KETOCONAZOLE

Chemistry - An imidazole antifungal agent, ketoconazole occurs as a white to slightly beigepowder 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 inwell-closed containers.

Pharmacology - KETOCONAZOLE

At usual doses and serum concentrations, ketoconazole is fungistatic againstsusceptible fungi. At higher concentrations for prolonged periods of time or against very susceptible organisms, ketoconazole may be fungicidal. It is believed that ketoconazole increases cel ularmembrane permeability and causes secondary metabolic effects and growth inhibition. The exactmechanism for these effects have not been determined, but may be due to ketoconazole interferingwith ergosterol synthesis. The fungicidal action of ketoconazole may be due to a direct effect on cellmembranes.
Ketoconazole has activity against most pathogenic fungi, including Blastomyces, Coccidiodes,
Cryptococcus, Histoplasma, Microsporum and Trichophyton. Higher levels are necessary to treatmost strains of Aspergillus and Sporothrix. Resistance to ketoconazole has been documented forsome 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 areunknown.
Ketoconazole also has endocrine effects as steroid synthesis is directly inhibited by blockingseveral P-450 enzyme systems. Measurable reductions in testosterone or cortisol synthesis canoccur at dosages used for antifungal therapy, but higher dosages are generally required to reducelevels of testosterone or cortisol to be clinically useful in the treatment of prostatic carcinoma orhyperadrenocorticism. 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 fungalinfections in dogs, cats and other small species. See the Dosage section or Pharmacology sectionfor specifics. Although newer antifungal agents (fluconazole, itraconazole) have advantages overketoconazole?usually less toxicity and/or enhanced efficacy?ketoconazole is significantly lessexpensive.
Ketoconazole is also used clinically for the medical treatment of hyperadrenocorticism in dogs(and sometimes cats).

Pharmacokinetics - KETOCONAZOLE

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 etal. 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 1and 4.25 hours after dosing and peak serum levels in the 6 dogs studied ranged from 1.1 - 45.6micrograms/ml. This wide interpatient variation may have significant clinical implications from botha toxicity and efficacy standpoint, particularly since ketoconazole is often used in life-threateninginfections and assays for measuring serum levels are not readily available.
Ketoconazole absorption is enhanced in an acidic environment and should not be administered (atthe same time) with H2 blockers or antacids (see Drug Interactions below). Whether to administerketoconazole with meals or during a fasted state to maximize absorption is controversial. Themanufacturer recommends giving with food in human patients. Dogs or cats who developanorexia/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 ifthe meninges are inflamed. High levels of the drug are found in the liver, adrenals and pituitarygland, while more moderate levels are found in the kidneys, lungs, bladder, bone marrow andmyocardium. At usual doses (10 mg/kg), attained levels are probably inadequate in the brain, testisand eyes to treat most infections; higher dosages are required. Ketoconazole is 84-99% bound toplasma 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. Thesemetabolites are excreted primarily into the feces via the bile. About 13% of a given dose is excretedinto the urine and only 2-4% of the drug is excreted unchanged in the urine. Half-life in dogs isabout 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 hepaticdisease 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 consideredabsolutely 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 arethe most common adverse effects seen with ketoconazole therapy. Anorexia may be minimized bydividing the dose and/or giving with meals. Hepatic toxicity consisting of cholangiohepatitis andincreased liver enzymes has been reported with ketoconazole, and may be either idiosyncratic innature or a dose-related phenomenon. Cats may be more prone to developing hepatoxicity thandogs. Thrombocytopenia has also been reported with ketoconazole therapy, but is rarelyencountered. A reversible lightening of haircoat may also occur in patients treated withketoconazole.
Ketoconazole has a transient dose-related suppressant effect on gonadal and adrenal steroidsynthesis. Doses as low as 10 mg/kg depressed serum testosterone levels in dogs within 3-4 hoursafter dosing, but levels returned to normal within 10 hours. Doses of 30 mg/kg/day have beendemonstrated to suppress serum cortisol levels in dogs with hyperadrenocorticism (see Dosagessection). Dogs undergoing high dose antifungal therapy may need additional glucocorticoidsupport 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 overdoseoccur, the manufacturer recommends employing supportive measures, including gastric lavage withsodium bicarbonate.

Drug Interactions

Antacids, anticholinergics (propantheline, etc.) H2 blockers (e.g., cimetidine, ranitidine) increase stomach pH and may inhibit the absorption of ketoconazole. Ifthese agents must be used with ketoconazole, they should be given 2 hours after the ketoconazoledose.
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 ofcytochrome P450 enzymes.
Ketoconazole may increase the anticoagulant effects of warfarin. Prothrombin times should bemonitored and dosage adjustments made as required.
Phenytoin and ketoconazole may alter the metabolism of each other. Phenytoin levels and ketoconazole efficacy/toxicity should be monitored. Ketoconazole alters the disposition and extendsthe duration of activity of methylprednisolone.
Elevated concentrations of cisapride with resultant ventricular arrhythmias may result ifcoadministered with ketoconazole, itraconazole, IV miconazole or troleandomycin. At present, themanufacturer states that cisapride should not be used with these drugs.
Ketoconazole may decrease serum theophylline concentrations in some patients; theophyllinelevels should be monitored.
Ethanol may interact with ketoconazole and produce a disulfiram-like reaction (vomiting).
Rifampin may decrease the serum levels of ketoconazole if administered together. If these drugsmust 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.