al. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell. 2010;17(4):388-399. doi:10.1016/j.ccr.2010.02.027 Landmark study identifying itraconazole’s unique hedgehog pathway inhibition, providing mechanistic basis for its anticancer properties.
- Lestner J, Hope WW. Itraconazole: an update on pharmacology and clinical use for treatment of invasive and allergic fungal infections. Expert Opin Drug Metab Toxicol. 2013;9(7):911-926. doi:10.1517/17425255.2013.794785 Comprehensive review of itraconazole pharmacology including CYP3A4 substrate/inhibitor properties and therapeutic drug monitoring rationale.
- Barone JA, Koh JG, Bierman RH, et al. Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers. Antimicrob Agents Chemother. 1993;37(4):778-784. doi:10.1128/AAC.37.4.778 Foundational PK study demonstrating the critical requirement for food with capsule administration and characterizing non-linear accumulation kinetics.
- Poirier JM, Cheymol G. Optimisation of itraconazole therapy using target drug plasma concentrations. Clin Pharmacokinet. 1998;35(6):461-473. doi:10.2165/00003088-199835060-00004 Key study establishing therapeutic trough concentration targets (≥0.5 mcg/mL prophylaxis, ≥1.0 mcg/mL treatment) that underpin current TDM recommendations.
- LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Itraconazole. National Institute of Diabetes and Digestive and Kidney Diseases. ncbi.nlm.nih.gov NIH resource detailing itraconazole-induced hepatotoxicity patterns, including 1–5% incidence of transaminase elevations and rare but fatal cholestatic/hepatocellular injury.
- De Beule K, Van Gestel J. Pharmacology of itraconazole. Drugs. 2001;61(Suppl 1):27-37. doi:10.2165/00003495-200161001-00003 Review of itraconazole pharmacology including tissue distribution, keratinous tissue persistence, and the role of hydroxy-itraconazole as an active metabolite.