Ketoconazole (Systemic)

Brand names: Nizoral
Drug class: Antineoplastic Agents

Usage of Ketoconazole (Systemic)

Blastomycosis

Alternative for treatment of blastomycosis caused by Blastomyces dermatitidis. 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.

Drugs of choice are IV amphotericin B or oral itraconazole; oral fluconazole is an alternative. Ketoconazole has been used as an alternative, but may be less effective.

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.

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

Chromomycosis

Alternative for treatment of chromomycosis (chromoblastomycosis) caused by Phialophora; a response may not be attained in those with more extensive disease. 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.

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

Coccidioidomycosis

Alternative for treatment of coccidioidomycosis caused by Coccidioides immitis. 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.

Drugs of choice for initial treatment of symptomatic pulmonary, chronic fibrocavitary, or disseminated coccidioidomycosis are oral fluconazole or oral itraconazole; 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).

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.

Consult current IDSA clinical practice guidelines available at [Web] 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.

Histoplasmosis

Alternative for treatment of histoplasmosis caused by Histoplasma capsulatum. 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.

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

Consult current IDSA clinical practice guidelines available at [Web] 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 histoplasmosis.

Paracoccidioidomycosis

Alternative for treatment of paracoccidioidomycosis (South American blastomycosis) caused by Paracoccidioides brasiliensis. 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.

IV amphotericin B is drug of choice for initial treatment of severe paracoccidioidomycosis. 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.

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]†). No longer recommended and no longer labeled by FDA for these infections.

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

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†. 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.

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.

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

Hirsutism and Precocious Puberty

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

Has been used in a limited number of boys for treatment of precocious puberty†.

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

Hypercalcemia

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

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

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

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

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†.

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

Relate drugs

How to use Ketoconazole (Systemic)

Administration

Oral Administration

Administer orally.

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. (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; however, because this strategy may not be adequate in all patients with achlorhydria, monitor closely for therapeutic failure.

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.

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

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†.

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

Adults

General Adult Dosage Treatment of Fungal Infections Oral

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

Do not exceed recommended dosage; higher dosage associated with increased toxicity. (See Cautions.)

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

Blastomycosis Oral

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

Usual duration of treatment is 6–12 months.

Chromomycosis Oral

200–400 mg daily.

Coccidioidomycosis Oral

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

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.

Histoplasmosis Oral

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

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

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

Paracocciodioidomycosis Oral

200–400 mg once daily.

Hypercalcemia† Oral

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

Prostate Cancer† Oral

400 mg every 8 hours has been used for treatment of prostatic carcinoma† or as an adjunct in the management of disseminated intravascular coagulation (DIC) associated with prostatic carcinoma†. Consider risk of toxicity, including risk of depressed adrenocortical function, if dosage exceeds 400 mg daily (see Cautions).

Prescribing Limits

Adults

Oral

400 mg daily.

Warnings

Contraindications

  • Hypersensitivity to ketoconazole.
  • Acute or chronic liver disease.
  • Concomitant use with certain drugs metabolized by CYP3A4 (e.g., colchicine, eplerenone, ergot alkaloids, felodipine, irinotecan, lovastatin, lurasidone, nisoldipine, simvastatin, tolvaptan); increased plasma concentrations of these drugs may occur and increase or prolong their therapeutic and/or adverse effects. (See Interactions.)
  • Concomitant use with certain drugs (e.g., cisapride, disopyramide, dofetilide, dronedarone, methadone, pimozide, quinidine, ranolazine); 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. (See Interactions.)
  • Concomitant use with certain benzodiazepines (e.g., alprazolam, oral midazolam, oral triazolam); increased plasma concentrations of these drugs may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic use.

    • Warnings/Precautions

    Warnings

    Serious Adverse Effects

    Serious adverse effects (e.g., hepatotoxicity, adrenal insufficiency) and drug interactions reported with oral ketoconazole. 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.

    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. (See Interactions.)

    Hepatotoxicity

    Serious hepatotoxicity reported, including cases that were fatal or required liver transplantation.

    Symptomatic hepatotoxicity usually apparent within first few months of ketoconazole therapy, but occasionally may be apparent within first week of therapy. Although ketoconazole-induced hepatotoxicity usually reversible following discontinuance of the drug, recovery may take several months; rarely, death has occurred.

    Ketoconazole-induced hepatotoxicity has been reported in patients who had no obvious risk factors for liver disease. 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. Many cases were reported in patients receiving the drug for tinea unguium (onychomycosis)† or chronic, refractory dermatophytoses†.

    Ketoconazole-induced hepatitis has been reported in children.

    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.

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

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

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

    QT Prolongation

    Prolonged QT interval reported.

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

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

    Endocrine and Metabolic Effects

    Decreased adrenal corticosteroid secretion reported with ketoconazole dosage ≥400 mg. Can inhibit cortisol synthesis, particularly in patients receiving relatively high daily dosage or divided daily dosing. The adrenocortical response to corticotropin (ACTH) may be at least transiently diminished and a reduction in urinary free and serum cortisol concentrations may occur. Adrenocortical insufficiency reported rarely.

    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. These patients had serious underlying disease; not possible to ascertain from available information whether these deaths were related to ketoconazole or adrenocortical insufficiency.

    Adrenocortical hypofunction generally reversible following discontinuance of the drug, but rarely may be persistent.

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

    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).

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

    Sensitivity Reactions

    Hypersensitivity Reactions

    Anaphylaxis reported after first dose.

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

    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.

    Specific Populations

    Pregnancy

    Category C.

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

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

    Fertility

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

    Lactation

    Distributed into human milk. Discontinue nursing or the drug.

    Pediatric Use

    Use in pediatric patients only when potential benefits outweigh risks.

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

    Common Adverse Effects

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

    What other drugs will affect Ketoconazole (Systemic)

    Inhibits CYP3A4; metabolized by CYP3A4.

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

    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.

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

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

    Drugs Affecting or Affected by P-glycoprotein Transport

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

    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. Concomitant use with these drugs contraindicated.

    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.

    Hepatotoxic Drugs

    Avoid concomitant use with other potentially hepatotoxic drugs. (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; usually resolved within a few hours

    Avoid alcohol consumption during ketoconazole therapy; some clinicians recommend avoiding alcohol during and for 48 hours after discontinuance of the drug

    Aliskiren

    Possible increased aliskiren concentrations

    Use concomitantly with caution; carefully monitor for increased or prolonged aliskiren effects; reduce aliskiren dosage if needed

    Antacids

    Possible decreased absorption of ketoconazole

    Use concomitantly with caution

    Administer ketoconazole with acidic beverage (e.g., non-diet cola) and administer antacid ≥1 hour before or ≥2 hours after ketoconazole; monitor antifungal activity and adjust ketoconazole dosage if needed

    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 pointes

    Disopyramide, dofetilide, dronedarone, quinidine: Concomitant use contraindicated; in addition, do not use for up to 1 week after completion of ketoconazole treatment

    Anticoagulants, oral (dabigatran, rivaroxaban, warfarin)

    Dabigatran, rivaroxaban: Possible increased anticoagulant concentrations

    Warfarin: Possible enhanced anticoagulant effects

    Dabigatran: Use concomitantly with caution; carefully monitor for increased or prolonged dabigatran effects; in patients with moderate renal impairment (Clcr 50–80 mL/minute), consider decreased dabigatran dosage of 75 mg twice daily

    Rivaroxaban: Avoid during and for up to 1 week after discontinuance of ketoconazole; if concomitant use cannot be avoided, monitor for increased or prolonged rivaroxaban effects

    Warfarin: Use concomitantly with caution; monitor PT or other appropriate tests closely; adjust anticoagulant dosage if needed

    Anticonvulsants (Carbamazepine, phenytoin)

    Carbamazepine: Possible increased carbamazepine concentrations; possible decreased ketoconazole concentrations and decreased antifungal efficacy

    Phenytoin: Possible decreased ketoconazole concentrations

    Carbamazepine: Avoid for 2 weeks prior to and during ketoconazole treatment and avoid for up to 1 week after discontinuance of ketoconazole; if concomitant use cannot be avoided, monitor for increased or prolonged carbamazepine effects and reduce or interrupt carbamazepine dosage if needed; also monitor for antifungal activity and increase ketoconazole dosage if needed

    Phenytoin: Avoid for 2 weeks prior to and during ketoconazole treatment; if concomitant use cannot be avoided, monitor for antifungal activity and increase ketoconazole dosage if needed

    Antidiabetic agents (repaglinide, saxagliptin)

    Repaglinide, saxagliptin: Possible increased concentrations of the antidiabetic agent

    Repaglinide, saxagliptin: Use concomitantly with caution; monitor for increased or prolonged effects of the antidiabetic agent and reduce antidiabetic agent dosage if needed

    Antihistamines (loratadine)

    Loratadine: Increased concentrations and AUCs of loratadine and its active metabolite; no evidence of changes in QT interval or incidence of adverse effects

    Antimalarials

    Fixed combination of artemether and lumefantrine (artemether/lumefantrine): Increased concentrations of artemether, active metabolite of artemether, and lumefantrine; increased risk of QT interval prolongation

    Mefloquine: Substantially increased mefloquine concentrations, AUC, and elimination half-life; increased risk of potentially fatal prolongation of QTc interval

    Quinine: Increased quinine AUC and decreased quinine clearance

    Artemether/lumefantrine: Dosage adjustment for artemether/lumefantrine not needed; use concomitantly with caution

    Mefloquine: Do not use ketoconazole concomitantly with mefloquine or within 15 weeks after last mefloquine dose

    Quinine: Dosage adjustment of quinine not required; monitor closely for quinine-associated adverse effects

    Antimycobacterials (isoniazid, rifabutin, rifampin)

    Isoniazid: Possible decreased ketoconazole concentrations

    Rifabutin: Possible increased rifabutin concentrations; possible decreased ketoconazole concentrations and decreased antifungal efficacy

    Rifampin: Decreased ketoconazole concentrations and possible decreased antifungal efficacy

    Isoniazid: Avoid for 2 weeks prior to and during ketoconazole treatment; if concomitant use cannot be avoided, monitor for antifungal activity and increase ketoconazole dosage if needed

    Rifabutin: Avoid for 2 weeks prior to and during ketoconazole treatment and avoid for up to 1 week after discontinuance of ketoconazole; if concomitant use cannot be avoided, monitor for increased or prolonged rifabutin effects and reduce or interrupt rifabutin dosage if needed; also monitor for antifungal activity and increase ketoconazole dosage if needed

    Rifampin: Avoid for 2 weeks prior to and during ketoconazole treatment; if concomitant use cannot be avoided, monitor for antifungal activity and increase ketoconazole dosage if needed

    Antiretrovirals, HIV entry inhibitors

    Maraviroc: Possible increased maraviroc concentrations

    Maraviroc: Use concomitantly with caution; monitor for maraviroc-associated adverse effects and reduce maraviroc dosage if needed

    Antiretrovirals, HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs)

    Delavirdine: Possible increased delavirdine concentrations

    Efavirenz, nevirapine: Possible decreased ketoconazole concentrations and reduced antifungal efficacy

    Etravirine: Possible increased etravirine concentrations and decreased ketoconazole concentrations

    Rilpivirine: Increased rilpivirine concentrations and AUC; decreased ketoconazole concentrations and AUC

    Efavirenz, nevirapine: Concomitant use not recommended; avoid for 2 weeks prior to and during ketoconazole treatment; if concomitant use cannot be avoided, monitor antifungal activity and increase ketoconazole dosage if needed

    Etravirine: Dosage adjustment of ketoconazole may be needed depending on other concomitantly administered drugs

    Rilpivirine: Dosage adjustment of rilpivirine not needed; monitor for breakthrough fungal infections

    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); altered concentrations of the PI and/or the antifungal

    Ritonavir-boosted or cobicistat-boosted atazanavir: Use concomitantly with caution

    Ritonavir-boosted or cobicistat-boosted darunavir: Use concomitantly with caution; closely monitor for increased ketoconazole-, darunavir-, and ritonavir- or cobicistat-associated adverse effects; consider decreased ketoconazole dosage and monitor ketoconazole plasma concentrations if needed; do not exceed ketoconazole dosage of 200 mg daily in those receiving ritonavir-boosted darunavir

    Ritonavir-boosted fosamprenavir: Use concomitantly with caution; monitor for ketoconazole-associated adverse effects; consider decreased ketoconazole dosage and monitor ketoconazole plasma concentrations if needed; do not exceed ketoconazole dosage of 200 mg daily

    Fosamprenavir (without low-dose ritonavir): Decreased ketoconazole dosage may be needed in those receiving >400 mg of ketoconazole daily

    Indinavir (without low-dose ritonavir): Use concomitantly with caution; monitor for indinavir-associated adverse effects; use indinavir dosage of 600 mg every 8 hours

    Lopinavir/ritonavir: Do not exceed ketoconazole dosage of 200 mg daily

    Ritonavir-boosted saquinavir: Use concomitantly with caution and carefully monitor; do not exceed ketoconazole dosage of 200 mg daily

    Ritonavir-boosted tipranavir: Use concomitantly with caution; do not exceed ketoconazole dosage of 200 mg daily

    Aprepitant

    Possible increased aprepitant concentrations

    Use concomitantly with caution; monitor for increased or prolonged aprepitant effects and reduce aprepitant dosage if needed

    Aripiprazole

    Increased exposures of aripiprazole and its active metabolite

    Use concomitantly with caution; reduce aripiprazole dosage by 50%; monitor for increased or prolonged aripiprazole effects

    Benzodiazepines (alprazolam, midazolam, triazolam)

    Alprazolam, midazolam, triazolam: Increased benzodiazepine concentrations; possible prolonged sedative and hypnotic effects, especially in those receiving repeated or chronic therapy with the drugs

    Alprazolam, oral midazolam, oral triazolam: Concomitant use with ketoconazole contraindicated; in addition, do not use for up to 1 week after completion of ketoconazole treatment

    Parenteral midazolam: Use concomitantly with caution; monitor for increased or prolonged midazolam effects and reduce midazolam dosage if needed

    Bortezomib

    Possible increased bortezomib concentrations

    Use concomitantly with caution; monitor for increased or prolonged bortezomib effects and reduce bortezomib dosage if needed

    Bosentan

    Increased bosentan concentrations and AUC

    Use concomitantly with caution; adjustment of bosentan dosage not needed; monitor closely for increased bosentan-associated adverse effects

    Buspirone

    Increased buspirone concentrations

    Use concomitantly with caution; monitor for increased or prolonged buspirone effects and reduce buspirone dosage if needed

    Busulfan

    Possible decreased busulfan clearance and increased systemic exposure

    Use concomitantly with caution; monitor for increased or prolonged busulfan effects and reduce busulfan dosage if needed;

    Calcium-channel blockers

    Amlodipine, felodipine, nicardipine, nifedipine, verapamil: Increased concentrations of the calcium-channel blocker; negative inotropic effect of calcium-channel blockers may be additive to that of ketoconazole; possible increased risk of edema and congestive heart failure

    Felodipine, nisoldipine: Concomitant use contraindicated; in addition, do not use for up to 1 week after completion of ketoconazole treatment

    Other dihydropyridines (e.g., amlodipine, nicardipine, nifedipine): Use concomitantly with caution; monitor for increased or prolonged effects of the calcium-channel blocker and reduce dosage of the calcium-channel blocker if needed

    Verapamil: Use concomitantly with caution; monitor for increased or prolonged verapamil effects and reduce verapamil dosage if needed

    Cilostazol

    Increased concentrations and AUC of cilostazol

    Use concomitantly with caution; monitor for increased or prolonged cilostazol effects and reduce cilostazol dosage if needed

    CinaCalcet

    Possible increased cinacalcet concentrations

    Use concomitantly with caution; monitor for increased or prolonged cinacalcet effects and reduce cinacalcet dosage if needed

    Cisapride

    Increased cisapride concentrations and increased risk of adverse effects (e.g., cardiovascular effects)

    Concomitant use contraindicated; in addition, do not use for up to 1 week after completion of ketoconazole treatment

    Colchicine

    Possible increased colchicine concentrations and increased risk of potentially fatal adverse effects

    Patients with renal or hepatic impairment: Concomitant use contraindicated; in addition, do not use for up to 1 week after ketoconazole treatment is complete

    Patients without renal or hepatic impairment: Concomitant use not recommended; avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of colchicine-associated adverse effects; if concomitant use cannot be avoided, monitor for increased or prolonged colchicine effects and reduce or interrupt colchicine dosage if needed

    Corticosteroids

    Budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, prednisolone: Possible increased corticosteroid concentrations; possible enhancement of adrenal suppressive effects

    Budesonide, ciclesonide, dexamethasone, methylprednisolone: Use concomitantly with caution; monitor for increased or prolonged corticosteroid effects and reduce corticosteroid dosage if needed

    Fluticasone propionate: Concomitant use not recommended unless potential benefits outweigh potential risks of systemic corticosteroid adverse effects

    Prednisolone: Carefully monitor; adjustment of prednisolone dosage may be needed

    Dasatinib

    Possible increased dasatinib concentrations

    Concomitant use not recommended; avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of dasatinib-associated adverse effects; if concomitant use cannot be avoided, monitor for increased or prolonged dasatinib effects and reduce or interrupt dasatinib dosage if needed

    Digoxin

    Increased digoxin concentrations reported; causative relationship unclear

    Use concomitantly with caution and monitor digoxin concentrations

    Docetaxel

    Decreased clearance of docetaxel in cancer patients

    Use concomitantly with caution; monitor for increased or prolonged docetaxel effects and reduce docetaxel dosage if needed

    Eletriptan

    Possible increased eletriptan concentrations

    Do not use within 72 hours of ketoconazole treatment; if used concomitantly, caution advised; monitor for increased or prolonged eletriptan effects and reduce eletriptan dosage if needed

    Eplerenone

    Increased AUC of eplerenone; increased risk of hyperkalemia and hypotension

    Concomitant use contraindicated; in addition, do not use for up to 1 week after completion of ketoconazole treatment

    Ergot alkaloids

    Increased ergot alkaloid concentrations; possible ergotism (i.e., risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities)

    Concomitant use contraindicated; in addition, do not use for up to 1 week after completion of ketoconazole treatment

    Erlotinib

    Possible increased erlotinib concentrations

    Use concomitantly with caution; monitor for increased or prolonged erlotinib effects and reduce erlotinib dosage if needed

    Fesoterodine

    Possible increased fesoterodine concentrations

    Use concomitantly with caution; monitor for increased or prolonged fesoterodine effects and reduce fesoterodine dosage if needed

    Haloperidol

    Possible increased haloperidol concentrations

    Use concomitantly with caution; monitor for increased or prolonged haloperidol effects and reduce haloperidol dosage if needed

    HCV polymerase inhibitors

    Fixed combination of ombitasvir, paritaprevir and ritonavir (ombitasvir/paritaprevir/ritonavir) with dasabuvir: Increased ketoconazole AUC

    Ombitasvir/paritaprevir/ritonavir with dasabuvir: Do not exceed ketoconazole dosage of 200 mg daily

    HCV protease inhibitors

    Ombitasvir/paritaprevir/ritonavir with dasabuvir: Increased ketoconazole AUC

    Simeprevir: Possible increased simeprevir concentrations

    Ombitasvir/paritaprevir/ritonavir with or without dasabuvir: Do not exceed ketoconazole dosage of 200 mg daily

    Simeprevir: Concomitant use not recommended

    HCV replication complex inhibitors

    Daclatasvir: Increased daclatasvir concentrations and AUC

    Elbasvir or grazoprevir: Increased concentrations and AUC of elbasvir or grazoprevir; possible increased risk of hepatotoxicity

    Ombitasvir/paritaprevir/ritonavir with dasabuvir: Increased ketoconazole AUC

    Velpatasvir: No clinically important interaction

    Daclatasvir: If used concomitantly with ketoconazole, use daclatasvir dosage of 30 mg once daily

    Fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir): Concomitant use with ketoconazole not recommended

    Ombitasvir/paritaprevir/ritonavir with or without dasabuvir: Do not exceed ketoconazole dosage of 200 mg daily

    Histamine H2-receptor antagonists (e.g., cimetidine, ranitidine)

    Possible decreased absorption of ketoconazole

    Use concomitantly with caution

    Administer ketoconazole with acidic beverage (e.g., non-diet cola) and administer H2-receptor antagonist ≥1 hour before or ≥2 hours after ketoconazole; monitor antifungal activity and adjust ketoconazole dosage if needed

    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)

    Atorvastatin: Use concomitantly with caution; monitor for increased or prolonged atorvastatin effects and reduce atorvastatin dosage if needed

    Lovastatin, simvastatin: Concomitant use contraindicated; in addition, do not use for up to 1 week after completion of ketoconazole treatment

    Imatinib

    Possible increased imatinib concentrations

    Use concomitantly with caution; monitor for increased or prolonged imatinib effects and reduce imatinib dosage if needed

    Immunosuppressive agents (cyclosporine, everolimus, sirolimus, tacrolimus)

    Cyclosporine: Increased cyclosporine concentrations; increased Scr

    Everolimus: Possible increased everolimus concentrations

    Sirolimus: Increased concentrations and AUC of sirolimus

    Tacrolimus: Increased tacrolimus concentrations

    Cyclosporine: Use concomitantly with caution; careful monitoring, with possible dosage adjustment, recommended; monitor renal function and cyclosporine concentrations; consider reduced cyclosporine dosage or use of another immunosuppressive agent; patients stabilized on both drugs may require an increase in cyclosporine dosage when ketoconazole discontinued

    Everolimus: Concomitant use not recommended; avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of adverse effects; if concomitant use cannot be avoided, monitor for increased or prolonged everolimus effects and reduce or interrupt everolimus dosage if needed

    Sirolimus: Concomitant use not recommended; avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of adverse effects; if concomitant use cannot be avoided, monitor for increased or prolonged sirolimus effects and reduce or interrupt sirolimus dosage if needed

    Tacrolimus: Use concomitantly with caution; monitor for increased or prolonged tacrolimus effects and reduce tacrolimus dosage if needed

    Irinotecan

    Possible increased irinotecan concentrations; possible increased risk of fatal adverse effects

    Concomitant use contraindicated; in addition, do not use for up to 1 week after completion of ketoconazole treatment

    Ixabepilone

    Possible increased ixabepilone concentrations

    Use concomitantly with caution; monitor for increased or prolonged ixabepilone effects and reduce ixabepilone dosage if needed

    Lapatinib

    Possible increased lapatinib concentrations

    Concomitant use not recommended; avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of adverse effects; if concomitant use cannot be avoided, monitor for increased or prolonged lapatinib effects and reduce or interrupt lapatinib dosage if needed

    Lurasidone

    Possible increased lurasidone concentrations

    Concomitant use contraindicated; in addition, do not use for up to 1 week after completion of ketoconazole treatment

    Nadolol

    Possible increased nadolol concentrations

    Use concomitantly with caution; monitor for increased or prolonged nadolol effects and reduce nadolol dosage if needed

    Nilotinib

    Possible increased nilotinib concentrations

    Concomitant use not recommended; avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of adverse effects; if concomitant use cannot be avoided, monitor for increased or prolonged nilotinib effects and reduce or interrupt nilotinib dosage if needed

    Opiate agonists or partial agonists

    Alfentanil, fentanyl, sufentanil: Possible increased opiate agonist concentrations; possible increased risk of potentially fatal respiratory depression

    Buprenorphine: Possible increased buprenorphine concentrations

    Methadone: Possible increased methadone concentrations and increased risk of serious adverse cardiovascular effects, including QT interval prolongation

    Oxycodone: Possible increased oxycodone concentrations

    Alfentanil, fentanyl, sufentanil: Use concomitantly with caution; monitor for increased or prolonged opiate effects and reduce opiate agonist dosage if needed

    Buprenorphine: Use concomitantly with caution; monitor for increased or prolonged buprenorphine effects and reduce buprenorphine dosage if needed

    Methadone: Concomitant use contraindicated; in addition, do not use for up to 1 week after completion of ketoconazole treatment

    Oxycodone: Use concomitantly with caution; monitor for increased or prolonged oxycodone effects and reduce oxycodone dosage if needed

    Paclitaxel

    In vitro evidence that ketoconazole can inhibit metabolism of paclitaxel

    Clinical importance unclear; use concomitantly with caution; monitor for increased or prolonged paclitaxel effects and reduce paclitaxel dosage if needed

    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)

    Sildenafil: Use concomitantly with caution; monitor for increased or prolonged sildenafil effects and reduce sildenafil dosage if needed; manufacturer of sildenafil states consider initial sildenafil dosage of 25 mg in those receiving ketoconazole

    Tadalafil: Use concomitantly with caution; monitor for increased or prolonged tadalafil effects and reduce tadalafil dosage if needed; manufacturer of tadalafil recommends no more than 10 mg of tadalafil once every 72 hours in those receiving ketoconazole; if a once-daily tadalafil regimen is used, no more than 2.5 mg of tadalafil once daily recommended

    Vardenafil: Use concomitantly with caution; monitor for increased or prolonged vardenafil effects and reduce vardenafil dosage if needed; 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 daily

    Pimozide

    Possible increased pimozide concentrations; may result in QTc interval prolongation, sometimes resulting in life-threatening ventricular tachyarrhythmias such as torsades de pointes

    Concomitant use contraindicated; in addition, do not use for up to 1 week after completion of ketoconazole treatment

    Praziquantel

    Possible increased praziquantel concentrations

    Use concomitantly with caution; monitor for increased or prolonged praziquantel effects and reduce praziquantel dosage if needed

    Proton-pump inhibitors

    Possible decreased absorption of ketoconazole

    Use concomitantly with caution

    Administer ketoconazole with acidic beverage (e.g., non-diet cola) and administer proton-pump inhibitor ≥1 hour before or ≥2 hours after ketoconazole; monitor antifungal activity and adjust ketoconazole dosage if needed

    Quetiapine

    Possible increased quetiapine concentrations

    Use concomitantly with caution; monitor for increased or prolonged quetiapine effects and reduce quetiapine dosage if needed

    Ramelteon

    Possible increased ramelteon concentrations

    Use concomitantly with caution; monitor for increased or prolonged ramelteon effects and reduce ramelteon dosage if needed

    Ranolazine

    Possible increased ranolazine concentrations and increased risk of serious adverse cardiovascular effects, including QT interval prolongation

    Concomitant use contraindicated; in addition, do not use for up to 1 week after completion of ketoconazole treatment

    Risperidone

    Possible increased risperidone concentrations

    Use concomitantly with caution; monitor for increased or prolonged risperidone effects and reduce risperidone dosage if needed

    Salmeterol

    Possible increased salmeterol concentrations

    Concomitant use not recommended; avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of adverse effects; if concomitant use cannot be avoided, monitor for increased or prolonged salmeterol effects and reduce or interrupt salmeterol dosage if needed

    Solifenacin

    Possible increased solifenacin concentrations

    Use concomitantly with caution; monitor for increased or prolonged solifenacin effects and reduce solifenacin dosage if needed

    Tamsulosin

    Possible increased tamsulosin concentrations

    Concomitant use not recommended; avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of adverse effects; if concomitant use cannot be avoided, monitor for increased or prolonged tamsulosin effects and reduce or interrupt tamsulosin dosage if needed

    Telithromycin

    Possible increased AUC of telithromycin; increased risk of telithromycin-associated adverse events

    Use concomitantly with caution; monitor for increased or prolonged telithromycin effects and reduce telithromycin dosage if needed

    Temsirolimus

    Possible increased temsirolimus concentrations

    Concomitant use not recommended; avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of adverse effects; if concomitant use cannot be avoided, monitor for increased or prolonged temsirolimus effects and reduce or interrupt temsirolimus dosage if needed

    Theophylline

    Conflicting data; possible decreased theophylline concentrations

    Pending further accumulation of data, monitor theophylline concentrations and adjust theophylline dosage if necessary when ketoconazole is initiated or discontinued in patients receiving theophylline

    Tolterodine

    Decreased apparent oral clearance of tolterodine and increased tolterodine concentrations

    Use concomitantly with caution; monitor for increased or prolonged tolterodine effects and reduce tolterodine dosage if needed

    Tolvaptan

    Increased tolvaptan exposures; increased ketoconazole dosage expected to produce larger increases in tolvaptan exposures

    Concomitant use contraindicated; in addition, do not use for up to 1 week after completion of ketoconazole treatment; data insufficient to define safe tolvaptan dosage adjustment if used concomitantly with potent CYP3A inhibitors

    Trazodone

    Possible substantially increased plasma trazodone concentrations and potential for adverse effects

    Consider reduced trazodone dosage in patients receiving ketoconazole

    Trimetrexate

    Possible inhibition of trimetrexate metabolism and increased trimetrexate concentrations

    Use concomitantly with caution; monitor for increased or prolonged trimetrexate effects and reduce trimetrexate dosage if needed

    Vinca alkaloids

    Vincristine, vinblastine, vinorelbine: Possible inhibition of metabolism of the vinca alkaloid and increased vinca alkaloid concentrations

    Use concomitantly with caution; monitor for increased or prolonged vinca alkaloid effects and reduce vinca alkaloid dosage if needed

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