Brands, Medical Use, Clinical Data
Drug Category
Dosage Forms
- Tablets
- Shampoo
- Cream
- Suspension
Brands / Synonyms
Extina; Fungarest; Fungoral; Ketocanazole; Ketoconazol; Ketoconazol [Inn-Spanish]; Ketoconazole [Usan:Ban:Inn:Jan]; Ketoconazolum [Inn-Latin]; Ketoderm; Ketoisdin; Ketozole; Nizoral; Nizoral a-D; Nizoral a-D Shampoo; Nizoral Cream; Nizoral Shampoo; Orifungal; Orifungal M; Panfungol
Indications
For the treatment of the following systemic fungal infections: candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis.
Pharmacology
Ketoconazole, like clotrimazole, fluconazole, itraconazole, and miconazole, is an imidazole antifungal agent.
Mechanism of Action
Ketoconazole interacts with 14-α demethylase, a cytochrome P-450 enzyme necessary for the conversion of lanosterol to ergosterol. This results in inhibition of ergosterol synthesis and increased fungal cellular permeability. Other mechanisms may involve the inhibition of endogenous respiration, interaction with membrane phospholipids, inhibition of yeast transformation to mycelial forms, inhibition of purine uptake, and impairment of triglyceride and/or phospholipid biosynthesis. Ketoconazole can also inhibit the synthesis of thromboxane and sterols such as aldosterone, cortisol, and testosterone.
Absorption
Moderate
Toxicity
Hepatotoxicity, LD50=86 mg/kg (orally in rat)
Biotrnasformation / Drug Metabolism
Hepatic
Contraindications
Tablets and Shampoo
Ketoconazole is contraindicated in patients who have shown hypersensitivity to the drug or excipients of the
formulation(s).
Tablets
Coadministration of terfenadine or astemizole with ketoconazole tablets is contraindicated.
Concomitant administration of NIZORAL® Tablets with oral triazolam is contraindicated.
NIZORAL® is contraindicated in patients who have shown hypersensitivity
to the drug.
Drug Interactions
Ketoconazole is a potent inhibitor of the cytochrome P450 3A4 enzyme system. Coadministration of
NIZORAL® Tablets and drugs primarily metabolized by the cytochrome P450 3A4
enzyme system may result in increased plasma concentrations of the drugs that could increase or prolong both
therapeutic and adverse effects. Therefore, unless otherwise specified, appropriate dosage adjustments may be
necessary. The following drug interactions have been identified involving NIZORAL® Tablets and other drugs metabolized by the cytochrome P450 3A4 enzyme system:
Ketoconazole tablets inhibit the metabolism of terfenadine, resulting in an increased plasma concentration of
terfenadine and a delay in the elimination of its acid metabolite. The increased plasma concentration of terfenadine
or its metabolite may result in prolonged QT intervals.
Pharmacokinetic data indicate that oral ketoconazole inhibits the metabolism of astemizole, resulting in elevated
plasma levels of astemizole and its active metabolite desmethylastemizole which may prolong QT intervals.
Coadministration of astemizole with ketoconazole tablets is therefore contraindicated.
Human pharmacokinetics data indicate that oral ketoconazole potently inhibits the metabolism of cisapride
resulting in a mean eight-fold increase in AUC of cisapride. Data suggest that coadministration of oral ketoconazole
and cisapride can result in prolongation of the QT interval on the ECG. Therefore concomitant administration of
ketoconazole tablets with cisapride is contraindicated.
Ketoconazole tablets may alter the metabolism of cyclosporine, tacrolimus, and methylprednisolone, resulting in
elevated plasma concentrations of the latter drugs. Dosage adjustment may be required if cyclosporine, tacrolimus, or
methylprednisolone are given concomitantly with NIZORAL® Tablets.
Coadministration of NIZORAL® Tablets with midazolam or triazolam has
resulted in elevated plasma concentrations of the latter two drugs. This may potentiate and prolong hypnotic and
sedative effects, especially with repeated dosing or chronic administration of these agents. These agents should not
be used in patients treated with NIZORAL® Tablets. If midazolam is
administered parenterally, special precaution is required since the sedative effect may be prolonged.
Rare cases of elevated plasma concentrations of digoxin have been reported. It is not clear whether this was due
to the combination of therapy. It is, therefore, advisable to monitor digoxin concentrations in patients receiving
ketoconazole.
When taken orally , imidazole compounds like ketoconazole may enhance the anticoagulant effect of coumarin-like
drugs. In simultaneous treatment with imidazole drugs and coumarin drugs, the anticoagulant effect should be
carefully titrated and monitored.
Because severe hypoglycemia has been reported in patients concomitantly receiving oral miconazole (an imidazole)
and oral hypoglycemic agents, such a potential interaction involving the latter agents when used concomitantly with
ketoconazole tablets (an imidazole) can not be ruled out.
Concomitant administration of ketoconazole tablets with phenytoin may alter the metabolism of one or both of the
drugs. It is suggested to monitor both ketoconazole and phenytoin.
Concomitant administration of rifampin with ketoconazole tablets reduces the blood levels of the latter. INH
(Isoniazid) is also reported to affect ketoconazole concentrations adversely. These drugs should not be given
concomitantly.
After the coadministration of 200 mg oral ketoconazole twice daily and one 20 mg dose of loratadine to 11
subjects, the AUC and Cmax of loratadine averaged 302% (± 142 S.D.) and 251% (± 68 S.D.),
respectively, of those obtained after co-treatment with placebo. The AUC and Cmax of
descarboethoxyloratadine, an active metabolite, averaged 155% (± 27 S.D.) and 141% (± 35 S.D.),
respectively. However, no related changes were noted in the QT0 on ECG taken at 2, 6, and 24 hours after
the coadministration. Also, there were no clinically significant differences in adverse events when loratadine was
administered with or without ketoconazole.
Rare cases of a disulfiram-like reaction to alcohol have been reported. These experiences have been characterized
by flushing, rash, peripheral edema, nausea, and headache. Symptoms resolved within a few hours.
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