Monograph of Itraconazole

Introduction / Overview

Itraconazole is a triazole antifungal agent that has become a cornerstone in the management of numerous superficial and systemic mycoses. The drug was first introduced in the early 1980s and has since been integrated into clinical practice worldwide. Its broad spectrum of activity, coupled with convenient oral dosing options, renders itraconazole an essential therapeutic choice for clinicians treating fungal infections ranging from dermatophytosis to invasive aspergillosis. The pharmacologic profile of itraconazole, including its unique formulation strategies and extensive drug interaction potential, requires a comprehensive understanding by both pharmacists and medical practitioners.

Learning objectives for this chapter include:

• Identify the chemical classification and key structural features of itraconazole.
• Explain the pharmacodynamic mechanisms underlying antifungal activity.
• Describe the absorption, distribution, metabolism, and elimination characteristics of the drug.
• Summarize approved therapeutic indications and common off‑label uses.
• Recognize major adverse effects, drug interactions, and special population considerations.

Classification

Drug Class and Category

Itraconazole belongs to the azole class of antifungal agents. Within this group, it is specifically classified as a triazole, distinguished by the presence of a triazole ring that confers potent inhibition of fungal lanosterol 14α‑demethylase. The drug is marketed under several brand names, including Sporanox® and Sporanox® (generic itraconazole), and is available in capsule, tablet, and oral solution formulations.

Chemical Classification

As a triazole, itraconazole features a 1,2,4‑triazole moiety attached to a bis‑pyridyl system. The molecular formula is C₃₈H₄₉N₅O₆, and the molecular weight is 603.75 g/mol. The lipophilic nature of the molecule contributes to its extensive tissue penetration, while the presence of ionizable groups influences solubility and absorption characteristics.

Mechanism of Action

Pharmacodynamic Overview

Itraconazole exerts its antifungal effect by selectively inhibiting the fungal cytochrome P450‑dependent enzyme lanosterol 14α‑demethylase (CYP51). This enzyme catalyzes the conversion of lanosterol to ergosterol, a critical component of the fungal cell membrane. Inhibition of CYP51 leads to depletion of ergosterol and accumulation of toxic methylated sterol intermediates, which ultimately disrupts membrane integrity and cell function. The drug’s affinity for the fungal enzyme is substantially higher than for the human homolog, conferring selective antifungal activity.

Molecular Interactions

The triazole nitrogen atoms of itraconazole coordinate with the heme iron of CYP51, forming a stable complex that blocks access to the catalytic site. Binding of the drug to the enzyme follows a reversible, non‑competitive inhibition model. The apparent inhibition constant (K_i) for itraconazole against Aspergillus fumigatus CYP51 is reported to be in the low nanomolar range, underscoring its potency. In vitro studies suggest that the drug may also interfere with other fungal P450 enzymes, potentially contributing to its broad spectrum.

Cellular Consequences

Disruption of ergosterol synthesis compromises membrane fluidity, permeability, and the function of membrane‑bound proteins. These alterations impair nutrient transport, cell wall synthesis, and signal transduction pathways. Additionally, the accumulation of methylated sterols can induce oxidative stress and apoptosis in fungal cells. The cumulative effect is a fungistatic or fungicidal outcome depending on the organism, infection site, and drug concentration achieved.

Pharmacokinetics

Absorption

Itraconazole absorption is highly dependent on gastric pH and formulation. The capsule form, which contains a poly(vinylpyrrolidone) core, requires an acidic environment for optimal dissolution. In patients with achlorhydria or those receiving proton pump inhibitors (PPIs), the oral bioavailability of the capsule can be diminished by up to 50 %. The oral solution formulation, on the other hand, contains a lipid‑based vehicle that enhances solubility across a broader pH range, resulting in more consistent absorption. Peak plasma concentrations (C_max) are typically achieved 3–6 h after dosing for the capsule and 1–3 h for the solution. The bioavailability of the capsule ranges from 30–50 %, whereas the solution can reach up to 100 % in some studies.

Distribution

Itraconazole is highly protein‑bound, with 99 % affinity for plasma proteins, predominantly albumin and α‑1‑acid glycoprotein. The drug exhibits extensive tissue distribution, achieving concentrations in the lung, liver, spleen, and skin that exceed plasma levels by 2–5×. The volume of distribution (V_d) is approximately 15 L/kg, reflecting its lipophilic nature. Owing to its high tissue penetration, itraconazole is effective against deep mycoses such as invasive aspergillosis and cryptococcosis. The penetration into the central nervous system is limited, with cerebrospinal fluid concentrations typically <0.01 % of plasma levels, though higher concentrations can be achieved in the presence of meningeal inflammation.

Metabolism

Metabolism is predominantly hepatic, mediated by the cytochrome P450 3A4 (CYP3A4) isoenzyme and, to a lesser extent, CYP2C9. The metabolic pathway produces several hydroxylated and desmethylated metabolites, most of which retain antifungal activity, though generally less potent than the parent compound. The intrinsic clearance (Cl_int) reflects a moderate hepatic extraction ratio. Notably, itraconazole is a strong inhibitor of CYP3A4, which contributes to its extensive drug interaction profile. Concomitant administration of strong CYP3A4 inducers (e.g., rifampin, carbamazepine) can markedly reduce itraconazole bioavailability, potentially compromising therapeutic efficacy.

Excretion

Excretion occurs via both biliary and renal routes. Approximately 30–40 % of a dose is excreted unchanged in feces, while 10–15 % is eliminated unchanged in urine. The remaining drug undergoes hepatic metabolism before biliary excretion. Renal clearance is relatively low, and the drug is not considered nephrotoxic under standard dosing regimens. The terminal elimination half‑life (t_1/2) is approximately 30–50 h, depending on formulation and patient characteristics, supporting once‑daily dosing schedules for most indications.

Dosing Considerations

The standard adult dosing regimen typically involves an initial loading dose of 200 mg twice daily for 3–5 days, followed by a maintenance dose of 200 mg once daily. For severe systemic infections, a higher maintenance dose of 400 mg daily may be required. Dose adjustments are necessary in patients with hepatic impairment due to altered metabolism, while renal impairment generally does not necessitate modification. When using the oral solution, patient adherence may be enhanced due to improved tolerability and absorption, particularly in individuals on acid‑suppressive therapy.

Therapeutic Uses / Clinical Applications

Approved Indications

Itraconazole is approved for the treatment of a variety of fungal diseases, including:

• Onychomycosis (tinea unguium) of the nail plate
• Dermatophytosis of the skin (tinea corporis, tinea versicolor)
• Invasive aspergillosis, particularly in patients with neutropenia or immunosuppression
• Invasive candidiasis, as part of salvage therapy or in patients intolerant to other azoles
• Cryptococcal meningitis, in combination with amphotericin B and flucytosine, especially where fluconazole resistance is suspected
• Histoplasmosis, both acute and chronic forms

Common Off‑Label Uses

Off‑label applications are frequently encountered in clinical practice, such as:

• Prophylaxis of invasive fungal infections in hematopoietic stem cell transplant recipients
• Treatment of severe chronic pulmonary aspergillosis (CPA) and allergic bronchopulmonary aspergillosis (ABPA)
• Management of sporotrichosis, especially when other agents are contraindicated
• Adjunctive therapy for mucormycosis, often combined with liposomal amphotericin B
• Therapy for invasive fusariosis and other rare molds

These off‑label uses are supported by clinical experience and case series, though formal randomized trials are limited. Clinicians should weigh the benefit–risk profile and discuss the evidence base with patients when considering these indications.

Adverse Effects

Common Side Effects

Patients receiving itraconazole may develop a range of nonspecific adverse reactions. The most frequently reported include gastrointestinal disturbances such as nausea, vomiting, dyspepsia, and abdominal pain. Dermatologic manifestations such as pruritus and rash occur in a minority of cases. Hepatic enzymes (ALT, AST) may be transiently elevated; routine monitoring is recommended, particularly during the first 4–6 weeks of therapy. Other common but less frequent effects involve dizziness, headache, and mild myalgia.

Serious / Rare Adverse Reactions

Serious adverse events are infrequent but may have significant clinical implications. Hepatotoxicity, ranging from asymptomatic enzyme elevations to acute liver failure, has been documented, especially when itraconazole is combined with other hepatotoxic agents or in patients with pre‑existing liver disease. Cardiac effects include QT interval prolongation and, in rare instances, torsades de pointes, particularly when co‑administered with other QT‑prolonging drugs. Ocular toxicity, manifesting as blurred vision or retinal pigment epithelium changes, has been reported, although causality remains uncertain. Rare allergic reactions, including anaphylaxis, may occur, particularly with the oral solution formulation. Patients with a history of hypersensitivity to azoles should be closely monitored.

Black Box Warning

A black box warning is present for itraconazole regarding the potential for hepatotoxicity. The warning emphasizes the need for baseline liver function tests and periodic monitoring, especially during prolonged therapy. Clinicians should discontinue the drug immediately if severe hepatic injury is suspected and consider alternative antifungal options.

Drug Interactions

Major Drug‑Drug Interactions

Itraconazole’s strong inhibition of CYP3A4 creates a substantial interaction risk with many medications. Co‑administration with potent CYP3A4 inducers such as rifampin, carbamazepine, phenytoin, and phenobarbital can drastically reduce itraconazole plasma concentrations, potentially leading to treatment failure. Conversely, itraconazole can elevate plasma levels of drugs metabolized by CYP3A4, including statins (e.g., simvastatin), calcium channel blockers (e.g., verapamil), and certain antiretrovirals, thereby increasing the risk of toxicity.

Itraconazole also inhibits P‑glycoprotein (P‑gp), which may alter the pharmacokinetics of drugs that are P‑gp substrates, such as digoxin and certain chemotherapeutic agents. The interaction profile necessitates careful medication reconciliation and, when feasible, therapeutic drug monitoring (TDM). Dosage adjustments or alternative agents should be considered when interacting drugs cannot be avoided.

Contraindications

Itraconazole is contraindicated in patients with severe hepatic impairment (Child‑Pugh Class C) due to the risk of exacerbated hepatotoxicity. Additionally, the drug should be avoided in individuals with a history of hypersensitivity to itraconazole or other azoles. Concomitant use with drugs that have a narrow therapeutic index and are metabolized by CYP3A4, when alternative antifungals are available, should be approached with caution.

Special Considerations

Use in Pregnancy / Lactation

The safety of itraconazole during pregnancy has not been conclusively established, and animal studies have suggested potential teratogenic effects. Consequently, itraconazole is generally classified as pregnancy category D, and its use is reserved for situations where the benefits outweigh the risks. In lactation, itraconazole is excreted into breast milk, and exposure to nursing infants may be significant; therefore, discontinuation of therapy is recommended while breastfeeding unless the infant is clinically indicated for treatment.

Pediatric / Geriatric Considerations

Pediatric dosing is weight‑based, typically 5–10 mg/kg/day divided into two doses, with adjustments for age and liver function. Limited data exist regarding pharmacokinetics in infants and neonates; thus, cautious use is advised. In geriatric patients, reduced hepatic and renal function may alter drug disposition, necessitating closer monitoring of hepatic enzymes and potential dose adjustments. The risk of drug interactions is amplified in older adults due to polypharmacy.

Renal / Hepatic Impairment

Renal impairment does not significantly influence itraconazole clearance, and dose modification is generally unnecessary. Hepatic impairment, however, can reduce metabolic clearance and increase systemic exposure, thereby heightening the risk of hepatotoxicity. In patients with mild to moderate hepatic dysfunction, a lower maintenance dose (e.g., 100 mg daily) may be considered, and hepatic function should be monitored periodically.

Summary / Key Points

• Itraconazole is a triazole antifungal that selectively inhibits fungal lanosterol 14α‑demethylase, disrupting ergosterol synthesis.
• Absorption is pH‑dependent; the oral solution formulation offers more consistent bioavailability compared to the capsule.
• Extensive tissue distribution and moderate hepatic metabolism via CYP3A4 underscore its therapeutic efficacy and interaction potential.
• Approved indications include dermatophytosis, onychomycosis, invasive aspergillosis, and candidiasis; off‑label uses involve prophylaxis and management of rare molds.
• Common adverse effects are gastrointestinal; serious events include hepatotoxicity and QT prolongation. A black box warning emphasizes liver monitoring.
• Itraconazole’s strong CYP3A4 inhibition results in numerous drug interactions; careful medication review and possible therapeutic drug monitoring are warranted.
• Special populations (pregnancy, lactation, pediatrics, geriatrics) require individualized dosing and monitoring strategies.

Incorporation of these pharmacologic principles into clinical decision‑making can enhance therapeutic outcomes while minimizing adverse events and drug interactions associated with itraconazole therapy.

References

1. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
2. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
3. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
4. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
5. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
6. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
7. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
8. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.