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Chemistry – A synthetic triazole antifungal, itraconazole is structurally related to fluconazole. It has a molecular weight of 706 and a pKa of 3.7.
Pharmacology – Itraconazole is a fungistatic triazole compound. Triazole-derivative agents, like the imidazoles (clotrimazole, ketoconazole, etc.), presumably act by altering the cellular membranes of susceptible fungi, thereby increasing membrane permeability and allowing leakage of cellular contents and impaired uptake of purine and pyrimidine precursors. Itraconazole has efficacy against a variety of pathogenic fungi, including yeasts and dermatophytes. In vivo studies using laboratory models have shown that itraconazole has fungistatic activity against many strains of Candida, Aspergillus, Cryptococcus, Histoplasma, Blastomyces and Trypanosoma cruzi.
Uses/Indications – Itraconazole may have use in veterinary medicine in the treatment of systemic mycoses, including aspergillosis, cryptococcal meningitis, blastomycosis, and histoplasmosis. It may also be useful for superficial candidiasis or dermatophytosis. Itraconazole does not have appreciable effects (unlike ketoconazole) on hormone synthesis and may have fewer side effects than ketoconazole in small animals.
In horses, itraconazole may be useful in the treatment of sporotrichosis and Coccidioides immitis osteomyelitis.
Pharmacokinetics – Itraconazole absorption is highly dependent on gastric pH and presence of food. When given on an empty stomach bioavailability may only be 50% or less, with food it may approach 100%.
Itraconazole has very high protein binding and is widely distributed throughout the body, particularly to tissues high in lipids (drug is highly lipophilic). Skin, female reproductive tract and pus all have concentrations greater than found in the serum. Only minimal concentration are found in the CSF, aqueous humor and saliva, however.
Itraconazole is metabolized by the liver to many different metabolites, including to hydroxyitraconazole which is active. In humans, itraconazole’s serum half life ranges from 21-64 hours. Elimination may be a saturable process.
Contraindications/Precautions/Reproductive Safety – Itraconazole should not be used in patients hypersensitive to it or other azole antifungal agents, in patients with hepatic impairment, or achlorhydria (or hypochlorhydria) only when the potential benefits outweigh the risks.
In laboratory animals, itraconazole has caused dose-related maternotoxicity, fetotoxicity and teratogenicity at high dosages (5-20 times labeled). As safety has not been established, use only when the benefits outweigh the potential risks. Itraconazole does enter maternal milk, significance is unknown.
Adverse Effects/Warnings – In dogs, hepatic toxicity appears to be the most significant adverse effect. Approximately 10% of dogs receiving 10 mg/kg/day and 5% of dogs receiving 5 mg/kg/day develop hepatic toxicosis serious enough to discontinue (at least temporarily) treatment. Hepatic injury is determined by an increased ALT activity. Anorexia is often the symptomatic marker for toxicity and usually occurs in the second month of treatment. Some dogs given itraconazole at the higher dosage rate (10 mg/kg/day) may develop ulcerative skin lesions/vasculitis and limb edema that may require dosage reduction.
In cats, adverse effects appear to be dose related. GI effects (anorexia, weight loss, vomiting), hepatotoxicity (increased ALT, jaundice) and depression and have been noted. Should adverse effects occur and ALT is elevated, the drug should be discontinued. Once ALT levels return to normal and other adverse effects have diminished, and if necessary, the drug may be restarted at a lower dosage or longer dosing interval with intense monitoring.
Overdosage/Acute Toxicity – There is very limited information on the acute toxicity of itraconazole. Giving oral antacids may help reduce absorption. If a large overdose occurs, consider gut emptying and give supportive therapy as required. Itraconazole is not removed by dialysis. In chronic toxicity studies, dogs receiving 40 mg/kg PO daily for 3 months demonstrated no overt toxicity.
Drug Interactions – Itraconazole requires an acidic environment for maximal absorption, therefore antacids, Histamine2-blockers (cimetidine, ranitidine, etc) or didanosine will cause marked reduction in absorption of itraconazole. Didanosine must not be taken concurrently with itraconazole, the others (noted above), if required, should be given two hours after itraconazole dose. Itraconazole may cause increased prothrombin times in patients receiving warfarin or other coumarin anticoagulants. Rifampin may enhance the rate of metabolism of itraconazole; itraconazole dosage adjustment may be required. Itraconazole may decrease the metabolism of phenytoin or cyclosporine. Veterinary significance is unclear. Itraconazole may increase the risks of cardiovascular effects occurring if used concomitantly with either terfenadine or astemizole. If itraconazole is required, it is best to switch to another antihistamine. Itraconazole may increase serum digoxin concentrations; monitor serum digoxin levels. Itraconazole may increase the serum levels of oral antidiabetic agents (e.g.,chlorpropamide, glipizide, etc.) which may result in hypoglycemia. Elevated concentrations of cisapride with resultant ventricular arrhythmias may result if coadministered with ketoconazole, itraconazole, IV miconazole or troleandomycin. At present, the manufacturer states that cisapride should not be used with these drugs.
Laboratory Considerations – Itraconazole may cause hypokalemia or increases in liver function tests in a small percentage of patients.
a) 3 mg/kg twice a day (Legendre 1993)
A method to prepare an itraconazole suspension has been provided by the manufacturer with the following caveats: 1) No bioavailability data available; 2) Use only if no other alternative.
Empty 24 (twenty four) 100 mg capsules into a glass mortar. Add 4 to 5 ml of 95% ethyl alcohol USP and let stand 3 to 4 minutes to soften. Grind to a heavy paste; this will leave a powder when the alcohol dries. Slowly triturate with 15 ml of simple syrup. Transfer to a 60 ml amber bottle and continue to rinse mortar with simple syrup to get 60 ml. Shake Well and Refrigerate. Discard after 35 days. Janssen Corp.: 1-800-526-7736
Monitoring Parameters – 1) Clinical Efficacy; 2) With long-term therapy, routine liver function tests are recommended (monthly ALT) 3) Appetite 4) Physical assessment for ulcerative skin lesions in dogs
Client Information – Compliance with treatment recommendations must be stressed. Have clients report any potential adverse effects. Give with food.
Dosage Forms/Preparations/FDA Approval Status/Withholding Times –
Veterinary-Approved Products: None
Itraconazole Oral Capsules 100 mg; Sporanox® (Janssen); (Rx)