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Chemistry – An imidazole antifungal agent, ketoconazole occurs as a white to slightly beige powder with pKas of 2.9 and 6.5. It is practically insoluble in water.
Storage/Stability/Compatibility – Ketoconazole tablets should be stored at room temperature in well-closed containers.
Pharmacology – At usual doses and serum concentrations, ketoconazole is fungistatic against susceptible fungi. At higher concentrations for prolonged periods of time or against very susceptible organisms, ketoconazole may be fungicidal. It is believed that ketoconazole increases cellular membrane permeability and causes secondary metabolic effects and growth inhibition. The exact mechanism for these effects have not been determined, but may be due to ketoconazole interfering with ergosterol synthesis. The fungicidal action of ketoconazole may be due to a direct effect on cell membranes.
Ketoconazole has activity against most pathogenic fungi, including Blastomyces, Coccidiodes, Cryptococcus, Histoplasma, Microsporum and Trichophyton. Higher levels are necessary to treat most strains of Aspergillus and Sporothrix. Resistance to ketoconazole has been documented for some strains of Candida albicans.
Ketoconazole also has in vitro activity against Staphylococcus aureas and epidermidis, Nocardia, enterococci, and herpes simplex virus types 1 & 2. The clinical implications of this activity are unknown.
Ketoconazole also has endocrine effects as steroid synthesis is directly inhibited by blocking several P-450 enzyme systems. Measurable reductions in testosterone or cortisol synthesis can occur at dosages used for antifungal therapy, but higher dosages are generally required to reduce levels of testosterone or cortisol to be clinically useful in the treatment of prostatic carcinoma or hyperadrenocorticism. Effects on mineralocorticoids are negligible.
Uses/Indications – Because of its comparative lack of toxicity when compared to amphotericin B, oral administration and relatively good efficacy, ketoconazole is used to treat several fungal infections in dogs, cats and other small species. See the Dosage section or Pharmacology section for specifics. Although newer antifungal agents (fluconazole, itraconazole) have advantages over ketoconazole–usually less toxicity and/or enhanced efficacy–ketoconazole is significantly less expensive.
Ketoconazole is also used clinically for the medical treatment of hyperadrenocorticism in dogs (and sometimes cats).
Pharmacokinetics – Although it is reported that ketoconazole is well absorbed after oral administration, oral bioavailability of ketoconazole tablets in dogs is highly variable. One study (Baxter et al. 1986) in six normal dogs, found bioavailabilities ranging from 0.04-0.89 (4-89%) after 400 mg (19.5 – 25.2 mg/kg) were administered to fasted dogs. Peak serum concentrations occur between 1 and 4.25 hours after dosing and peak serum levels in the 6 dogs studied ranged from 1.1 – 45.6 micrograms/ml. This wide interpatient variation may have significant clinical implications from both a toxicity and efficacy standpoint, particularly since ketoconazole is often used in life-threatening infections and assays for measuring serum levels are not readily available.
Ketoconazole absorption is enhanced in an acidic environment and should not be administered (at the same time) with H2 blockers or antacids (see Drug Interactions below). Whether to administer ketoconazole with meals or during a fasted state to maximize absorption is controversial. The manufacturer recommends giving with food in human patients. Dogs or cats who develop anorexia/vomiting during therapy may benefit from administration with meals.
After absorption, ketoconazole is distributed into the bile, cerumen, saliva, urine, synovial fluid and CSF. CSF levels are generally less than 10% of those found in the serum, but may be increased if the meninges are inflamed. High levels of the drug are found in the liver, adrenals and pituitary gland, while more moderate levels are found in the kidneys, lungs, bladder, bone marrow and myocardium. At usual doses (10 mg/kg), attained levels are probably inadequate in the brain, testis and eyes to treat most infections; higher dosages are required. Ketoconazole is 84-99% bound to plasma proteins and crosses the placenta (at least in rats). The drug is found in bitch’s milk.
Ketoconazole is metabolized extensively by the liver into several inactive metabolites. These metabolites are excreted primarily into the feces via the bile. About 13% of a given dose is excreted into the urine and only 2-4% of the drug is excreted unchanged in the urine. Half-life in dogs is about 1-6 hours (avg. 2.7 hours).
Contraindications/Precautions/Reproductive Safety – Ketoconazole is contraindicated in patients with know hypersensitivity to it. It should be used with caution in patients with hepatic disease or thrombocytopenia.
Ketoconazole is a known teratogen and embryotoxin in rats. There have been reports of mummified fetuses and stillbirths in dogs who have been treated. Ketoconazole should not be considered absolutely contraindicated in pregnant animals, however, as it is often used in potentially life-threatening infections. The benefits of therapy should be weighed against the potential risks.
Ketoconazole may cause infertility in male dogs by decreasing testosterone synthesis. Testosterone production rebounds once the drug is discontinued.
Adverse Effects/Warnings – Gastrointestinal symptoms of anorexia, vomiting, and/or diarrhea are the most common adverse effects seen with ketoconazole therapy. Anorexia may be minimized by dividing the dose and/or giving with meals. Hepatic toxicity consisting of cholangiohepatitis and increased liver enzymes has been reported with ketoconazole, and may be either idiosyncratic in nature or a dose-related phenomenon. Cats may be more prone to developing hepatoxicity than dogs. Thrombocytopenia has also been reported with ketoconazole therapy, but is rarely encountered. A reversible lightening of haircoat may also occur in patients treated with ketoconazole.
Ketoconazole has a transient dose-related suppressant effect on gonadal and adrenal steroid synthesis. Doses as low as 10 mg/kg depressed serum testosterone levels in dogs within 3-4 hours after dosing, but levels returned to normal within 10 hours. Doses of 30 mg/kg/day have been demonstrated to suppress serum cortisol levels in dogs with hyperadrenocorticism (see Dosages section). Dogs undergoing high dose antifungal therapy may need additional glucocorticoid support during periods of acute stress.
Overdosage/Acute Toxicity – No reports of acute toxicity associated with overdosage were located. The oral LD50 in dogs after oral administration is >500 mg/kg. Should an acute overdose occur, the manufacturer recommends employing supportive measures, including gastric lavage with sodium bicarbonate.
Drug Interactions – Antacids, anticholinergics (propantheline, etc.) H2 blockers (e.g., cimetidine, ranitidine)increase stomach pH and may inhibit the absorption of ketoconazole. If these agents must be used with ketoconazole, they should be given 2 hours after the ketoconazole dose. Mitotane and ketoconazole are not recommended to be used together to treat hyperadrenocorticism as the adrenolytic effects of mitotane may be inhibited by ketoconazole’s inhibition of cytochrome P450 enzymes. Ketoconazole may increase the anticoagulant effects of warfarin. Prothrombin times should be monitored and dosage adjustments made as required. Phenytoinand ketoconazole may alter the metabolism of each other. Phenytoin levels and ketoconazole efficacy/toxicity should be monitored. Ketoconazole alters the disposition and extends the duration of activity of methylprednisolone.
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.
Ketoconazole may decrease serum theophylline concentrations in some patients; theophylline levels should be monitored. Ethanol may interact with ketoconazole and produce a disulfiram-like reaction (vomiting). Rifampinmay decrease the serum levels of ketoconazole if administered together. If these drugs must be used together, ketoconazole dosages may need to be adjusted. Ketoconazole may exhibit synergism with acyclovir against herpes simplex viruses. Cyclosporin blood levels may be increased by ketoconazole. Because ketoconazole can cause hepatoxicity, it should be used cautiously with other hepatotoxic agents.
Doses – (Note: Clinical antifungal effects may require 10-14 days of therapy)
For susceptible fungal infections:
a) 10 mg/kg PO daily (McConnell and Hughey 1987)
Monitoring Parameters –
1) Liver enzymes with chronic therapy (at least every 2 months; some clinicians say monthly)
2) CBC with platelets
3) Efficacy and other adverse effects
Client Information – If animal develops gastrointestinal symptoms divide dose and administer with meals. Long-term therapy with adequate dosing compliance is usually necessary for successful results; clients must be committed for both the financial and dosing burdens associated with therapy.
Dosage Forms/Preparations/FDA Approval Status/Withholding Times –
Veterinary-Approved Products: None
Ketoconazole 200 mg Tablets (scored); Nizoral® (Janssen); (Rx)