Itraconazole

Overview

Itraconazole (Itrafungol®, Sporanox®) is a triazole antifungal used in dogs and cats for the treatment of dermatophytosis and a variety of systemic and cutaneous fungal infections. The veterinary oral solution is FDA-approved for the treatment of Microsporum canis dermatophytosis in cats.

Commercial oral formulations should be used, as compounded oral itraconazole products may not be adequately absorbed. In cats, the commercial oral solution provides higher serum concentrations than capsules, allowing lower doses to be used; this difference has not been demonstrated in dogs.

Mechanism of Action (MOA): Itraconazole is a fungistatic triazole that inhibits a fungal CYP450-dependent demethylation enzyme involved in ergosterol synthesis. This results in intracellular accumulation of methylated sterols, disruption of fungal cell membrane integrity, increased membrane permeability, leakage of cellular contents, and impaired uptake of purine and pyrimidine precursors.

Indications

Itraconazole is used in dogs and cats for the treatment of dermatophytosis and a variety of systemic and cutaneous fungal infections. It is most appropriate for non-life-threatening systemic mycoses that do not involve the central nervous system.

• Dermatophytosis: FDA-approved for the treatment of Microsporum canis dermatophytosis in cats; also used extra-label for dermatophytosis in dogs.
• Systemic mycoses: Used for aspergillosis, cryptococcosis, blastomycosis, coccidioidomycosis, histoplasmosis, and sporotrichosis; it is also used for candidiasis.
• Adjunctive antifungal therapy: May be used as part of combination treatment for pythiosis, lagenidiosis, zygomycosis, phaeohyphomycosis, and hyalohyphomycosis.
• Other fungal infections: May be useful for fungal osteomyelitis, onychomycosis, and Malassezia dermatitis.
• Non-fungal infections: Used in dogs for protothecosis (an algal infection) and, with amiodarone, for Trypanosoma cruzi infection (Chagas disease).

Dosage (Reference)

Dog

In dogs, itraconazole is administered orally using commercially available formulations. Capsules should be given with food to maximize absorption. Treatment duration depends on the infecting organism and site of infection, and prolonged therapy is commonly required. Compounded formulations should be avoided.

Cat

In cats, commercially available oral solution produces higher serum concentrations than capsules, allowing lower doses to be used. Depending on the indication, treatment may be continuous or administered as pulse therapy.

Warnings & Precautions

Itraconazole should be used cautiously in dogs and cats because treatment is often prolonged and adverse effects are dose dependent. Careful patient selection and periodic monitoring are recommended, particularly in animals with pre-existing hepatic, renal, or cardiac disease.

• Hypersensitivity: Contraindicated in animals with known hypersensitivity to itraconazole or other azole antifungal agents.
• Hepatic or renal impairment: Avoid itraconazole in severe or active liver disease and during pregnancy unless treatment of a serious infection offers a compelling benefit over the risks. In milder hepatic disease or renal impairment, use only after individualized assessment and with appropriate monitoring. Product-specific contraindications apply; some feline oral solutions prohibit use in cats with hepatic or renal impairment.
• Cardiac disease: Itraconazole may have a negative inotropic effect, particularly at higher dosages. Use cautiously in animals with reduced cardiac function.
• Pregnancy and lactation: Avoid use during pregnancy because fetal toxicity and teratogenic effects have been reported. Use cautiously in lactating animals as the drug enters milk; consider milk replacer if treatment is necessary.
• Compounded formulations: Avoid compounded oral capsules or solutions prepared from bulk powder because inadequate absorption may result in therapeutic failure. Use commercially available formulations whenever possible.
• Reduced gastric acidity: Absorption may be impaired in patients with achlorhydria or hypochlorhydria, increasing the risk of treatment failure.
• Long-term therapy: Periodic monitoring of hepatic and renal parameters is recommended during prolonged treatment. Consider monitoring serum itraconazole trough concentrations when available for systemic infections.
• Clinical monitoring: Monitor for gastrointestinal adverse effects (eg, inappetence, vomiting, diarrhea) and examine dogs receiving prolonged therapy for ulcerative skin lesions.
• Neuropathy: Peripheral neuropathy has been reported in humans receiving long-term itraconazole therapy; its significance in veterinary patients is unknown.

Drug Interactions

Itraconazole is a potent inhibitor of CYP3A4 and P-glycoprotein in humans and is metabolized by CYP3A4. It has numerous potential drug interactions that may alter drug absorption, metabolism, or plasma concentrations. Careful monitoring and dose adjustment are recommended when itraconazole is administered with the following medications.

• Amphotericin B: Concurrent use may be antagonistic against Aspergillus spp. or Candida spp.; the clinical significance is uncertain.
• Antacids, H₂-blockers, and Proton Pump Inhibitors (PPIs): Increased gastric pH may reduce itraconazole absorption. Administer itraconazole at least 1 hour before or 2 hours after oral antacids.
• Isoniazid, Phenobarbital, and Primidone: May decrease itraconazole concentrations, potentially reducing antifungal efficacy.
• Macrolide antibiotics (eg, clarithromycin, erythromycin): May increase itraconazole concentrations, while itraconazole may also increase macrolide concentrations.
• Rifampin: May decrease itraconazole concentrations, and itraconazole may increase rifampin concentrations. Concurrent use, or use within 2 weeks of discontinuing itraconazole, is contraindicated.
• Highly protein-bound drugs (eg, NSAIDs, phenytoin, salicylates, sulfonamides, sulfonylureas, warfarin): Itraconazole may theoretically displace these drugs from plasma proteins, although this interaction has not been shown to be clinically significant.
• Meloxicam: May decrease peak meloxicam concentrations and reduce overall drug exposure.
• Toceranib: Increased concentrations of either toceranib or itraconazole may occur.
• Calcium channel blockers (eg, amlodipine, diltiazem): Itraconazole may increase their concentrations and toxicity, while negative inotropic effects may be potentiated. Use cautiously in patients with heart failure.
• Corticosteroids (eg, dexamethasone, prednisolone): Itraconazole may inhibit corticosteroid metabolism, increasing the risk of hepatotoxicity and gastrointestinal adverse effects.
• Cyclosporine, Digoxin, Doxorubicin, Benzodiazepines, Buspirone, Busulfan, Cannabidiol, Fentanyl, Alfentanil, Ivermectin, Loperamide, Praziquantel, Sildenafil, Tricyclic antidepressants, Vincristine, Vinblastine, and Warfarin: Itraconazole may increase plasma concentrations or drug exposure, increasing the risk of toxicity.
• Cisapride, Disopyramide, Ergot alkaloids (eg, bromocriptine, cabergoline), Methadone, Quinidine, Rivaroxaban, Tamsulosin, and Colchicine (in patients with hepatic or renal impairment): Concurrent use is contraindicated in humans because of the potential for serious toxicity.
• Ciprofloxacin: May increase itraconazole exposure (documented in people).
• Sucralfate and adsorbents: May reduce itraconazole absorption.
• Sulfonylurea antidiabetic agents (eg, glipizide, glyburide): Itraconazole may increase their concentrations, and hypoglycemia is possible.
• Cefovecin and tolfenamic acid: Concurrent administration is advised against in cats.

Side Effects & Overdose

Side Effects

Adverse effects of itraconazole are generally dose dependent and are reported more frequently with prolonged therapy or higher dosages. Gastrointestinal disturbances and hepatotoxicity are the most commonly recognized adverse effects in dogs and cats.

• Dogs: Anorexia is the most common adverse effect and is often the earliest clinical indicator of toxicity. It is typically dose dependent and commonly develops during the second month of treatment.
• Hepatotoxicity: Increased ALT activity may occur in both dogs and cats. In dogs, approximately 5% receiving 5 mg/kg/day and 10% receiving 10 mg/kg/day developed hepatotoxicity severe enough to temporarily discontinue treatment.
• Dermatologic reactions (dogs): Ulcerative skin lesions, vasculitis, and limb edema may occur and generally resolve after drug discontinuation. Re-exposure is not recommended because these reactions are likely idiosyncratic and may recur more severely.
• Severe cutaneous reactions (dogs): Rare cases of erythema multiforme and toxic epidermal necrolysis have been reported.
• Gastrointestinal effects (cats): Anorexia, vomiting, diarrhea, hypersalivation, weight loss, and depression are dose dependent and become more common at dosages above 10 mg/kg.
• Monitoring liver enzymes: Marked ALT elevation accompanied by adverse effects warrants discontinuation of therapy. Increased liver enzyme activity alone does not necessarily require dose reduction or drug withdrawal. Once ALT activity returns to normal and adverse effects resolve, treatment may be restarted at a lower dose or with longer dosing intervals under close monitoring.
• Compared with ketoconazole: Itraconazole has minimal effects on hormone synthesis and generally produces fewer adverse effects in dogs and cats.

Overdose

Information regarding acute itraconazole overdose in dogs and cats is limited. Toxic effects are primarily associated with excessive gastrointestinal signs and hepatotoxicity, and treatment is supportive.

• Clinical signs: Hypersalivation and increased liver enzyme activity have been reported following high dosages in cats. Inflammatory lesions in the lungs and kidneys have also been reported after administration of the oral solution and were attributed to the oral vehicle (HP-beta-cyclodextrin).
• Decontamination: Following a large oral overdose, gastric decontamination should be considered. Oral antacids may help reduce itraconazole absorption.
• Supportive care: Provide supportive treatment and monitor hepatic function as required.
• Dialysis: Itraconazole is not removed by dialysis; however, dialysis may remove HP-beta-cyclodextrin following ingestion of the oral solution.
• IV lipid emulsion: Itraconazole effects may be reversed with intravenous lipid emulsion therapy.

Key Notes

Practical clinical points that help optimize the effective use of itraconazole in dogs and cats in everyday veterinary practice:

• Commercial formulations preferred: FDA-approved commercial products provide more reliable bioavailability than compounded formulations and are recommended whenever possible.
• Capsules vs oral solution: In cats, the commercial oral solution achieves higher systemic exposure than capsules, allowing lower doses. This difference has not been demonstrated in dogs.
• Administration with food: Give capsules or capsule contents with food to maximize absorption, whereas the veterinary oral solution can be given to cats with or without food and the human-labeled oral solution is best given on an empty stomach.
• Treatment duration: Most systemic fungal infections require prolonged therapy, and treatment is generally continued well beyond clinical resolution of disease.
• Fluconazole comparison: Fluconazole may be a better choice for some infections involving the CNS or eyes, particularly cryptococcosis.
• Combination therapy: Certain invasive fungal infections may require surgical intervention and/or additional antifungal agents to achieve successful treatment.
• Intermittent dosing: Pulse-therapy protocols are effective for selected dermatologic fungal infections and may reduce overall drug exposure.
• Therapeutic monitoring: Serum itraconazole trough concentrations may be useful, when available, during prolonged treatment of systemic mycoses.