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Ketoconazole (Systemic)

Class: Azoles
VA Class: AM700
CAS Number: 65277-42-1
Brands: Nizoral

Medically reviewed by Drugs.com on Sep 23, 2021. Written by ASHP.

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 (e.g., tinea capitis, tinea corporis, tinea pedis, tinea unguium [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.

Ketoconazole (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
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.

Cautions for Ketoconazole (Systemic)

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.

Interactions for 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

Ketoconazole (Systemic) Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed from GI tract; peak plasma concentrations attained within 1–2 hours.

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

Food

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

Plasma Concentrations

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

Special Populations

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

Distribution

Extent

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

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

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

Plasma Protein Binding

84–99% bound to plasma proteins, primarily albumin.

Elimination

Metabolism

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

Based on in vitro studies, principally metabolized by CYP3A4.

Elimination Route

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

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

Half-life

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

Special Populations

Pharmacokinetics not substantially affected by renal or hepatic impairment.

Stability

Storage

Oral

Tablets

20–25°C; protect from moisture.

Actions and Spectrum

  • Imidazole-derivative azole antifungal.

  • Usually fungistatic in action.

  • Presumably exerts its antifungal activity by altering cellular membranes resulting in increased membrane permeability, leakage of essential elements (e.g., amino acids, potassium), and impaired uptake of precursor molecules (e.g., purine and pyrimidine precursors to DNA). Inhibits cytochrome P-450 14-α-desmethylase in susceptible fungi, which leads to accumulation of C-14 methylated sterols (e.g., lanosterol) and decreased concentrations of ergosterol.

  • Spectrum of antifungal activity includes many fungi, including yeasts and dermatophytes. Has some in vitro activity against some gram-positive bacteria (e.g., staphylococci, Nocardia) and some protozoa (e.g., Acanthamoeba, Leishmania).

  • Active against Blastomyces dermatitidis, Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, Paracoccidioides brasiliensis, Penicillium marneffei, and Phialophoa. Also active against Actinomadura madurae, Aspergillus flavus, A. fumigatus, Malassezia furfur (Pityrosporum orbiculare), Petriellidium boydii, and Sporothrix schenckii. May be active against some strains of Exophiala castellanii and Scopulariopsis, including some strains of S. acremonium and S. brevicaulis.

  • In vitro and in vivo studies indicate ketoconazole can directly inhibit synthesis of adrenal steroids and testosterone. Appears to inhibit steroid synthesis principally by blocking several P-450 enzyme systems (e.g., 11β-hydroxylase, C-17,20-lyase, cholesterol side-chain cleavage enzyme).

  • Inhibits cortisol synthesis in a dose-dependent manner in individuals with normal adrenocortical function and in patients with Cushing’s syndrome (hypercortisolism).

Advice to Patients

  • Advise patients that oral ketoconazole is used only for treatment of certain serious systemic fungal infections and is prescribed only when other effective antifungals not available or not tolerated and potential benefits of the drug outweigh potential risks.

  • Advise patients that oral ketoconazole is not used for treatment of fungal infections of the skin or nails.

  • Risk of hepatotoxicity; importance of reporting any signs or symptoms of possible hepatic dysfunction (e.g., unusual fatigue, anorexia, nausea and/or vomiting, abdominal pain, jaundice, dark urine, pale feces) to their clinician.

  • Risk of QT interval prolongation, especially if certain medications are used concomitantly. Importance of informing their clinicians if they have had an abnormal ECG or have a family member with a history of congenital long QT syndrome. Importance of contacting their clinicians if symptoms of QT interval prolongation occur (e.g., feeling faint, lightheaded, dizzy, irregular or fast heart beat).

  • Risk of adrenal insufficiency if high dosage is used. Importance of informing their clinicians if they have a history of adrenal insufficiency. Importance of contacting their clinicians if symptoms of adrenal insufficiency occur (e.g., tiredness, weakness, dizziness, nausea, vomiting).

  • Risk of hypersensitivity reactions. Importance of discontinuing ketoconazole and immediately contacting their clinicians if signs of an allergic reaction occur (e.g., rash, itching, hives, fever, swelling of lips or tongue, chest pain, trouble breathing).

  • Advise patients not to consume alcohol during ketoconazole therapy.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

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

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

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

Ketoconazole

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

200 mg*

Ketoconazole Tablets

AHFS DI Essentials™. © Copyright 2022, Selected Revisions October 3, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

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