indication

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.

toxicity

Hepatotoxicity, LD₅₀=86 mg/kg (orally in rat)

biotransformation

Hepatic

absorption

Moderate

half life

2 hours

drug interactions

Acenocoumarol: Ketoconazole may increase the anticoagulant effect of acenocoumarol.

Alfentanil: Ketoconazole may increase the effect and toxicity of alfentanil.

Alfuzosin: The antifungal increases the effect of alfuzosin

Almotriptan: This potent CYP3A4 inhibitor increases the effect and toxicity of the triptan

Alprazolam: Ketoconazole may increase the effect of the benzodiazepine, alprazolam.

Aluminium: Aluminum-containing antacids may decrease the effect of ketoconazole.

Amitriptyline: Ketoconazole, a moderate CYP2D6 inhibitor, may increase the serum concentration of amitriptyline by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of amitriptyline if ketoconazole is initiated, discontinued or dose changed.

Anisindione: Ketoconazole may increase the anticoagulant effect of anisindione.

Aprepitant: This CYP3A4 inhibitor increases the effect and toxicity of aprepitant

Aripiprazole: Ketoconazole may increase the effect of aripiprazole.

Astemizole: Increased risk of cardiotoxicity and arrhythmias

Atorvastatin: Increased risk of myopathy/rhabdomyolysis

Bosentan: Ketoconazole may increase the effect and toxicity of bosentan.

Bromazepam: Ketoconazole may increase the serum concentration of bromazepam by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of bromazepam if ketoconazole is initiated, discontinued or dose changed.

Budesonide: Ketoconazole may increase levels/effect of budesonide.

Calcium: Calcium-containing antacids may decrease the absorption of ketoconazole.

Carbamazepine: Ketoconazole may increase the effect of carbamazepine.

Cerivastatin: Increased risk of myopathy/rhabdomyolysis

Chlordiazepoxide: Ketoconazole may increase the effect of the benzodiazepine, chlordiazepoxide.

Ciclesonide: Increased effects/toxicity of ciclesonide

Cilostazol: Ketoconazole may increase the effect of cilostazol.

Cimetidine: The H2-receptor antagonist, cimetidine, may decrease the absorption of ketoconazole.

Cinacalcet: Ketoconazole may increase the effect and toxicity of cinacalcet.

Cisapride: Increased risk of cardiotoxicity and arrhythmias

Clonazepam: Ketoconazole may increase the effect of the benzodiazepine, clonazepam.

Clorazepate: Ketoconazole may increase the effect of the benzodiazepine, clorazepate.

Conivaptan: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Conivaptan. Concomitant use of conivaptan with strong CYP3A4 inhibitors (e.g., azole antifungals) is contraindicated.

Cyclosporine: Ketoconazole may increase the effect of cyclosporine.

Dantrolene: Ketoconazole may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if ketoconazole is initiated, discontinued or dose changed.

Darifenacin: This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism

Diazepam: Ketoconazole may increase the effect of the benzodiazepine, diazepam.

Dicumarol: Ketoconazole may increase the anticoagulant effect of dicumarol.

Dihydroergotamine: Possible ergotism and severe ischemia with this combination

Docetaxel: Ketoconazole may increase the serum levels and toxicity of docetaxel.

Dofetilide: This strong CYP3A4 inhibitor increases the effect and toxicity of dofetilide

Eletriptan: This potent CYP3A4 inhibitor increases the effect and toxicity of the triptan

Eplerenone: Ketoconazole, a CYP3A4 inhibitor, may increase the effect and toxicity of eplerenone.

Ergotamine: Possible ergotism and severe ischemia with this combination.

Erlotinib: This CYP3A4 inhibitor increases levels/toxicity of erlotinib

Esomeprazole: The proton pump inhibitor, esomeprazole, may decrease the absorption of ketoconazole.

Estazolam: Ketoconazole may increase the effect of the benzodiazepine, estazolam.

Ethinyl Estradiol: This anti-infectious agent could decrease the effect of the oral contraceptive

Everolimus: Ketoconazole may increase everolimus levels/toxicity.

Famotidine: The H2-receptor antagonist, famotidine, may decrease the absorption of ketoconazole.

Fentanyl: Ketoconazole may increase levels/toxicity of fentanyl.

Flurazepam: Ketoconazole may increase the effect of the benzodiazepine, flurazepam.

Galantamine: Ketoconazole increases the effect and toxicity of galantamine

Gefitinib: This CYP3A4 inhibitor increases levels/toxicity of gefitinib

Glimepiride: Ketoconazole increases the effect of rosiglitazone

Halazepam: Ketoconazole may increase the effect of the benzodiazepine, halazepam.

Haloperidol: Ketoconazole may increase the effect and toxicity of haloperidol.

Imatinib: Ketoconazole may increase the levels of imatinib.

Imipramine: Ketoconazole, a moderate CYP2D6 inhibitor, may increase the serum concentration of imipramine by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of imipramine if ketoconazole is initiated, discontinued or dose changed.

Indinavir: Indinavir may increase the serum concentration of ketoconazole. Ketoconazole may increase the serum concentration of indinavir. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of both agents if either agent is initiated, discontinued or dose changed.

Irinotecan: Ketoconazole increases the effect and toxicity of irinotecan

Isoniazid: Isoniazid decreases the effect of ketoconazole

Lansoprazole: The proton pump inhibitor, lansoprazole, may decrease the absorption of ketoconazole.

Lovastatin: Increased risk of myopathy/rhabdomyolysis

Magnesium oxide: The antacid, magnesium oxide, may decrease the effect of ketoconazole by decreasing its absorption.

Mestranol: This anti-infectious agent could decrease the effect of the oral contraceptive

Methylprednisolone: The imidazole, ketoconazole, may increase the effect and toxicity of the corticosteroid, methylprednisolone.

Midazolam: Ketoconazole may increase the effect of the benzodiazepine, midazolam.

Nevirapine: Nevirapine, a strong CYP3A4 inducer, may decrease the serum concentration of ketoconazole by increasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of ketoconazole if nevirapine is initiated, discontinued or dose changed.

Nizatidine: The H2-receptor antagonist, nizatidine, may decrease the absorption of ketoconazole.

Nortriptyline: Ketoconazole, a moderate CYP2D6 inhibitor, may increase the serum concentration of nortriptyline by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of nortriptyline if ketoconazole is initiated, discontinued or dose changed.

Omeprazole: The proton pump inhibitor, omeprazole, may decrease the absorption of ketoconazole.

Pantoprazole: The proton pump inhibitor, pantoprazole, may decrease the absorption of ketoconazole.

Pimozide: Increased risk of cardiotoxicity and arrhythmias

Pioglitazone: Ketoconazole increases the effect of pioglitazone

Prednisolone: The imidazole, ketoconazole, may increase the effect and toxicity of the corticosteroid, prednisolone.

Prednisone: The imidazole, ketoconazole, may increase the effect and toxicity of the corticosteroid, prednisone.

Quazepam: Ketoconazole may increase the effect of the benzodiazepine, quazepam.

Quetiapine: Ketoconazole may increase the therapeutic and adverse effects of quetiapine.

Quinidine: Ketoconazole may increase the effect and toxicity of quinidine.

Quinidine barbiturate: Ketoconazole may increase the effect and toxicity of quinidine barbiturate.

Rabeprazole: The proton pump inhibitor, rabeprazole, may decrease the absorption of ketoconazole.

Ramelteon: Ketoconazole may increase the serum levels and toxicity of ramelteon.

Ranitidine: The H2-receptor antagonist, ranitidine, may decrease the absorption of ketoconazole.

Ranolazine: Increased levels of ranolazine - risk of toxicity

Rifampin: Rifampin may decrease the effect of ketoconazole.

Ritonavir: Ketoconazole may increase the effect and toxicity of ritonavir.

Rivaroxaban: Use of rivaroxaban with agents that are strong inhibitors of both CYP3A4 and P-glycoproteins are contraindicated.

Rosiglitazone: Ketoconazole increases the effect of rosiglitazone

Saquinavir: Ketoconazole may increase the effect and toxicity of saquinavir.

Sibutramine: Ketoconazole increases the levels and toxicity of sibutramine

Sildenafil: Ketoconazole may increase the effect and toxicity of sildenafil.

Simvastatin: Increased risk of myopathy/rhabdomyolysis

Sirolimus: Ketoconazole may increase the effect and toxicity of sirolimus.

Solifenacin: This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism

Sucralfate: Sucralfate may decrease the absorption of ketoconazole.

Sunitinib: Possible increase in sunitinib levels

Tacrine: The metabolism of Tacrine, a CYP1A2 substrate, may be reduced by strong CYP1A2 inhibitors such as Ketoconazole. Consider modifying therapy to avoid Tacrine toxicity. Monitor the efficacy and toxicity of Tacrine if Ketoconazole is initiated, discontinued or if the dose is changed.

Tacrolimus: The antifungal, Ketoconazole, may increase serum concentrations of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Ketoconzole therapy is initiated, discontinued or altered.

Tadalafil: Ketoconazole may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Tamoxifen: Ketoconazole may increase the serum concentration of Tamoxifen by decreasing its metabolism and clearance. Ketoconazole may also decrease the therapeutic effect of Tamoxifen by decreasing active metabolite production. Monitor for changes in the therapeutic/adverse effects of Tamoxifen if Ketoconazole is initiated, discontinued or dose changed.

Tamsulosin: Ketoconazole, a CYP3A4/2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4/2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Ketoconzole is initiated, discontinued, or dose changed.

Telithromycin: Ketoconazole may increase the plasma concentration of Telithromycin. Consider alternate therapy or monitor therapeutic/adverse effects.

Temsirolimus: Ketoconazole may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Teniposide: The strong CYP3A4 inhibitor, Ketoconazole, may decrease the metabolism and clearance of Teniposide, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Teniposide if Ketoconazole is initiated, discontinued or dose changed.

Terfenadine: Increased risk of cardiotoxicity and arrhythmias

Thiothixene: The strong CYP1A2 inhibitor, Ketoconazole, may decrease the metabolism and clearance of Thiothixene, a CYP1A2 substrate. Consider alternate therapy or monitor for changes in Thiothixene therapeutic and adverse effects if Ketoconazole is initiated, discontinued or dose changed.

Tiagabine: The strong CYP3A4 inhibitor, Ketoconazole, may decrease the metabolism and clearance of Tiagabine, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Tiagabine if Ketoconazole is initiated, discontinued or dose changed.

Tipranavir: Tipranavir may increase the serum concentration of Ketoconazole.

Tizanidine: Ketoconazole may decrease the metabolism and clearance of Tizanidine. Consider alternate therapy or use caution during co-administration.

Tolbutamide: Ketoconazole, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Tolbutamide, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in Tolbutamide therapeutic and adverse effects if Ketoconazole is initiated, discontinued or dose changed.

Tolterodine: Ketoconazole may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.

Topotecan: The p-glycoprotein inhibitor, Ketoconazole, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.

Torasemide: Ketoconazole, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Ketoconazole is initiated, discontinued or dose changed.

Tramadol: Ketoconazole may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Ketoconazole may decrease the effect of Tramadol by decreasing active metabolite production.

Trazodone: The CYP3A4 inhibitor, Ketoconazole, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. Consider alternate therapy or monitor for changes in Trazodone efficacy/toxicity if Ketoconazole is initiated, discontinued or dose changed.

Triazolam: Ketoconazole may increase the effect of the benzodiazepine, triazolam.

Trimethoprim: The strong CYP2C9 inhibitor, Ketoconazole, may decrease the metabolism and clearance of Trimethoprim, a CYP2C9 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimethoprim if Ketoconazole is initiated, discontinued or dose changed.

Trimipramine: The strong CYP3A4 inhibitor, Ketoconazole, may decrease the metabolism and clearance of Trimipramine, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimipramine if Ketoconazole is initiated, discontinued or dose changed.

Valdecoxib: Ketoconazole may increase the effect and toxicity of valdecoxib.

Vardenafil: Ketoconazole, a potent CYP3A4 inhibitor, may decrease the metabolism and clearance of Vardenafil. Concomitant therapy is contraindicated.

Venlafaxine: Ketoconazole, a CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Ketoconazole is initiated, discontinued, or dose changed.

Verapamil: Ketoconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of Veramapil, a CYP3A4 substrate, by decreasing its metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Verapamil if Ketoconazole is initiated, discontinued or dose changed.

Vilazodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vilazodone. imit maximum adult vilazodone dose to 20 mg/day in patients receiving strong CYP3A4 inhibitors.

Vinblastine: Ketoconazole, a strong CYP3A4 inhibitor, may decrease the metabolism of Vinblastine. Consider alternate therapy to avoid Vinblastine toxicity. Monitor for changes in the therapeutic/adverse effects of Vinblastine if Ketoconazole is initiated, discontinued or dose changed.

Vincristine: Ketoconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of Vincristine by decreasing its metabolism. Consider alternate therapy to avoid Vincristine toxicity. Monitor for changes in the therapeutic and adverse effects of Vincristine if Ketoconazole is initiated, discontinued or dose changed.

Vinorelbine: Ketoconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of Vinorelbine by decreasing its metabolism. Consider alternate therapy to avoid Vinorelbine toxicity. Monitor for changes in the therapeutic and adverse effects of Vinorelbine if Ketoconazole is initiated, discontinued or dose changed.

Voriconazole: Ketoconazole, a strong CYP2C9 inhibitor, may increase the serum concentration of voriconazole by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of voriconazole if ketoconazole is initiated, discontinued or dose changed.

Warfarin: Ketoconazole, a strong CYP2C9 inhibitor, may decrease the metabolism of warfarin. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of warfarin if ketoconazole is initiated, discontinued or dose changed.

Zafirlukast: Ketoconazole, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of zafirlukast. Consider alternate therapy or monitor for changes in zafirlukast therapeutic and adverse effects if ketoconazole is initiated, discontinued or dose changed.

Ziprasidone: Ketoconazole increases the effect and toxicity of ziprasidone

Zolpidem: Ketoconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of zolpidem by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zolpidem if ketoconazole is initiated, discontinued or dose changed.

Zonisamide: Ketonconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if ketoconazole is initiated, discontinued or dose changed.

Zopiclone: Ketonconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if ketoconazole is initiated, discontinued or dose changed.