Ketoconazole (Monograph)

Brand name: Nizoral
Drug class: Azoles

Medically reviewed by Drugs.com on Apr 10, 2024. Written by ASHP.

Warning

Use only when other effective antifungals not available or not tolerated and potential benefits of oral ketoconazole outweigh potential risks.²⁶³ ³⁸⁴
Serious hepatotoxicity has occurred in patients receiving oral ketoconazole, including cases that were fatal or required liver transplantation.²⁶³ ³⁸⁴ Inform patients of the risk and monitor closely.²⁶³ ³⁸⁴ (See Hepatotoxicity under Cautions.)
Concomitant use with certain drugs (cisapride, dofetilide, pimozide, quinidine) contraindicated because increased plasma concentrations of these drugs may occur and can lead to QT interval prolongation, sometimes resulting in life-threatening ventricular tachyarrhythmias such as torsades de pointes.²⁶³ ³⁸⁴ (See Interactions.)

Introduction

Antifungal; azole (imidazole derivative).²⁶³ ³⁸⁴

Uses for Ketoconazole

Blastomycosis

Alternative for treatment of blastomycosis caused by Blastomyces dermatitidis.²²⁰ ²³⁴ ²⁶³ ²⁸⁸ ²⁹¹ ²⁹² ²⁹⁹ ³⁰⁰ ³⁸⁴ ⁴²⁴ Use only if infection is serious or life-threatening, other effective antifungals not available or not tolerated, and potential benefits of oral ketoconazole outweigh potential risks.²⁶³ ³⁸⁴ ⁴⁴⁹ ⁴⁵⁰

Drugs of choice are IV amphotericin B or oral itraconazole;²⁸⁸ ²⁹² ²⁹⁶ ²⁹⁷ ²⁹⁸ ²⁹⁹ ³³² ³³³ ⁴²⁴ ⁴³⁶ oral fluconazole is an alternative.²⁸⁸ ²⁹² ²⁹⁷ ²⁹⁹ ⁴³⁶ ⁴²⁴ Ketoconazole has been used as an alternative,⁴²⁴ but may be less effective.⁴²⁴

Do not use for infections that involve the CNS, including cerebral blastomycosis; ketoconazole CSF concentrations are unpredictable and may be negligible following oral administration, and treatment failures or relapses reported.¹⁹² ²⁶³ ²⁸⁸ ²⁹⁵ ³⁸⁴

Consult current IDSA clinical practice guidelines available at [Web] for additional information on management of blastomycosis.⁴²⁴

Chromomycosis

Alternative for treatment of chromomycosis (chromoblastomycosis) caused by Phialophora;²⁶³ ²⁸⁸ ³³⁵ ³⁸⁴ a response may not be attained in those with more extensive disease.³³⁵ Use only if infection is serious or life-threatening, other effective antifungals not available or not tolerated, and potential benefits of oral ketoconazole outweigh potential risks.²⁶³ ³⁸⁴ ⁴⁴⁹ ⁴⁵⁰

Optimum regimens for chromomycosis not identified.²⁸⁸ ³³⁵ Flucytosine may be a drug of choice used alone or in conjunction with another antifungal (e.g., IV amphotericin B, oral itraconazole).²⁸⁸ ³³⁵

Coccidioidomycosis

Alternative for treatment of coccidioidomycosis caused by Coccidioides immitis.²⁶³ ²⁸⁰ ²⁹² ²⁹³ ³⁰³ ³⁰⁴ ³⁰⁵ ³⁸⁴ ⁴²⁶ Use only if infection is serious or life-threatening, other effective antifungals not available or not tolerated, and potential benefits of oral ketoconazole outweigh potential risks.²⁶³ ³⁸⁴ ⁴⁴⁹ ⁴⁵⁰

Drugs of choice for initial treatment of symptomatic pulmonary, chronic fibrocavitary, or disseminated coccidioidomycosis are oral fluconazole or oral itraconazole;⁴²⁶ ⁴³⁶ ⁴⁴⁰ ⁴⁴¹ IV amphotericin B recommended as an alternative and preferred for initial treatment of severely ill patients who have hypoxia or rapidly progressing disease, for immunocompromised patients, or when azole antifungals cannot be used (e.g., pregnant women).²⁸⁰ ²⁸⁸ ²⁹² ²⁹⁴ ³⁰² ³⁰³ ⁴²⁶ ⁴³⁶ ⁴⁴⁰ ⁴⁴¹

Do not use for fungal infections that involve the CNS, including coccidioidal meningitis; ketoconazole CSF concentrations are unpredictable and may be negligible following oral administration, and treatment failures or relapses reported.²⁶³ ²⁸⁸ ³⁰² ³⁸⁴

Consult current IDSA clinical practice guidelines available at [Web]⁴²⁶ and current CDC, NIH, and IDSA clinical practice guidelines on prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web] for additional information on management of coccidioidomycosis.⁴⁴⁰ ⁴⁴¹

Histoplasmosis

Alternative for treatment of histoplasmosis caused by Histoplasma capsulatum.²³⁴ ²⁶³ ²⁸⁸ ²⁹¹ ²⁹² ²⁹³ ³⁸⁴ ⁴²⁸ Use only if infection is serious or life-threatening, other effective antifungals not available or not tolerated, and potential benefits of oral ketoconazole outweigh potential risks.²⁶³ ³⁸⁴ ⁴⁴⁹ ⁴⁵⁰

IV amphotericin B or oral itraconazole are drugs of choice.⁴²⁸ ⁴³⁶ ⁴⁴⁰ IV amphotericin B preferred for initial treatment of severe, life-threatening infections, especially in immunocompromised patients (including HIV-infected patients).⁴²⁸ ⁴³⁶ ⁴⁴⁰ Other azole antifungals (fluconazole, ketoconazole, posaconazole, voriconazole) considered second-line alternatives to oral itraconazole.⁴²⁸ ⁴³⁶

Consult current IDSA clinical practice guidelines available at [Web]⁴²⁸ and current CDC, NIH, and IDSA clinical practice guidelines on prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web]⁴⁴⁰ ⁴⁴¹ for additional information on management of histoplasmosis.

Paracoccidioidomycosis

Alternative for treatment of paracoccidioidomycosis (South American blastomycosis) caused by Paracoccidioides brasiliensis.²⁶³ ²⁸⁸ ²⁹¹ ³¹¹ ³³⁵ ³⁸⁴ ⁴³⁶ Use only if infection is serious or life-threatening, other effective antifungals not available or not tolerated, and potential benefits of oral ketoconazole outweigh potential risks.²⁶³ ³⁸⁴ ⁴⁴⁹ ⁴⁵⁰

IV amphotericin B is drug of choice for initial treatment of severe paracoccidioidomycosis.²⁸⁸ ²⁹¹ ²⁹³ ³¹⁰ ³¹¹ ³³⁵ ⁴³⁶ Oral itraconazole is drug of choice for less severe or localized infections and for follow-up therapy of severe infections after response has been obtained with IV amphotericin B.²⁸⁸ ²⁹¹ ³³⁵ ⁴³⁶

Dermatophytoses

Was used orally in the past for treatment of dermatophyte infections^{† [off-label]} (e.g., tinea capitis^{† [off-label]}, tinea corporis^{† [off-label]}, tinea pedis^{† [off-label]}, tinea unguium^{† [off-label]} [onychomycosis]^†).²⁹¹ ³²⁴ ³²⁵ No longer recommended and no longer labeled by FDA for these infections.²⁶³ ³⁸⁴ ⁴⁴⁹ ⁴⁵⁰

Do not use for treatment of dermatophyte infections.⁴⁵⁰ Skin and nail fungal infections in otherwise healthy individuals are not life-threatening and risks associated with oral ketoconazole outweigh benefits.⁴⁵⁰

Acanthamoeba Infections

Has been used in conjunction with a topical anti-infective (e.g., miconazole, neomycin, metronidazole, propamidine isethionate) in the treatment of Acanthamoeba keratitis^†.¹³⁴ ¹³⁵ ¹³⁶ ¹³⁷ ¹³⁸ ¹³⁹ ¹⁴⁰ ²²⁵ Optimum therapy for Acanthamoeba keratitis remains to be clearly established, but prolonged local and systemic therapy with multiple anti-infectives and often surgical treatment (e.g., penetrating keratoplasty) usually required.¹³⁴ ¹³⁵ ¹³⁶ ¹³⁷ ¹³⁸ ¹³⁹ ¹⁴⁰

Cushing’s Syndrome

Has been used effectively for palliative treatment of Cushing’s syndrome^† (hypercortisolism), including adrenocortical hyperfunction associated with adrenal or pituitary adenoma or ectopic corticotropin-secreting tumors.¹¹² ¹¹³ ¹¹⁴ ¹⁵¹ ¹⁵⁴ ²²⁴ ³⁴²

Safety and efficacy not established and not labeled by FDA for this use.²⁶³ ³⁸⁴

Hirsutism and Precocious Puberty

Has been used with some success in a limited number of patients for treatment of dysfunctional hirsutism^†.¹¹⁵ ³⁷⁰

Has been used in a limited number of boys for treatment of precocious puberty^†.¹¹⁶ ¹⁸⁵ ¹⁸⁶

Safety and efficacy not established and not labeled by FDA for these uses.²⁶³ ³⁸⁴

Hypercalcemia

Has been used with some success for treatment of hypercalcemia in adults with sarcoidosis^†.³⁶³ ³⁶⁴ ³⁶⁵ ³⁶⁶ ³⁹⁴ ³⁹⁵ Has reduced serum calcium concentrations in some, but not all, patients with sarcoidosis-associated hypercalcemia;³⁶⁴ ³⁶⁵ ³⁶⁶ ³⁹⁴ ³⁹⁵ hypercalcemia and increased serum 1,25-dihydroxyvitamin D concentrations may recur when ketoconazole dosage is decreased or the drug discontinued.³⁶⁵ ³⁶⁶ Considered an alternative in patients who fail to respond to or cannot tolerate corticosteroids.³⁶³ ³⁶⁵ ³⁹³ ³⁹⁴ ³⁹⁵

Has been effective in a few adolescents for treatment of tuberculosis-associated hypercalcemia^†.³⁶⁷

Has been effective in a few infants^† for treatment of idiopathic infantile hypercalcemia and hypercalciuria^†.³⁹²

Safety and efficacy not established and not labeled by FDA for these uses.²⁶³ ³⁸⁴

Prostate Cancer

Because of ketoconazole’s ability to inhibit testicular and adrenal steroid synthesis, the drug has been used in the treatment of advanced prostatic carcinoma^†.¹⁰⁶ ¹⁰⁷ ¹⁰⁸ ¹⁵¹ ¹⁷⁹ ¹⁸⁰ ¹⁸¹ ¹⁸² ¹⁸³ ¹⁸⁴ ²⁸⁴ ²⁸⁵ ²⁸⁶ ³⁶⁸ ³⁶⁹

Safety and efficacy not established and not labeled by FDA for this use.²⁶³ ³⁸⁴

Ketoconazole Dosage and Administration

Administration

Oral Administration

Administer orally.²⁶³ ³⁸⁴

Patients receiving a drug that decreases gastric acid output or increases gastric pH: Take ketoconazole tablets with an acidic beverage (e.g., non-diet cola) and take the acid-reducing drug at least 1 hour before or 2 hours after ketoconazole.³⁸⁴ (See Drugs Affecting Gastric Acidity under Interactions.)

Patients with achlorhydria: To ensure absorption (see Absorption under Pharmacokinetics), some clinicians suggest taking each 200 mg of ketoconazole with an acidic beverage (e.g., Coca-Cola, Pepsi) or dissolving the dose in 60 mL of citrus juice;²⁷³ however, because this strategy may not be adequate in all patients with achlorhydria, monitor closely for therapeutic failure.²⁷³

Dosage

Pediatric Patients

General Pediatric Dosage

Treatment of Fungal Infections

Oral

Children >2 years of age: 3.3–6.6 mg/kg once daily has been used.²⁶³ ³⁸⁴

Manufacturer states usual duration of treatment for systemic fungal infections is 6 months; continue until active fungal infection subsides.²⁶³ ³⁸⁴

Hypercalcemia†

Oral

3–9 mg/kg daily has been used for treatment of idiopathic infantile hypercalcemia and hypercalciuria^† in infants 4 days to 17 months of age^†.³⁹²

3 mg/kg every 8 hours has been used in adolescents with tuberculosis-associated hypercalcemia^†.³⁶⁷

Adults

General Adult Dosage

Treatment of Fungal Infections

Oral

200 mg once daily.²⁶³ ³⁸⁴ Dosage may be increased to 400 mg once daily if expected clinical response not achieved.²⁶³ ³⁸⁴

Do not exceed recommended dosage;²⁶³ ³⁸⁴ higher dosage associated with increased toxicity.²³⁴ ²⁶³ ²⁸⁸ ²⁹⁰ ³⁸⁴ (See Cautions.)

Manufacturer states usual duration of treatment for systemic fungal infections is 6 months; continue until active fungal infection subsides.²⁶³ ³⁸⁴

Blastomycosis

Oral

Initial dosage of 400 mg daily; if response is inadequate, some clinicians suggest dosage may be increased to 800 mg daily.²²⁰ ²³⁴ ²⁸⁸ ⁴²⁴ Dosage of 400–800 mg daily has been used as follow-up after a response was obtained with IV amphotericin B.²⁹⁶ Consider risk of toxicity if dosage exceeds 400 mg daily (see Cautions).²⁶³ ³⁸⁴

Usual duration of treatment is 6–12 months.⁴²⁴

Chromomycosis

Oral

200–400 mg daily.³³⁵

Coccidioidomycosis

Oral

400 mg once daily.⁴²⁶ Long-term treatment (months to years) is necessary.⁴²⁶

HIV-infected patients adequately treated for coccidioidomycosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) with oral itraconazole or oral fluconazole to prevent relapse.⁴⁴⁰

Histoplasmosis

Oral

400–800 mg daily.²³⁴ ²⁸⁸ Consider risk of toxicity if dosage exceeds 400 mg daily (see Cautions).²⁶³ ³⁸⁴

Usually treated for 6–12 weeks; more prolonged treatment (at least 12 months) may be necessary for chronic cavitary pulmonary disease or disseminated histoplasmosis.⁴²⁸

HIV-infected patients adequately treated for histoplasmosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) with oral itraconazole to prevent relapse.⁴⁴⁰

Paracocciodioidomycosis

Oral

200–400 mg once daily.³³⁵

Hypercalcemia†

Oral

200–800 mg daily has been used for treatment of hypercalcemia in adults with sarcoidosis.³⁶³ ³⁶⁵ ³⁶⁶ Consider risk of toxicity if dosage exceeds 400 mg daily (see Cautions).²⁶³ ³⁸⁴

Prostate Cancer†

Oral

400 mg every 8 hours has been used for treatment of prostatic carcinoma^†¹⁰⁶ ¹⁰⁸ ¹⁸⁰ ¹⁸¹ ¹⁸² ¹⁸³ ²⁸⁵ or as an adjunct in the management of disseminated intravascular coagulation (DIC) associated with prostatic carcinoma^†.¹⁵² ¹⁷⁸ Consider risk of toxicity, including risk of depressed adrenocortical function, if dosage exceeds 400 mg daily (see Cautions).²⁶³ ³⁸⁴

Prescribing Limits

Adults

Oral

400 mg daily.²⁶³ ³⁸⁴

Cautions for Ketoconazole

Contraindications

Hypersensitivity to ketoconazole.²⁶³ ³⁸⁴
Acute or chronic liver disease.²⁶³ ³⁸⁴
Concomitant use with certain drugs metabolized by CYP3A4 (e.g., colchicine, eplerenone, ergot alkaloids, felodipine, irinotecan, lovastatin, lurasidone, nisoldipine, simvastatin, tolvaptan);²⁶³ ³⁸⁴ increased plasma concentrations of these drugs may occur and increase or prolong their therapeutic and/or adverse effects.²⁶³ ³⁸⁴ (See Interactions.)
Concomitant use with certain drugs (e.g., cisapride, disopyramide, dofetilide, dronedarone, methadone, pimozide, quinidine, ranolazine);²⁶³ ³⁸⁴ increased plasma concentrations of these drugs may occur and can lead to QT interval prolongation, sometimes resulting in life-threatening ventricular tachyarrhythmias such as torsades de pointes.²⁶³ ³⁸⁴ (See Interactions.)
Concomitant use with certain benzodiazepines (e.g., alprazolam, oral midazolam, oral triazolam);²⁶³ ³⁸⁴ increased plasma concentrations of these drugs may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic use.³⁸⁴

Warnings/Precautions

Warnings

Serious Adverse Effects

Serious adverse effects (e.g., hepatotoxicity, adrenal insufficiency) and drug interactions reported with oral ketoconazole.²⁶³ ³⁸⁴ Use only in serious or life-threatening fungal infections when other effective antifungals not available or not tolerated and potential benefits of oral ketoconazole outweigh potential risks.²⁶³ ³⁸⁴ ⁴⁴⁹ ⁴⁵⁰

Because drug interactions may result in serious or potentially life-threatening adverse effects, review all drugs patient is receiving to assess for possible interactions with ketoconazole.⁴⁴⁹ (See Interactions.)

Hepatotoxicity

Serious hepatotoxicity reported, including cases that were fatal or required liver transplantation.¹⁶⁴ ¹⁶⁵ ¹⁶⁶ ¹⁶⁷ ¹⁶⁸ ¹⁶⁹ ¹⁷⁰ ¹⁹¹ ¹⁹³ ²⁶³ ³⁸⁴ ⁴⁴⁹

Symptomatic hepatotoxicity usually apparent within first few months of ketoconazole therapy,⁵⁰ ⁶¹ ¹⁶⁴ ¹⁶⁷ ¹⁶⁸ ¹⁶⁹ ¹⁷⁰ ¹⁸⁸ ¹⁸⁹ ¹⁹⁰ ¹⁹¹ ²⁶³ ³⁸⁴ but occasionally may be apparent within first week of therapy.¹⁶⁴ ¹⁶⁶ ¹⁶⁷ ¹⁹¹ ²⁶³ ³⁸⁴ Although ketoconazole-induced hepatotoxicity usually reversible following discontinuance of the drug,⁵⁰ ¹⁶⁴ ¹⁶⁵ ¹⁶⁶ ¹⁶⁷ ¹⁸⁸ ¹⁸⁹ ¹⁹⁰ ¹⁹¹ ²⁶³ ³⁸⁴ recovery may take several months;¹⁶⁴ ¹⁶⁵ ¹⁶⁷ ¹⁸⁸ ¹⁹⁰ ²⁶³ ³⁸⁴ rarely, death has occurred.¹⁶⁴ ¹⁶⁵ ¹⁶⁷ ¹⁶⁸ ¹⁶⁹ ¹⁷⁰ ¹⁹¹ ¹⁹³ ²⁶³ ³⁸⁴

Ketoconazole-induced hepatotoxicity has been reported in patients who had no obvious risk factors for liver disease.²⁶³ ³⁸⁴ ⁴⁴⁹ Some cases reported in patients receiving high oral ketoconazole dosage for short treatment durations; others reported in those receiving low oral dosage for long durations.²⁶³ ³⁸⁴ ⁴⁴⁹ Many cases were reported in patients receiving the drug for tinea unguium (onychomycosis)^†⁵⁰ ¹⁶⁷ ¹⁶⁸ ¹⁶⁹ ¹⁸⁸ ¹⁸⁹ ¹⁹⁰ ¹⁹¹ ¹⁹³ ²⁶³ ³⁸⁴ or chronic, refractory dermatophytoses^†.¹⁶⁷ ¹⁹¹

Ketoconazole-induced hepatitis has been reported in children.¹⁶⁵ ¹⁶⁷ ¹⁸⁹ ¹⁹¹ ²⁶³ ³⁸⁴

Prior to initiation of oral ketoconazole, perform liver function tests, including serum AST, ALT, alkaline phosphatase, γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP), and total bilirubin, as well as PT, INR, and tests for viral hepatitides.¹⁶⁴ ¹⁶⁶ ¹⁶⁷ ¹⁶⁹ ¹⁷⁰ ¹⁸⁸ ¹⁸⁹ ¹⁹⁰ ¹⁹³ ²⁶³ ³⁸⁴ ⁴⁴⁹

During ketoconazole therapy, monitor serum ALT concentrations weekly.²⁶³ ³⁸⁴ ⁴⁴⁹ Prompt recognition of liver injury is essential.²⁶³ ³⁸⁴ ⁴⁴⁹ If ALT increases above ULN or 30% above baseline or if patient develops symptoms, interrupt ketoconazole therapy and perform full set of liver tests.²⁶³ ³⁸⁴ ⁴⁴⁹ Repeat liver tests to ensure that values normalize.²⁶³ ³⁸⁴ ⁴⁴⁹

Minor, asymptomatic elevations in liver function test results may return to pretreatment concentrations during continued ketoconazole therapy.¹⁶⁴ ¹⁶⁷ ¹⁹¹ ¹⁹³ If oral ketoconazole is restarted, monitor patient frequently to detect any recurring liver injury; hepatotoxicity has occurred following reinitiation of the drug (rechallenge).²⁶³ ³⁸⁴ ⁴⁴⁹

Advise patients to avoid alcohol consumption during ketoconazole therapy.²⁶³ ³⁸⁴ ⁴⁴⁹ In addition, avoid concomitant use of other potentially hepatotoxic drugs.²⁶³ ³⁸⁴ ⁴⁴⁹ (See Interactions.)

QT Prolongation

Prolonged QT interval reported.²⁶³ ³⁸⁴

Oral dosage of 200 mg twice daily for 3–7 days increased corrected QT (QT_c) interval; mean maximum increase of about 6–12 msec reported approximately 1–4 hours after a dose.²⁶³ ³⁸⁴

Concomitant use with certain drugs that prolong QT interval (e.g., cisapride, disopyramide, dofetilide, dronedarone, methadone, pimozide, quinidine, ranolazine) contraindicated.²⁶³ ³⁸⁴ (See Interactions.)

Endocrine and Metabolic Effects

Decreased adrenal corticosteroid secretion reported with ketoconazole dosage ≥400 mg.²⁶³ ³⁸⁴ Can inhibit cortisol synthesis, particularly in patients receiving relatively high daily dosage or divided daily dosing.¹⁰⁹ ¹¹² ¹¹³ ¹¹⁴ ¹⁵¹ ¹⁵⁴ ¹⁵⁶ ¹⁵⁷ ¹⁵⁸ ¹⁵⁹ ¹⁶⁶ ¹⁷³ ²²⁹ ²³⁰ The adrenocortical response to corticotropin (ACTH) may be at least transiently diminished and a reduction in urinary free and serum cortisol concentrations may occur.¹⁰⁹ ¹¹⁰ ¹¹² ¹¹³ ¹¹⁴ ¹⁵¹ ¹⁵⁴ ¹⁵⁶ ¹⁵⁷ ¹⁵⁸ ¹⁵⁹ ¹⁶⁶ ¹⁷³ Adrenocortical insufficiency reported rarely.¹⁰⁹ ¹⁵⁹ ¹⁶⁰ ¹⁶⁶ ¹⁷³ ²²⁹

In 350 patients receiving high-dose ketoconazole (1.2 g daily) for metastatic prostatic carcinoma, 11 deaths occurred within 2 weeks after initiation of the drug.²⁶³ ³⁸⁴ These patients had serious underlying disease; not possible to ascertain from available information whether these deaths were related to ketoconazole or adrenocortical insufficiency.²⁶³ ³⁸⁴

Adrenocortical hypofunction generally reversible following discontinuance of the drug,¹⁵⁴ ¹⁵⁶ ¹⁵⁷ ¹⁶⁶ but rarely may be persistent.¹⁵⁹

Gynecomastia reported in patients receiving ketoconazole.²⁶³ ³⁸⁴ The drug can inhibit testosterone synthesis and transient decreases in serum testosterone may occur;¹⁰⁹ ¹¹⁰ ¹⁵¹ ¹⁷⁴ ²⁶³ ³⁸⁴ concentrations usually return to baseline values after the drug discontinued.²⁶³ ³⁸⁴ Ketoconazole dosages of 800 mg daily decrease serum testosterone levels; clinical manifestations of these decreased levels may include gynecomastia, impotence, and oligospermia.²⁶³ ³⁸⁴

Monitor adrenal function in patients with adrenal insufficiency or with borderline adrenal function and in those under prolonged periods of stress (e.g., major surgery, intensive care).²⁶³ ³⁸⁴ ⁴⁴⁹

To minimize risk of possible endocrine and metabolic effects, do not exceed recommended dosage (i.e., 200–400 mg daily in adults).²⁶³ ³⁸⁴

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylaxis reported after first dose.¹⁰² ²⁶³ ³⁸⁴

Other hypersensitivity reactions, including anaphylactoid reaction, erythema multiforme, rash, dermatitis, erythema, urticaria, and pruritus, have occurred.²⁶³ ³⁸⁴ Acute generalized exanthematous pustulosis, photosensitivity, angioedema, alopecia, and xeroderma also reported.²⁶³ ³⁸⁴

General Precautions

Meningitis and Other CNS Infections

Because CSF concentrations of ketoconazole are unpredictable and may be negligible following oral administration and because treatment failures or relapses have been reported, do not use to treat fungal infections that involve the CNS, including cerebral blastomycosis or coccidioidal meningitis.¹⁹² ²⁶³ ²⁸⁸ ²⁹¹ ²⁹⁵ ³⁰² ³⁰⁶ ³⁸⁴ ³⁸⁴

Specific Populations

Pregnancy

Category C.²⁶³ ³⁸⁴

No adequate and controlled studies in pregnant women;³⁸⁴ use only when potential benefits justify potential risks to fetus.³⁸⁴

Has been teratogenic (syndactylia and oligodactylia) in animal studies.³⁸⁴

Fertility

Oligospermia and, rarely, azoospermia reported in adult males receiving dosages >400 mg daily^†.¹⁰⁹ ²⁶³ ³⁸⁴

Lactation

Distributed into human milk.²⁶³ ³⁸⁴ Discontinue nursing or the drug.²⁶³ ³⁸⁴

Pediatric Use

Use in pediatric patients only when potential benefits outweigh risks.²⁶³ ³⁸⁴

Not systematically studied in children of any age.²⁶³ ³⁸⁴ Has been used in a limited number of children >2 years of age;²⁶³ ³⁸⁴ essentially no information available on use in children <2 years of age.²⁶³ ³⁸⁴

Common Adverse Effects

GI effects (nausea, diarrhea, abdominal pain), headache, abnormal liver function test results.²⁶³ ³⁸⁴

Drug Interactions

Inhibits CYP3A4; metabolized by CYP3A4.²⁶³ ³⁸⁴

Inhibits P-glycoprotein (P-gp) transport system.³⁸⁴

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP3A4 substrates: Possible increased concentrations of the CYP3A4 substrate and increased or prolonged therapeutic and/or adverse effects associated with such drugs.²⁶³ ³⁸⁴

CYP3A4 inhibitors: Possible increased ketoconazole concentrations and increased risk of adverse effects associated with the antifungal.²⁶³ ³⁸⁴

CYP3A4 inducers: Possible decreased ketoconazole concentrations and decreased efficacy of the antifungal.²⁶³ ³⁸⁴

Drugs Affecting or Affected by P-glycoprotein Transport

P-gp substrates: Possible increased concentrations of such substrates.³⁸⁴

Drugs that Prolong the QT Interval

Potential interaction with drugs that are CYP3A4 substrates that prolong the QT interval; possible increased concentrations of the concomitantly administered CYP3A4 substrate which can lead to QT interval prolongation, sometimes resulting in life-threatening ventricular dysarrhythmias such as torsades de pointes.²⁶³ ³⁸⁴ Concomitant use with these drugs contraindicated.²⁶³ ³⁸⁴

Drugs Affecting Gastric Acidity

Because gastric acidity necessary for dissolution and absorption of ketoconazole, concomitant use of drugs that decrease gastric acid output or increase gastric pH may decrease ketoconazole absorption resulting in decreased concentrations of the antifungal.²⁶³ ³⁸⁴

Hepatotoxic Drugs

Avoid concomitant use with other potentially hepatotoxic drugs.²⁶³ ³⁸⁴ (See Hepatotoxicity under Cautions.)

Specific Drugs

Drug	Interaction	Comments
Alcohol	Disulfiram reactions (flushing, rash, peripheral edema, nausea, headache) reported rarely when alcohol ingested while receiving ketoconazole;²⁶³ ²⁶⁷ ²⁶⁸ ³⁸⁴ usually resolved within a few hours²⁶³ ³⁸⁴	Avoid alcohol consumption during ketoconazole therapy;²⁶³ ³⁸⁴ some clinicians recommend avoiding alcohol during and for 48 hours after discontinuance of the drug²⁶⁷
Aliskiren	Possible increased aliskiren concentrations³⁸⁴	Use concomitantly with caution;³⁸⁴ carefully monitor for increased or prolonged aliskiren effects;³⁸⁴ reduce aliskiren dosage if needed³⁸⁴
Antacids	Possible decreased absorption of ketoconazole²⁶³ ³⁸⁴	Use concomitantly with caution³⁸⁴ Administer ketoconazole with acidic beverage (e.g., non-diet cola) and administer antacid ≥1 hour before or ≥2 hours after ketoconazole;³⁸⁴ monitor antifungal activity and adjust ketoconazole dosage if needed³⁸⁴
Antiarrhythmic agents (disopyramide, dofetilide, dronedarone, quinidine)	Disopyramide, dofetilide, dronedarone, quinidine: Possible increased antiarrhythmic agent concentrations and increased risk of serious or life-threatening adverse cardiovascular effects, including QT interval prolongation and ventricular tachyarrhythmias such as torsades de pointes³⁸⁴	Disopyramide, dofetilide, dronedarone, quinidine: Concomitant use contraindicated;³⁸⁴ in addition, do not use for up to 1 week after completion of ketoconazole treatment³⁸⁴
Anticoagulants, oral (dabigatran, rivaroxaban, warfarin)	Dabigatran, rivaroxaban: Possible increased anticoagulant concentrations³⁸⁴ Warfarin: Possible enhanced anticoagulant effects²⁶³ ³⁸⁴	Dabigatran: Use concomitantly with caution;³⁸⁴ carefully monitor for increased or prolonged dabigatran effects;³⁸⁴ in patients with moderate renal impairment (Cl_cr 50–80 mL/minute), consider decreased dabigatran dosage of 75 mg twice daily³⁸⁴ Rivaroxaban: Avoid during and for up to 1 week after discontinuance of ketoconazole;³⁸⁴ if concomitant use cannot be avoided, monitor for increased or prolonged rivaroxaban effects³⁸⁴ Warfarin: Use concomitantly with caution;³⁸⁴ monitor PT or other appropriate tests closely; adjust anticoagulant dosage if needed²⁶³ ³⁸⁴
Anticonvulsants (carbamazepine, phenytoin)	Carbamazepine: Possible increased carbamazepine concentrations; possible decreased ketoconazole concentrations and decreased antifungal efficacy³⁸⁴ Phenytoin: Possible decreased ketoconazole concentrations³⁸⁴	Carbamazepine: Avoid for 2 weeks prior to and during ketoconazole treatment and avoid for up to 1 week after discontinuance of ketoconazole;³⁸⁴ if concomitant use cannot be avoided, monitor for increased or prolonged carbamazepine effects and reduce or interrupt carbamazepine dosage if needed;³⁸⁴ also monitor for antifungal activity and increase ketoconazole dosage if needed³⁸⁴ Phenytoin: Avoid for 2 weeks prior to and during ketoconazole treatment;³⁸⁴ if concomitant use cannot be avoided, monitor for antifungal activity and increase ketoconazole dosage if needed³⁸⁴
Antidiabetic agents (repaglinide, saxagliptin)	Repaglinide, saxagliptin: Possible increased concentrations of the antidiabetic agent³⁸⁴	Repaglinide, saxagliptin: Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged effects of the antidiabetic agent and reduce antidiabetic agent dosage if needed³⁸⁴
Antihistamines (loratadine)	Loratadine: Increased concentrations and AUCs of loratadine and its active metabolite; no evidence of changes in QT interval or incidence of adverse effects²⁶³ ³⁸⁴
Antimalarials	Fixed combination of artemether and lumefantrine (artemether/lumefantrine): Increased concentrations of artemether, active metabolite of artemether, and lumefantrine;⁴⁴⁸ increased risk of QT interval prolongation⁴⁴⁸ Mefloquine: Substantially increased mefloquine concentrations, AUC, and elimination half-life;⁴⁴⁶ increased risk of potentially fatal prolongation of QT_c interval⁴⁴⁶ Quinine: Increased quinine AUC and decreased quinine clearance⁴⁴⁷	Artemether/lumefantrine: Dosage adjustment for artemether/lumefantrine not needed;⁴⁴⁸ use concomitantly with caution⁴⁴⁸ Mefloquine: Do not use ketoconazole concomitantly with mefloquine or within 15 weeks after last mefloquine dose⁴⁴⁶ Quinine: Dosage adjustment of quinine not required; monitor closely for quinine-associated adverse effects⁴⁴⁷
Antimycobacterials (isoniazid, rifabutin, rifampin)	Isoniazid: Possible decreased ketoconazole concentrations³⁸⁴ Rifabutin: Possible increased rifabutin concentrations; possible decreased ketoconazole concentrations and decreased antifungal efficacy²⁶³ ³⁸⁴ Rifampin: Decreased ketoconazole concentrations and possible decreased antifungal efficacy¹¹¹ ¹⁴¹ ²²¹ ²⁶³ ³⁸⁴	Isoniazid: Avoid for 2 weeks prior to and during ketoconazole treatment;³⁸⁴ if concomitant use cannot be avoided, monitor for antifungal activity and increase ketoconazole dosage if needed³⁸⁴ Rifabutin: Avoid for 2 weeks prior to and during ketoconazole treatment and avoid for up to 1 week after discontinuance of ketoconazole;³⁸⁴ if concomitant use cannot be avoided, monitor for increased or prolonged rifabutin effects and reduce or interrupt rifabutin dosage if needed;³⁸⁴ also monitor for antifungal activity and increase ketoconazole dosage if needed³⁸⁴ Rifampin: Avoid for 2 weeks prior to and during ketoconazole treatment;³⁸⁴ if concomitant use cannot be avoided, monitor for antifungal activity and increase ketoconazole dosage if needed³⁸⁴
Antiretrovirals, HIV entry inhibitors	Maraviroc: Possible increased maraviroc concentrations³⁸⁴	Maraviroc: Use concomitantly with caution;³⁸⁴ monitor for maraviroc-associated adverse effects and reduce maraviroc dosage if needed³⁸⁴
Antiretrovirals, HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs)	Delavirdine: Possible increased delavirdine concentrations²¹² Efavirenz, nevirapine: Possible decreased ketoconazole concentrations and reduced antifungal efficacy²¹³ ³⁸⁴ Etravirine: Possible increased etravirine concentrations and decreased ketoconazole concentrations²¹⁴ Rilpivirine: Increased rilpivirine concentrations and AUC;²²⁶ decreased ketoconazole concentrations and AUC²²⁶	Efavirenz, nevirapine: Concomitant use not recommended;³⁸⁴ avoid for 2 weeks prior to and during ketoconazole treatment;³⁸⁴ if concomitant use cannot be avoided, monitor antifungal activity and increase ketoconazole dosage if needed³⁸⁴ Etravirine: Dosage adjustment of ketoconazole may be needed depending on other concomitantly administered drugs²¹⁴ Rilpivirine: Dosage adjustment of rilpivirine not needed;²²⁶ monitor for breakthrough fungal infections²²⁶
Antiretrovirals, HIV protease inhibitors (PIs)	Possible pharmacokinetic interactions if ketoconazole used in patients receiving PIs (e.g., ritonavir-boosted or cobicistat- boosted atazanavir, ritonavir-boosted or cobicistat-boosted darunavir, fosamprenavir [with or without low-dose ritonavir], indinavir, fixed combination of lopinavir and ritonavir [lopinavir/ritonavir], nelfinavir, ritonavir-boosted saquinavir, ritonavir-boosted tipranavir);²⁰³ ²⁰⁴ ²⁰⁵ ²⁰⁶ ²⁰⁷ ²⁰⁸ ²¹⁰ ²¹¹ ²³⁷ ²³⁸ ³⁸⁴ altered concentrations of the PI and/or the antifungal²⁰³ ²⁰⁴ ²⁰⁵ ²⁰⁶ ²⁰⁷ ²⁰⁸ ²¹⁰ ²¹¹ ²³⁷ ²³⁸ ³⁸⁴	Ritonavir-boosted or cobicistat-boosted atazanavir: Use concomitantly with caution²⁰³ ²³⁸ Ritonavir-boosted or cobicistat-boosted darunavir: Use concomitantly with caution;²⁰⁴ ³⁸⁴ closely monitor for increased ketoconazole-, darunavir-, and ritonavir- or cobicistat-associated adverse effects;²⁰⁴ ²³⁷ ³⁸⁴ consider decreased ketoconazole dosage and monitor ketoconazole plasma concentrations if needed;³⁸⁴ do not exceed ketoconazole dosage of 200 mg daily in those receiving ritonavir-boosted darunavir²⁰⁴ Ritonavir-boosted fosamprenavir: Use concomitantly with caution;³⁸⁴ monitor for ketoconazole-associated adverse effects;³⁸⁴ consider decreased ketoconazole dosage and monitor ketoconazole plasma concentrations if needed;³⁸⁴ do not exceed ketoconazole dosage of 200 mg daily²⁰⁵ Fosamprenavir (without low-dose ritonavir): Decreased ketoconazole dosage may be needed in those receiving >400 mg of ketoconazole daily²⁰⁵ Indinavir (without low-dose ritonavir): Use concomitantly with caution;³⁸⁴ monitor for indinavir-associated adverse effects;³⁸⁴ use indinavir dosage of 600 mg every 8 hours²⁰⁶ Lopinavir/ritonavir: Do not exceed ketoconazole dosage of 200 mg daily²⁰⁷ Ritonavir-boosted saquinavir: Use concomitantly with caution and carefully monitor;³⁸⁴ do not exceed ketoconazole dosage of 200 mg daily²¹⁰ Ritonavir-boosted tipranavir: Use concomitantly with caution;²¹¹ do not exceed ketoconazole dosage of 200 mg daily²¹¹
Aprepitant	Possible increased aprepitant concentrations³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged aprepitant effects and reduce aprepitant dosage if needed³⁸⁴
Aripiprazole	Increased exposures of aripiprazole and its active metabolite³⁸⁴	Use concomitantly with caution;³⁸⁴ reduce aripiprazole dosage by 50%;³⁸⁴ monitor for increased or prolonged aripiprazole effects³⁸⁴
Benzodiazepines (alprazolam, midazolam, triazolam)	Alprazolam, midazolam, triazolam: Increased benzodiazepine concentrations;²⁶³ ³⁸⁴ possible prolonged sedative and hypnotic effects, especially in those receiving repeated or chronic therapy with the drugs²⁶³ ³⁸⁴	Alprazolam, oral midazolam, oral triazolam: Concomitant use with ketoconazole contraindicated;²⁶³ ³⁸⁴ in addition, do not use for up to 1 week after completion of ketoconazole treatment³⁸⁴ Parenteral midazolam: Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged midazolam effects and reduce midazolam dosage if needed³⁸⁴
Bortezomib	Possible increased bortezomib concentrations³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged bortezomib effects and reduce bortezomib dosage if needed³⁸⁴
Bosentan	Increased bosentan concentrations and AUC²⁶³ ³⁸⁴	Use concomitantly with caution;³⁸⁴ adjustment of bosentan dosage not needed; monitor closely for increased bosentan-associated adverse effects²⁶³ ³⁸⁴
Buspirone	Increased buspirone concentrations²⁶³ ³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged buspirone effects and reduce buspirone dosage if needed³⁸⁴
Busulfan	Possible decreased busulfan clearance and increased systemic exposure²⁶³ ³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged busulfan effects and reduce busulfan dosage if needed;³⁸⁴
Calcium-channel blockers	Amlodipine, felodipine, nicardipine, nifedipine, verapamil: Increased concentrations of the calcium-channel blocker;²⁶³ ³⁸⁴ negative inotropic effect of calcium-channel blockers may be additive to that of ketoconazole;³⁸⁴ possible increased risk of edema and congestive heart failure³⁸⁴	Felodipine, nisoldipine: Concomitant use contraindicated;²⁶³ ³⁸⁴ in addition, do not use for up to 1 week after completion of ketoconazole treatment³⁸⁴ Other dihydropyridines (e.g., amlodipine, nicardipine, nifedipine): Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged effects of the calcium-channel blocker and reduce dosage of the calcium-channel blocker if needed³⁸⁴ Verapamil: Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged verapamil effects and reduce verapamil dosage if needed³⁸⁴
Cilostazol	Increased concentrations and AUC of cilostazol²⁶³ ³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged cilostazol effects and reduce cilostazol dosage if needed³⁸⁴
Cinacalcet	Possible increased cinacalcet concentrations³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged cinacalcet effects and reduce cinacalcet dosage if needed³⁸⁴
Cisapride	Increased cisapride concentrations and increased risk of adverse effects (e.g., cardiovascular effects)²⁶³ ²⁷⁶ ³⁸⁴	Concomitant use contraindicated;²⁶³ ³⁸⁴ in addition, do not use for up to 1 week after completion of ketoconazole treatment³⁸⁴
Colchicine	Possible increased colchicine concentrations and increased risk of potentially fatal adverse effects³⁸⁴	Patients with renal or hepatic impairment: Concomitant use contraindicated;³⁸⁴ in addition, do not use for up to 1 week after ketoconazole treatment is complete³⁸⁴ Patients without renal or hepatic impairment: Concomitant use not recommended;³⁸⁴ avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of colchicine-associated adverse effects;³⁸⁴ if concomitant use cannot be avoided, monitor for increased or prolonged colchicine effects and reduce or interrupt colchicine dosage if needed³⁸⁴
Corticosteroids	Budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, prednisolone: Possible increased corticosteroid concentrations;²²⁷ ²²⁸ ²³² ²³³ ²⁶³ ³⁸⁴ possible enhancement of adrenal suppressive effects²²⁸ ²³³	Budesonide, ciclesonide, dexamethasone, methylprednisolone: Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged corticosteroid effects and reduce corticosteroid dosage if needed³⁸⁴ Fluticasone propionate: Concomitant use not recommended unless potential benefits outweigh potential risks of systemic corticosteroid adverse effects³⁸⁴ Prednisolone: Carefully monitor; adjustment of prednisolone dosage may be needed²²⁷ ²²⁸ ²⁶³ ²³² ²³³
Dasatinib	Possible increased dasatinib concentrations³⁸⁴	Concomitant use not recommended;³⁸⁴ avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of dasatinib-associated adverse effects;³⁸⁴ if concomitant use cannot be avoided, monitor for increased or prolonged dasatinib effects and reduce or interrupt dasatinib dosage if needed³⁸⁴
Digoxin	Increased digoxin concentrations reported; causative relationship unclear²⁶³ ³⁸⁴	Use concomitantly with caution and monitor digoxin concentrations²⁶³ ³⁸⁴
Docetaxel	Decreased clearance of docetaxel in cancer patients²⁶³ ³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged docetaxel effects and reduce docetaxel dosage if needed³⁸⁴
Eletriptan	Possible increased eletriptan concentrations³⁸⁴	Do not use within 72 hours of ketoconazole treatment;³⁸⁴ if used concomitantly, caution advised;³⁸⁴ monitor for increased or prolonged eletriptan effects and reduce eletriptan dosage if needed³⁸⁴
Eplerenone	Increased AUC of eplerenone; increased risk of hyperkalemia and hypotension²⁶³ ³⁸⁴	Concomitant use contraindicated;²⁶³ ³⁸⁴ in addition, do not use for up to 1 week after completion of ketoconazole treatment³⁸⁴
Ergot alkaloids	Increased ergot alkaloid concentrations; possible ergotism (i.e., risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities)²⁶³ ³⁸⁴	Concomitant use contraindicated;²⁶³ ³⁸⁴ in addition, do not use for up to 1 week after completion of ketoconazole treatment³⁸⁴
Erlotinib	Possible increased erlotinib concentrations³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged erlotinib effects and reduce erlotinib dosage if needed³⁸⁴
Fesoterodine	Possible increased fesoterodine concentrations³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged fesoterodine effects and reduce fesoterodine dosage if needed³⁸⁴
Haloperidol	Possible increased haloperidol concentrations³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged haloperidol effects and reduce haloperidol dosage if needed³⁸⁴
HCV polymerase inhibitors	Fixed combination of ombitasvir, paritaprevir and ritonavir (ombitasvir/paritaprevir/ritonavir) with dasabuvir: Increased ketoconazole AUC⁴⁵⁵	Ombitasvir/paritaprevir/ritonavir with dasabuvir: Do not exceed ketoconazole dosage of 200 mg daily⁴⁵⁵
HCV protease inhibitors	Ombitasvir/paritaprevir/ritonavir with dasabuvir: Increased ketoconazole AUC⁴⁵⁴ ⁴⁵⁵ Simeprevir: Possible increased simeprevir concentrations⁴⁵¹	Ombitasvir/paritaprevir/ritonavir with or without dasabuvir: Do not exceed ketoconazole dosage of 200 mg daily⁴⁵⁴ ⁴⁵⁵ Simeprevir: Concomitant use not recommended⁴⁵¹
HCV replication complex inhibitors	Daclatasvir: Increased daclatasvir concentrations and AUC⁴⁵² Elbasvir or grazoprevir: Increased concentrations and AUC of elbasvir or grazoprevir;⁴⁵³ possible increased risk of hepatotoxicity ⁴⁵³ Ombitasvir/paritaprevir/ritonavir with dasabuvir: Increased ketoconazole AUC⁴⁵⁴ ⁴⁵⁵ Velpatasvir: No clinically important interaction⁴⁵⁶	Daclatasvir: If used concomitantly with ketoconazole, use daclatasvir dosage of 30 mg once daily⁴⁵² Fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir): Concomitant use with ketoconazole not recommended⁴⁵³ Ombitasvir/paritaprevir/ritonavir with or without dasabuvir: Do not exceed ketoconazole dosage of 200 mg daily⁴⁵⁴ ⁴⁵⁵
Histamine H₂-receptor antagonists (e.g., cimetidine, ranitidine)	Possible decreased absorption of ketoconazole²⁶³ ³⁸⁴	Use concomitantly with caution³⁸⁴ Administer ketoconazole with acidic beverage (e.g., non-diet cola) and administer H₂-receptor antagonist ≥1 hour before or ≥2 hours after ketoconazole;³⁸⁴ monitor antifungal activity and adjust ketoconazole dosage if needed³⁸⁴
HMG-CoA reductase inhibitors (statins)	Atorvastatin, lovastatin, simvastatin: Increased statin concentrations; increased statin effects and increased risk of statin-associated adverse effects (e.g., myopathy, rhabdomyolysis)²⁶³ ³⁸⁴	Atorvastatin: Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged atorvastatin effects and reduce atorvastatin dosage if needed³⁸⁴ Lovastatin, simvastatin: Concomitant use contraindicated;²⁶³ ³⁸⁴ in addition, do not use for up to 1 week after completion of ketoconazole treatment³⁸⁴
Imatinib	Possible increased imatinib concentrations³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged imatinib effects and reduce imatinib dosage if needed³⁸⁴
Immunosuppressive agents (cyclosporine, everolimus, sirolimus, tacrolimus)	Cyclosporine: Increased cyclosporine concentrations;¹⁴² ¹⁴³ ¹⁴⁴ ²⁶³ ³⁸⁴ increased S_cr¹⁴² ¹⁴³ ¹⁴⁴ Everolimus: Possible increased everolimus concentrations³⁸⁴ Sirolimus: Increased concentrations and AUC of sirolimus²⁶³ ³⁸⁴ Tacrolimus: Increased tacrolimus concentrations²⁶³ ³⁷² ³⁸⁴	Cyclosporine: Use concomitantly with caution;³⁸⁴ careful monitoring, with possible dosage adjustment, recommended;²⁶³ ³⁸⁴ monitor renal function and cyclosporine concentrations;¹⁴⁶ consider reduced cyclosporine dosage or use of another immunosuppressive agent;¹⁴⁶ patients stabilized on both drugs may require an increase in cyclosporine dosage when ketoconazole discontinued¹⁴⁶ Everolimus: Concomitant use not recommended;³⁸⁴ avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of adverse effects;³⁸⁴ if concomitant use cannot be avoided, monitor for increased or prolonged everolimus effects and reduce or interrupt everolimus dosage if needed³⁸⁴ Sirolimus: Concomitant use not recommended;²⁶³ ³⁸⁴ avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of adverse effects;³⁸⁴ if concomitant use cannot be avoided, monitor for increased or prolonged sirolimus effects and reduce or interrupt sirolimus dosage if needed³⁸⁴ Tacrolimus: Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged tacrolimus effects and reduce tacrolimus dosage if needed³⁸⁴
Irinotecan	Possible increased irinotecan concentrations;³⁸⁴ possible increased risk of fatal adverse effects³⁸⁴	Concomitant use contraindicated;³⁸⁴ in addition, do not use for up to 1 week after completion of ketoconazole treatment³⁸⁴
Ixabepilone	Possible increased ixabepilone concentrations³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged ixabepilone effects and reduce ixabepilone dosage if needed³⁸⁴
Lapatinib	Possible increased lapatinib concentrations³⁸⁴	Concomitant use not recommended;³⁸⁴ avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of adverse effects;³⁸⁴ if concomitant use cannot be avoided, monitor for increased or prolonged lapatinib effects and reduce or interrupt lapatinib dosage if needed³⁸⁴
Lurasidone	Possible increased lurasidone concentrations³⁸⁴	Concomitant use contraindicated;³⁸⁴ in addition, do not use for up to 1 week after completion of ketoconazole treatment³⁸⁴
Nadolol	Possible increased nadolol concentrations³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged nadolol effects and reduce nadolol dosage if needed³⁸⁴
Nilotinib	Possible increased nilotinib concentrations³⁸⁴	Concomitant use not recommended;³⁸⁴ avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of adverse effects;³⁸⁴ if concomitant use cannot be avoided, monitor for increased or prolonged nilotinib effects and reduce or interrupt nilotinib dosage if needed³⁸⁴
Opiate agonists or partial agonists	Alfentanil, fentanyl, sufentanil: Possible increased opiate agonist concentrations;²⁶³ ³⁸⁴ possible increased risk of potentially fatal respiratory depression³⁸⁴ Buprenorphine: Possible increased buprenorphine concentrations³⁸⁴ Methadone: Possible increased methadone concentrations and increased risk of serious adverse cardiovascular effects, including QT interval prolongation³⁸⁴ Oxycodone: Possible increased oxycodone concentrations³⁸⁴	Alfentanil, fentanyl, sufentanil: Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged opiate effects and reduce opiate agonist dosage if needed³⁸⁴ Buprenorphine: Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged buprenorphine effects and reduce buprenorphine dosage if needed³⁸⁴ Methadone: Concomitant use contraindicated;³⁸⁴ in addition, do not use for up to 1 week after completion of ketoconazole treatment³⁸⁴ Oxycodone: Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged oxycodone effects and reduce oxycodone dosage if needed³⁸⁴
Paclitaxel	In vitro evidence that ketoconazole can inhibit metabolism of paclitaxel²⁶⁹	Clinical importance unclear;³⁸⁴ use concomitantly with caution;³⁸⁴ monitor for increased or prolonged paclitaxel effects and reduce paclitaxel dosage if needed³⁸⁴
Phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil, vardenafil)	Increased concentrations of the PDE5 inhibitor and increased risk of PDE5 inhibitor-associated adverse effects (e.g., hypotension, syncope, visual changes, prolonged erection)²⁶³ ³⁷⁶ ³⁷⁸ ³⁷⁹ ³⁸⁴	Sildenafil: Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged sildenafil effects and reduce sildenafil dosage if needed;³⁸⁴ manufacturer of sildenafil states consider initial sildenafil dosage of 25 mg in those receiving ketoconazole⁴⁴⁵ Tadalafil: Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged tadalafil effects and reduce tadalafil dosage if needed;³⁸⁴ manufacturer of tadalafil recommends no more than 10 mg of tadalafil once every 72 hours in those receiving ketoconazole;³⁷⁸ if a once-daily tadalafil regimen is used, no more than 2.5 mg of tadalafil once daily recommended³⁷⁸ Vardenafil: Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged vardenafil effects and reduce vardenafil dosage if needed;³⁸⁴ manufacturer of vardenafil recommends no more than a single 5-mg dose of vardenafil in a 24-hour period in those receiving ketoconazole 200 mg daily and no more than a single 2.5-mg dose of vardenafil in a 24-hour period in those receiving ketoconazole 400 mg daily³⁷⁹
Pimozide	Possible increased pimozide concentrations; may result in QT_c interval prolongation, sometimes resulting in life-threatening ventricular tachyarrhythmias such as torsades de pointes²⁶³ ³⁸⁴	Concomitant use contraindicated;²⁶³ ³⁸⁴ in addition, do not use for up to 1 week after completion of ketoconazole treatment³⁸⁴
Praziquantel	Possible increased praziquantel concentrations³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged praziquantel effects and reduce praziquantel dosage if needed³⁸⁴
Proton-pump inhibitors	Possible decreased absorption of ketoconazole³⁸⁴	Use concomitantly with caution³⁸⁴ Administer ketoconazole with acidic beverage (e.g., non-diet cola) and administer proton-pump inhibitor ≥1 hour before or ≥2 hours after ketoconazole;³⁸⁴ monitor antifungal activity and adjust ketoconazole dosage if needed³⁸⁴
Quetiapine	Possible increased quetiapine concentrations³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged quetiapine effects and reduce quetiapine dosage if needed³⁸⁴
Ramelteon	Possible increased ramelteon concentrations³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged ramelteon effects and reduce ramelteon dosage if needed³⁸⁴
Ranolazine	Possible increased ranolazine concentrations and increased risk of serious adverse cardiovascular effects, including QT interval prolongation³⁸⁴	Concomitant use contraindicated;³⁸⁴ in addition, do not use for up to 1 week after completion of ketoconazole treatment³⁸⁴
Risperidone	Possible increased risperidone concentrations³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged risperidone effects and reduce risperidone dosage if needed³⁸⁴
Salmeterol	Possible increased salmeterol concentrations³⁸⁴	Concomitant use not recommended;³⁸⁴ avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of adverse effects;³⁸⁴ if concomitant use cannot be avoided, monitor for increased or prolonged salmeterol effects and reduce or interrupt salmeterol dosage if needed³⁸⁴
Solifenacin	Possible increased solifenacin concentrations³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged solifenacin effects and reduce solifenacin dosage if needed³⁸⁴
Tamsulosin	Possible increased tamsulosin concentrations³⁸⁴	Concomitant use not recommended;³⁸⁴ avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of adverse effects;³⁸⁴ if concomitant use cannot be avoided, monitor for increased or prolonged tamsulosin effects and reduce or interrupt tamsulosin dosage if needed³⁸⁴
Telithromycin	Possible increased AUC of telithromycin; increased risk of telithromycin-associated adverse events²⁶³ ³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged telithromycin effects and reduce telithromycin dosage if needed³⁸⁴
Temsirolimus	Possible increased temsirolimus concentrations³⁸⁴	Concomitant use not recommended;³⁸⁴ avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of adverse effects;³⁸⁴ if concomitant use cannot be avoided, monitor for increased or prolonged temsirolimus effects and reduce or interrupt temsirolimus dosage if needed³⁸⁴
Theophylline	Conflicting data;¹⁴⁷ ¹⁵⁰ possible decreased theophylline concentrations¹⁴⁷	Pending further accumulation of data, monitor theophylline concentrations and adjust theophylline dosage if necessary when ketoconazole is initiated or discontinued in patients receiving theophylline¹⁴⁷
Tolterodine	Decreased apparent oral clearance of tolterodine and increased tolterodine concentrations²⁶³ ³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged tolterodine effects and reduce tolterodine dosage if needed³⁸⁴
Tolvaptan	Increased tolvaptan exposures;³⁸⁴ increased ketoconazole dosage expected to produce larger increases in tolvaptan exposures³⁸⁴	Concomitant use contraindicated;³⁸⁴ in addition, do not use for up to 1 week after completion of ketoconazole treatment;³⁸⁴ data insufficient to define safe tolvaptan dosage adjustment if used concomitantly with potent CYP3A inhibitors³⁸⁴
Trazodone	Possible substantially increased plasma trazodone concentrations and potential for adverse effects³⁸⁰	Consider reduced trazodone dosage in patients receiving ketoconazole³⁸⁰
Trimetrexate	Possible inhibition of trimetrexate metabolism²⁶³ and increased trimetrexate concentrations³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged trimetrexate effects and reduce trimetrexate dosage if needed³⁸⁴
Vinca alkaloids	Vincristine, vinblastine, vinorelbine: Possible inhibition of metabolism of the vinca alkaloid²⁶³ and increased vinca alkaloid concentrations³⁸⁴	Use concomitantly with caution;³⁸⁴ monitor for increased or prolonged vinca alkaloid effects and reduce vinca alkaloid dosage if needed³⁸⁴

Ketoconazole Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed from GI tract;¹⁶² ¹⁶³ peak plasma concentrations attained within 1–2 hours.¹⁴⁹ ¹⁶² ²⁶³ ³⁸⁴

Ketoconazole must be dissolved in gastric secretions and converted to the hydrochloride salt prior to absorption from the stomach.^a Bioavailability depends on the pH of the gastric contents in the stomach; an increase in pH results in decreased absorption of the drug.^a ³⁸⁴ (See Absorption: Special Populations.)

Food

Effect of food on rate and extent of GI absorption of ketoconazole has not been clearly determined.¹⁶²

Plasma Concentrations

Considerable interindividual variations in peak plasma concentrations and AUCs have been reported.^a

Special Populations

Oral bioavailability may be decreased in patients with achlorhydria,^a including those with HIV-associated gastric hypochlorhydria.¹⁹⁸ Concomitant administration of an acidic beverage may increase bioavailability in some individuals.²⁷³ (See Oral Administration under Dosage and Administration.)

Distribution

Extent

Distributed into urine, bile, saliva, sebum, cerumen, and synovial fluid.^a

May be distributed into CSF following oral administration, but CNS penetration is unpredictable and may be negligible.^a ³⁸⁴

Not known whether crosses the placenta in humans; crosses the placenta in rats.^a Distributed into human milk.^a

Plasma Protein Binding

84–99% bound to plasma proteins, primarily albumin.²⁶³ ³⁸⁴ ^a

Elimination

Metabolism

Partially metabolized in the liver to several inactive metabolites by oxidation and degradation of the imidazole and piperazine rings, by oxidative O-dealkylation, and by aromatic hydroxylation.^a

Based on in vitro studies, principally metabolized by CYP3A4.³⁸⁴

Elimination Route

Major route of elimination of ketoconazole and its metabolites appears to be excretion into the feces via the bile.^a

In fasting adults with normal renal function, approximately 57% of a single 200-mg oral dose is excreted in feces within 4 days (20–65% of this is unchanged drug); approximately 13% of the dose is excreted in urine within 4 days (2–4% of this is unchanged drug).^a

Half-life

Plasma concentrations appear to decline in a biphasic manner with a half-life of approximately 2 hours in the initial phase and 8 hours in the terminal phase.²⁶³ ³⁸⁴

Special Populations

Pharmacokinetics not substantially affected by renal or hepatic impairment.³⁸⁴

Stability

Storage

Oral

Tablets

20–25°C;³⁸⁴ protect from moisture.³⁸⁴

Actions and Spectrum

Imidazole-derivative azole antifungal.¹²⁷ ³⁸⁴
Usually fungistatic in action.¹¹⁹ ¹²¹ ¹²⁷ ¹²⁹ ¹³⁰ ¹³¹ ¹³² ¹³³
Presumably exerts its antifungal activity by altering cellular membranes resulting in increased membrane permeability, leakage of essential elements (e.g., amino acids, potassium), and impaired uptake of precursor molecules (e.g., purine and pyrimidine precursors to DNA).¹²⁷ ¹²⁸ ¹³⁰ ¹³¹ Inhibits cytochrome P-450 14-α-desmethylase in susceptible fungi, which leads to accumulation of C-14 methylated sterols (e.g., lanosterol) and decreased concentrations of ergosterol.¹²⁸ ¹²⁹ ¹³⁰ ¹⁵¹
Spectrum of antifungal activity includes many fungi, including yeasts and dermatophytes.²⁶³ ³⁸⁴ ^a Has some in vitro activity against some gram-positive bacteria (e.g., staphylococci, Nocardia) and some protozoa (e.g., Acanthamoeba, Leishmania).¹³⁴ ¹³⁵ ¹³⁶ ^a
Active against Blastomyces dermatitidis,²⁶³ ³⁷¹ ³⁸⁴ Coccidioides immitis,²⁶³ ³⁸⁴ Cryptococcus neoformans,²⁶³ ³⁷³ ³⁸⁴ Histoplasma capsulatum,²⁶³ ³⁸⁴ Paracoccidioides brasiliensis,²⁶³ ³⁸⁴ Penicillium marneffei,³⁸⁹ ³⁹⁰ and Phialophoa.²⁶³ ³⁸⁴ Also active against Actinomadura madurae, Aspergillus flavus,¹²⁰ ¹²² ¹²⁴ A. fumigatus,¹²² ¹²⁴ Malassezia furfur (Pityrosporum orbiculare),^a Petriellidium boydii,¹²⁰ ¹²² and Sporothrix schenckii.¹²⁰ ¹²² ¹²⁴ May be active against some strains of Exophiala castellanii²⁷⁵ and Scopulariopsis, including some strains of S. acremonium and S. brevicaulis.³⁷⁴
In vitro and in vivo studies indicate ketoconazole can directly inhibit synthesis of adrenal steroids and testosterone.¹⁰⁹ ¹¹⁰ ¹¹² ¹¹³ ¹¹⁴ ¹¹⁵ ¹¹⁶ ¹¹⁷ ¹⁴⁸ ¹⁵¹ ¹⁵⁴ ¹⁵⁶ ¹⁵⁷ ¹⁵⁸ ¹⁵⁹ ¹⁶⁰ ¹⁶¹ ¹⁷¹ ¹⁷² ¹⁷³ ¹⁷⁴ ¹⁷⁵ ¹⁷⁶ Appears to inhibit steroid synthesis principally by blocking several P-450 enzyme systems (e.g., 11β-hydroxylase, C-17,20-lyase, cholesterol side-chain cleavage enzyme).¹¹² ¹¹⁴ ¹¹⁷ ¹⁵¹ ¹⁵² ¹⁵⁴ ¹⁵⁵ ¹⁵⁷ ¹⁵⁸ ¹⁵⁹ ¹⁷¹ ¹⁷² ¹⁷³ ¹⁷⁴ ¹⁷⁵ ¹⁷⁶ ²⁰¹
Inhibits cortisol synthesis in a dose-dependent manner in individuals with normal adrenocortical function and in patients with Cushing’s syndrome (hypercortisolism).¹⁰⁹ ¹¹² ¹¹³ ¹¹⁴ ¹⁵¹ ¹⁵⁴ ¹⁵⁶ ¹⁵⁷ ¹⁵⁸ ¹⁵⁹ ¹⁶⁶ ¹⁷³

Advice to Patients

Advise patients that oral ketoconazole is used only for treatment of certain serious systemic fungal infections and is prescribed only when other effective antifungals not available or not tolerated and potential benefits of the drug outweigh potential risks.²⁶³ ³⁸⁴ ⁴⁴⁹ ⁴⁵⁰
Advise patients that oral ketoconazole is not used for treatment of fungal infections of the skin or nails.²⁶³ ³⁸⁴ ⁴⁴⁹ ⁴⁵⁰
Risk of hepatotoxicity; importance of reporting any signs or symptoms of possible hepatic dysfunction (e.g., unusual fatigue, anorexia, nausea and/or vomiting, abdominal pain, jaundice, dark urine, pale feces) to their clinician.¹⁶⁷ ¹⁶⁸ ¹⁸⁸ ¹⁸⁹ ²⁶³ ³⁸⁴
Risk of QT interval prolongation, especially if certain medications are used concomitantly.²⁶³ ³⁸⁴ Importance of informing their clinicians if they have had an abnormal ECG or have a family member with a history of congenital long QT syndrome.²⁶³ ³⁸⁴ Importance of contacting their clinicians if symptoms of QT interval prolongation occur (e.g., feeling faint, lightheaded, dizzy, irregular or fast heart beat).²⁶³ ³⁸⁴
Risk of adrenal insufficiency if high dosage is used.²⁶³ ³⁸⁴ Importance of informing their clinicians if they have a history of adrenal insufficiency.²⁶³ ³⁸⁴ Importance of contacting their clinicians if symptoms of adrenal insufficiency occur (e.g., tiredness, weakness, dizziness, nausea, vomiting).²⁶³ ³⁸⁴
Risk of hypersensitivity reactions.²⁶³ ³⁸⁴ Importance of discontinuing ketoconazole and immediately contacting their clinicians if signs of an allergic reaction occur (e.g., rash, itching, hives, fever, swelling of lips or tongue, chest pain, trouble breathing).²⁶³ ³⁸⁴
Advise patients not to consume alcohol during ketoconazole therapy.²⁶³ ³⁸⁴
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.³⁸⁴
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.³⁸⁴
Importance of advising patients of other important precautionary information.³⁸⁴ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Ketoconazole
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	200 mg*	Ketoconazole Tablets

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

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Pill T 57 is Ketoconazole 200 mg — Ketoconazole 200 mg (T 57)