Itraconazole: Effect on Fungal Infections

Itraconazole (brand names Sempera, Itracol and generics) is a triazole antifungal with broad spectrum activity against yeasts, moulds and dimorphic fungi. In Germany it has been established since the 1990s and is approved for multiple indications, from superficial skin mycoses to invasive fungal infections such as aspergillosis and sporotrichosis. Itraconazole is available as hard capsules, oral solution and intravenous preparation. Correct selection of the formulation is clinically important because bioavailability and therapeutic levels differ significantly.

The substance has a complex pharmacological profile. It strongly inhibits CYP3A4 and P glycoprotein, leading to numerous clinically relevant drug interactions. Furthermore, absorption and drug levels of itraconazole are highly dependent on gastric acid. Patients taking proton pump inhibitors or having reduced acid production benefit from the oral solution instead of capsules, because the solution is absorbed more independently of pH.

Mechanism of Action

Itraconazole inhibits the fungal enzyme lanosterol 14 alpha demethylase, a cytochrome P450-dependent enzyme that is crucial for ergosterol synthesis. Ergosterol is the main component of the fungal cell membrane and is essential for its stability. By inhibiting ergosterol synthesis, toxic sterol precursors accumulate, the membrane becomes permeable and fungal growth is arrested. In yeasts, itraconazole acts fungistatic, in Aspergillus often fungicidal as well.

Itraconazole acts against a broad spectrum: Candida species including many non-albicans strains, Aspergillus, Cryptococcus, dermatophytes, Histoplasma, Blastomyces and Sporothrix. Weaknesses exist against Candida glabrata and C. krusei as well as certain Aspergillus strains with reduced susceptibility. The pharmacokinetic profile is complex: the half-life is approximately 21 hours, the active metabolite hydroxyitraconazole extends the effective duration of action.

Oral bioavailability of hard capsules is highly dependent on an acidic gastric environment and concurrent intake of a calorie-rich meal. The oral solution is better absorbed on an empty stomach and achieves higher plasma levels. Itraconazole distributes well into tissue including skin, nails and lung, less well into the central nervous system. Metabolism occurs predominantly hepatically via CYP3A4.

Applications

• Onychomycosis (nail fungus) caused by dermatophytes or Candida, pulse therapy established
• Tinea corporis, Tinea cruris, Tinea pedis in extensive or recurrent cases
• Pityriasis versicolor in extensive findings
• Vulvovaginal candidiasis in recurrent form, supplementary to topical therapy
• Aspergillosis, both invasive and chronic pulmonary, often as sequential therapy after voriconazole
• Histoplasmosis, blastomycosis, sporotrichosis, primarily in travel medicine and in travellers from endemic areas
• Prophylaxis in immunosuppressed patients, such as after stem cell transplantation, decided individually

Itraconazole is not first-line for Candida sepsis (echinocandins such as caspofungin here) and for CNS aspergillosis (voriconazole preferred due to better CSF penetration).

Dosage and Administration

Onychomycosis: Pulse therapy with 200 mg twice daily for seven days, followed by a three-week break. Two to three pulses for fingernails, three to four pulses for toenails. Alternatively continuous therapy with 200 mg daily for 6 to 12 weeks.

Tinea corporis and cruris: 100 mg twice daily for 7 to 15 days, depending on extent.

Vulvovaginal candidiasis: 200 mg twice daily for one day, in recurrent cases longer therapy schemes depending on resistance pattern.

Invasive aspergillosis: 200 mg twice daily orally or intravenously, often 600 mg per day in acute phase. Therapy duration is several weeks to months, depending on response and immune status.

Administration of hard capsules: with a calorie-rich meal, because gastric acid and fat improve absorption. Preferably not combined with acid inhibitors.

Administration of oral solution: on empty stomach, at least one hour before or two hours after a meal, because absorption is more pH-independent.

Renal insufficiency: usually no dose adjustment for oral therapy. The intravenous solution with cyclodextrin carrier is contraindicated in impaired renal function (eGFR below 30) due to accumulation of carrier material.

Hepatic insufficiency: Caution, dose reduction with moderate impairment, consider alternatives with severe hepatic dysfunction.

Adverse Effects

Common: Nausea, abdominal pain, diarrhoea, headache, rash, pruritus.

Occasional: Elevated liver transaminases, oedema, hypertension, hyperkalaemia, hypokalaemia, dizziness, fatigue.

Rare but relevant: Hepatotoxicity up to acute liver failure, congestive heart failure especially in patients with cardiac preexisting conditions, pulmonary oedema. Itraconazole carries a Black Box warning when used for onychomycosis, that it should not be used in patients with heart failure or a history thereof.

Endocrine: Inhibition of steroid hormone synthesis with possible effects on cortisol, aldosterone and sex hormones.

Cardiac: QT prolongation, especially in combination with other QT-prolonging substances or electrolyte disorders.

Allergic reactions: rarely Stevens Johnson syndrome, DRESS syndrome, anaphylaxis.

Drug Interactions

• CYP3A4 substrates (statins such as simvastatin or atorvastatin, calcium antagonists, immunosuppressants such as tacrolimus or sirolimus, some oncology drugs): levels rise significantly, risk of toxicity, dose adjustment or therapy change if needed.
• Direct oral anticoagulants (apixaban, rivaroxaban, edoxaban): level increase through CYP3A4 and P glycoprotein inhibition, increased bleeding risk, combination critical.
• QT-prolonging agents (methadone, amiodarone, citalopram, domperidone, some macrolides): cumulative QT prolongation with risk of torsade de pointes.
• Acid inhibitors (proton pump inhibitors, H2 blockers, antacids): reduce absorption of itraconazole capsules. Switch to oral solution or combine with acidic beverage.
• CYP3A4 inducers (rifampicin, phenytoin, carbamazepine, St. John's wort, efavirenz): lower itraconazole levels, often therapy failure, avoid combination if possible.
• Ergot alkaloids, pimozide, quinidine, cisapride, astemizole, terfenadine: contraindicated due to risk of severe arrhythmias.
• Glucocorticoids: level increase possible, additive Cushing risk with prolonged concomitant use.

Special Information

Pregnancy: Itraconazole may be teratogenic and is contraindicated for onychomycosis and other non-life-threatening indications. In life-threatening fungal infection, individual risk-benefit assessment. Women of childbearing potential require reliable contraception during therapy and for at least two months afterwards. Breastfeeding: Transfer into breast milk, breastfeeding during therapy not recommended.

Children: Limited data, use in pediatric indication only in specialized centres.

Elderly patients: Due to risks of congestive heart failure and QT prolongation, careful history and ECG before therapy.

Before starting therapy: History, ECG, liver and kidney values, electrolytes. In patients with risk factors, therapeutic drug monitoring of plasma levels, especially for aspergillosis.

Long-term therapy of onychomycosis: Patients benefit additionally from good foot hygiene, drying between toes, breathable footwear and shoe rotation. Without these measures, relapses are common.

Lifestyle: No alcohol abuse during therapy, as hepatotoxicity risk increases. Patients with diabetes benefit from good metabolic control, as recurrent fungal infections may indicate poor glycaemic control.

You may also be interested in

• Ketoconazole, older imidazole antifungal, today primarily topical
• Ciclopirox, antifungal for skin and nail infections
• Clarithromycin, macrolide with similar interactions via CYP3A4
• Erythromycin, older macrolide with CYP3A4 inhibition
• Clopidogrel, example of CYP interactions with relevant clinical significance

Frequently Asked Questions

Sources

• Gelbe Liste, Itraconazole Active Ingredient Profile
• BfArM, Federal Institute for Drugs and Medical Devices
• AWMF, Guidelines for Invasive Fungal Infection and Onychomycosis
• ECIL, European Conference on Infections in Leukemia