Generic name: nizoral
Availability: Prescription only
Pregnancy & Lactation: Risk data available
Brand names: Ketoconazole, Nizoral
What is Ketoconazole (systemic) (monograph)?
Warning
-
Use only when other effective antifungals not available or not tolerated and potential benefits of oral ketoconazole outweigh potential risks.
-
Serious hepatotoxicity has occurred in patients receiving oral ketoconazole, including cases that were fatal or required liver transplantation. Inform patients of the risk and monitor closely. (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. (See Interactions.)
Introduction
Antifungal; azole (imidazole derivative).
Uses for 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.
Related/similar drugs
fluconazole, ketoconazole, Diflucan, itraconazole, voriconazole, amphotericin b, NizoralKetoconazole (Systemic) Dosage and Administration
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
OralChildren >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
Oral200 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.
How should I use Ketoconazole (systemic) (monograph)
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
OralChildren >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
Oral200 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.
What other drugs will affect Ketoconazole (systemic) (monograph)?
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 |