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Ketoconazole

Pronunciation

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

Warning(s)

  • Use only when other effective antifungals not available or not tolerated and potential benefits of oral ketoconazole outweigh potential risks.263 384

  • Serious hepatotoxicity has occurred in patients receiving oral ketoconazole, including cases that were fatal or required liver transplantation.263 384 Inform patients of the risk and monitor closely.263 384 (See Hepatotoxicity under Cautions.)

  • Concomitant use with certain drugs (cisapride, dofetilide, pimozide, quinidine) contraindicated because increased plasma concentrations of these drugs may occur and can lead to QT interval prolongation, sometimes resulting in life-threatening ventricular tachyarrhythmias such as torsades de pointes.263 384 (See Interactions.)

Introduction

Antifungal; azole (imidazole derivative).263 384

Uses for Ketoconazole

Blastomycosis

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

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

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

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

Chromomycosis

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

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

Coccidioidomycosis

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

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

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

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

Histoplasmosis

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

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

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

Paracoccidioidomycosis

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

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

Dermatophytoses

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

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

Acanthamoeba Infections

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

Cushing’s Syndrome

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

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

Hirsutism and Precocious Puberty

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

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

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

Hypercalcemia

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

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

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

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

Prostate Cancer

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

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

Ketoconazole Dosage and Administration

Administration

Oral Administration

Administer orally.263 384

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

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

Dosage

Pediatric Patients

General Pediatric Dosage
Treatment of Fungal Infections
Oral

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

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

Hypercalcemia
Oral

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

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

Adults

General Adult Dosage
Treatment of Fungal Infections
Oral

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

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

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

Blastomycosis
Oral

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

Usual duration of treatment is 6–12 months.424

Chromomycosis
Oral

200–400 mg daily.335

Coccidioidomycosis
Oral

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

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

Histoplasmosis
Oral

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

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

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

Paracocciodioidomycosis
Oral

200–400 mg once daily.335

Hypercalcemia
Oral

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

Prostate Cancer
Oral

400 mg every 8 hours has been used for treatment of prostatic carcinoma106 108 180 181 182 183 285 or as an adjunct in the management of disseminated intravascular coagulation (DIC) associated with prostatic carcinoma.152 178 Consider risk of toxicity, including risk of depressed adrenocortical function, if dosage exceeds 400 mg daily (see Cautions).263 384

Prescribing Limits

Adults

Oral

400 mg daily.263 384

Cautions for Ketoconazole

Contraindications

  • Hypersensitivity to ketoconazole.263 384

  • Acute or chronic liver disease.263 384

  • Concomitant use with certain drugs metabolized by CYP3A4 (e.g., colchicine, eplerenone, ergot alkaloids, felodipine, irinotecan, lovastatin, lurasidone, nisoldipine, simvastatin, tolvaptan);263 384 increased plasma concentrations of these drugs may occur and increase or prolong their therapeutic and/or adverse effects.263 384 (See Interactions.)

  • Concomitant use with certain drugs (e.g., cisapride, disopyramide, dofetilide, dronedarone, methadone, pimozide, quinidine, ranolazine);263 384 increased plasma concentrations of these drugs may occur and can lead to QT interval prolongation, sometimes resulting in life-threatening ventricular tachyarrhythmias such as torsades de pointes.263 384 (See Interactions.)

  • Concomitant use with certain benzodiazepines (e.g., alprazolam, oral midazolam, oral triazolam);263 384 increased plasma concentrations of these drugs may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic use.384

Warnings/Precautions

Warnings

Serious Adverse Effects

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

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

Hepatotoxicity

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

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

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

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

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

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

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

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

QT Prolongation

Prolonged QT interval reported.263 384

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

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

Endocrine and Metabolic Effects

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

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

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

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

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

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

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylaxis reported after first dose.102 263 384

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

General Precautions

Meningitis and Other CNS Infections

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

Specific Populations

Pregnancy

Category C.263 384

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

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

Fertility

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

Lactation

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

Pediatric Use

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

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

Common Adverse Effects

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

Interactions for Ketoconazole

Inhibits CYP3A4; metabolized by CYP3A4.263 384

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

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

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

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

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

Drugs Affecting or Affected by P-glycoprotein Transport

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

Drugs that Prolong the QT Interval

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

Drugs Affecting Gastric Acidity

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

Hepatotoxic Drugs

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

Specific Drugs

Drug

Interaction

Comments

Alcohol

Disulfiram reactions (flushing, rash, peripheral edema, nausea, headache) reported rarely when alcohol ingested while receiving ketoconazole;263 267 268 384 usually resolved within a few hours263 384

Avoid alcohol consumption during ketoconazole therapy;263 384 some clinicians recommend avoiding alcohol during and for 48 hours after discontinuance of the drug267

Aliskiren

Possible increased aliskiren concentrations384

Use concomitantly with caution;384 carefully monitor for increased or prolonged aliskiren effects;384 reduce aliskiren dosage if needed384

Antacids

Possible decreased absorption of ketoconazole263 384

Use concomitantly with caution384

Administer ketoconazole with acidic beverage (e.g., non-diet cola) and administer antacid ≥1 hour before or ≥2 hours after ketoconazole;384 monitor antifungal activity and adjust ketoconazole dosage if needed384

Antiarrhythmic agents (disopyramide, dofetilide, dronedarone, quinidine)

Disopyramide, dofetilide, dronedarone, quinidine: Possible increased antiarrhythmic agent concentrations and increased risk of serious or life-threatening adverse cardiovascular effects, including QT interval prolongation and ventricular tachyarrhythmias such as torsades de pointes384

Disopyramide, dofetilide, dronedarone, quinidine: Concomitant use contraindicated;384 in addition, do not use for up to 1 week after completion of ketoconazole treatment384

Anticoagulants, oral (dabigatran, rivaroxaban, warfarin)

Dabigatran, rivaroxaban: Possible increased anticoagulant concentrations384

Warfarin: Possible enhanced anticoagulant effects263 384

Dabigatran: Use concomitantly with caution;384 carefully monitor for increased or prolonged dabigatran effects;384 in patients with moderate renal impairment (Clcr 50–80 mL/minute), consider decreased dabigatran dosage of 75 mg twice daily384

Rivaroxaban: Avoid during and for up to 1 week after discontinuance of ketoconazole;384 if concomitant use cannot be avoided, monitor for increased or prolonged rivaroxaban effects384

Warfarin: Use concomitantly with caution;384 monitor PT or other appropriate tests closely; adjust anticoagulant dosage if needed263 384

Anticonvulsants (carbamazepine, phenytoin)

Carbamazepine: Possible increased carbamazepine concentrations; possible decreased ketoconazole concentrations and decreased antifungal efficacy384

Phenytoin: Possible decreased ketoconazole concentrations384

Carbamazepine: Avoid for 2 weeks prior to and during ketoconazole treatment and avoid for up to 1 week after discontinuance of ketoconazole;384 if concomitant use cannot be avoided, monitor for increased or prolonged carbamazepine effects and reduce or interrupt carbamazepine dosage if needed;384 also monitor for antifungal activity and increase ketoconazole dosage if needed384

Phenytoin: Avoid for 2 weeks prior to and during ketoconazole treatment;384 if concomitant use cannot be avoided, monitor for antifungal activity and increase ketoconazole dosage if needed384

Antidiabetic agents (repaglinide, saxagliptin)

Repaglinide, saxagliptin: Possible increased concentrations of the antidiabetic agent384

Repaglinide, saxagliptin: Use concomitantly with caution;384 monitor for increased or prolonged effects of the antidiabetic agent and reduce antidiabetic agent dosage if needed384

Antihistamines (loratadine)

Loratadine: Increased concentrations and AUCs of loratadine and its active metabolite; no evidence of changes in QT interval or incidence of adverse effects263 384

Antimalarials

Fixed combination of artemether and lumefantrine (artemether/lumefantrine): Increased concentrations of artemether, active metabolite of artemether, and lumefantrine;448 increased risk of QT interval prolongation448

Mefloquine: Substantially increased mefloquine concentrations, AUC, and elimination half-life;446 increased risk of potentially fatal prolongation of QTc interval446

Quinine: Increased quinine AUC and decreased quinine clearance447

Artemether/lumefantrine: Dosage adjustment for artemether/lumefantrine not needed;448 use concomitantly with caution448

Mefloquine: Do not use ketoconazole concomitantly with mefloquine or within 15 weeks after last mefloquine dose446

Quinine: Dosage adjustment of quinine not required; monitor closely for quinine-associated adverse effects447

Antimycobacterials (isoniazid, rifabutin, rifampin)

Isoniazid: Possible decreased ketoconazole concentrations384

Rifabutin: Possible increased rifabutin concentrations; possible decreased ketoconazole concentrations and decreased antifungal efficacy263 384

Rifampin: Decreased ketoconazole concentrations and possible decreased antifungal efficacy111 141 221 263 384

Isoniazid: Avoid for 2 weeks prior to and during ketoconazole treatment;384 if concomitant use cannot be avoided, monitor for antifungal activity and increase ketoconazole dosage if needed384

Rifabutin: Avoid for 2 weeks prior to and during ketoconazole treatment and avoid for up to 1 week after discontinuance of ketoconazole;384 if concomitant use cannot be avoided, monitor for increased or prolonged rifabutin effects and reduce or interrupt rifabutin dosage if needed;384 also monitor for antifungal activity and increase ketoconazole dosage if needed384

Rifampin: Avoid for 2 weeks prior to and during ketoconazole treatment;384 if concomitant use cannot be avoided, monitor for antifungal activity and increase ketoconazole dosage if needed384

Antiretrovirals, HIV entry inhibitors

Maraviroc: Possible increased maraviroc concentrations384

Maraviroc: Use concomitantly with caution;384 monitor for maraviroc-associated adverse effects and reduce maraviroc dosage if needed384

Antiretrovirals, HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs)

Delavirdine: Possible increased delavirdine concentrations212

Efavirenz, nevirapine: Possible decreased ketoconazole concentrations and reduced antifungal efficacy213 384

Etravirine: Possible increased etravirine concentrations and decreased ketoconazole concentrations214

Rilpivirine: Increased rilpivirine concentrations and AUC;226 decreased ketoconazole concentrations and AUC226

Efavirenz, nevirapine: Concomitant use not recommended;384 avoid for 2 weeks prior to and during ketoconazole treatment;384 if concomitant use cannot be avoided, monitor antifungal activity and increase ketoconazole dosage if needed384

Etravirine: Dosage adjustment of ketoconazole may be needed depending on other concomitantly administered drugs214

Rilpivirine: Dosage adjustment of rilpivirine not needed;226 monitor for breakthrough fungal infections226

Antiretrovirals, HIV protease inhibitors (PIs)

Possible pharmacokinetic interactions if ketoconazole used in patients receiving PIs (e.g., ritonavir-boosted or cobicistat- boosted atazanavir, ritonavir-boosted or cobicistat-boosted darunavir, fosamprenavir [with or without low-dose ritonavir], indinavir, fixed combination of lopinavir and ritonavir [lopinavir/ritonavir], nelfinavir, ritonavir-boosted saquinavir, ritonavir-boosted tipranavir);203 204 205 206 207 208 210 211 237 238 384 altered concentrations of the PI and/or the antifungal203 204 205 206 207 208 210 211 237 238 384

Ritonavir-boosted or cobicistat-boosted atazanavir: Use concomitantly with caution203 238

Ritonavir-boosted or cobicistat-boosted darunavir: Use concomitantly with caution;204 384 closely monitor for increased ketoconazole-, darunavir-, and ritonavir- or cobicistat-associated adverse effects;204 237 384 consider decreased ketoconazole dosage and monitor ketoconazole plasma concentrations if needed;384 do not exceed ketoconazole dosage of 200 mg daily in those receiving ritonavir-boosted darunavir204

Ritonavir-boosted fosamprenavir: Use concomitantly with caution;384 monitor for ketoconazole-associated adverse effects;384 consider decreased ketoconazole dosage and monitor ketoconazole plasma concentrations if needed;384 do not exceed ketoconazole dosage of 200 mg daily205

Fosamprenavir (without low-dose ritonavir): Decreased ketoconazole dosage may be needed in those receiving >400 mg of ketoconazole daily205

Indinavir (without low-dose ritonavir): Use concomitantly with caution;384 monitor for indinavir-associated adverse effects;384 use indinavir dosage of 600 mg every 8 hours206

Lopinavir/ritonavir: Do not exceed ketoconazole dosage of 200 mg daily207

Ritonavir-boosted saquinavir: Use concomitantly with caution and carefully monitor;384 do not exceed ketoconazole dosage of 200 mg daily210

Ritonavir-boosted tipranavir: Use concomitantly with caution;211 do not exceed ketoconazole dosage of 200 mg daily211

Aprepitant

Possible increased aprepitant concentrations384

Use concomitantly with caution;384 monitor for increased or prolonged aprepitant effects and reduce aprepitant dosage if needed384

Aripiprazole

Increased exposures of aripiprazole and its active metabolite384

Use concomitantly with caution;384 reduce aripiprazole dosage by 50%;384 monitor for increased or prolonged aripiprazole effects384

Benzodiazepines (alprazolam, midazolam, triazolam)

Alprazolam, midazolam, triazolam: Increased benzodiazepine concentrations;263 384 possible prolonged sedative and hypnotic effects, especially in those receiving repeated or chronic therapy with the drugs263 384

Alprazolam, oral midazolam, oral triazolam: Concomitant use with ketoconazole contraindicated;263 384 in addition, do not use for up to 1 week after completion of ketoconazole treatment384

Parenteral midazolam: Use concomitantly with caution;384 monitor for increased or prolonged midazolam effects and reduce midazolam dosage if needed384

Bortezomib

Possible increased bortezomib concentrations384

Use concomitantly with caution;384 monitor for increased or prolonged bortezomib effects and reduce bortezomib dosage if needed384

Bosentan

Increased bosentan concentrations and AUC263 384

Use concomitantly with caution;384 adjustment of bosentan dosage not needed; monitor closely for increased bosentan-associated adverse effects263 384

Buspirone

Increased buspirone concentrations263 384

Use concomitantly with caution;384 monitor for increased or prolonged buspirone effects and reduce buspirone dosage if needed384

Busulfan

Possible decreased busulfan clearance and increased systemic exposure263 384

Use concomitantly with caution;384 monitor for increased or prolonged busulfan effects and reduce busulfan dosage if needed;384

Calcium-channel blockers

Amlodipine, felodipine, nicardipine, nifedipine, verapamil: Increased concentrations of the calcium-channel blocker;263 384 negative inotropic effect of calcium-channel blockers may be additive to that of ketoconazole;384 possible increased risk of edema and congestive heart failure384

Felodipine, nisoldipine: Concomitant use contraindicated;263 384 in addition, do not use for up to 1 week after completion of ketoconazole treatment384

Other dihydropyridines (e.g., amlodipine, nicardipine, nifedipine): Use concomitantly with caution;384 monitor for increased or prolonged effects of the calcium-channel blocker and reduce dosage of the calcium-channel blocker if needed384

Verapamil: Use concomitantly with caution;384 monitor for increased or prolonged verapamil effects and reduce verapamil dosage if needed384

Cilostazol

Increased concentrations and AUC of cilostazol263 384

Use concomitantly with caution;384 monitor for increased or prolonged cilostazol effects and reduce cilostazol dosage if needed384

Cinacalcet

Possible increased cinacalcet concentrations384

Use concomitantly with caution;384 monitor for increased or prolonged cinacalcet effects and reduce cinacalcet dosage if needed384

Cisapride

Increased cisapride concentrations and increased risk of adverse effects (e.g., cardiovascular effects)263 276 384

Concomitant use contraindicated;263 384 in addition, do not use for up to 1 week after completion of ketoconazole treatment384

Colchicine

Possible increased colchicine concentrations and increased risk of potentially fatal adverse effects384

Patients with renal or hepatic impairment: Concomitant use contraindicated;384 in addition, do not use for up to 1 week after ketoconazole treatment is complete384

Patients without renal or hepatic impairment: Concomitant use not recommended;384 avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of colchicine-associated adverse effects;384 if concomitant use cannot be avoided, monitor for increased or prolonged colchicine effects and reduce or interrupt colchicine dosage if needed384

Corticosteroids

Budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, prednisolone: Possible increased corticosteroid concentrations;227 228 232 233 263 384 possible enhancement of adrenal suppressive effects228 233

Budesonide, ciclesonide, dexamethasone, methylprednisolone: Use concomitantly with caution;384 monitor for increased or prolonged corticosteroid effects and reduce corticosteroid dosage if needed384

Fluticasone propionate: Concomitant use not recommended unless potential benefits outweigh potential risks of systemic corticosteroid adverse effects384

Prednisolone: Carefully monitor; adjustment of prednisolone dosage may be needed227 228 263 232 233

Dasatinib

Possible increased dasatinib concentrations384

Concomitant use not recommended;384 avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of dasatinib-associated adverse effects;384 if concomitant use cannot be avoided, monitor for increased or prolonged dasatinib effects and reduce or interrupt dasatinib dosage if needed384

Digoxin

Increased digoxin concentrations reported; causative relationship unclear263 384

Use concomitantly with caution and monitor digoxin concentrations263 384

Docetaxel

Decreased clearance of docetaxel in cancer patients263 384

Use concomitantly with caution;384 monitor for increased or prolonged docetaxel effects and reduce docetaxel dosage if needed384

Eletriptan

Possible increased eletriptan concentrations384

Do not use within 72 hours of ketoconazole treatment;384 if used concomitantly, caution advised;384 monitor for increased or prolonged eletriptan effects and reduce eletriptan dosage if needed384

Eplerenone

Increased AUC of eplerenone; increased risk of hyperkalemia and hypotension263 384

Concomitant use contraindicated;263 384 in addition, do not use for up to 1 week after completion of ketoconazole treatment384

Ergot alkaloids

Increased ergot alkaloid concentrations; possible ergotism (i.e., risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities)263 384

Concomitant use contraindicated;263 384 in addition, do not use for up to 1 week after completion of ketoconazole treatment384

Erlotinib

Possible increased erlotinib concentrations384

Use concomitantly with caution;384 monitor for increased or prolonged erlotinib effects and reduce erlotinib dosage if needed384

Fesoterodine

Possible increased fesoterodine concentrations384

Use concomitantly with caution;384 monitor for increased or prolonged fesoterodine effects and reduce fesoterodine dosage if needed384

Haloperidol

Possible increased haloperidol concentrations384

Use concomitantly with caution;384 monitor for increased or prolonged haloperidol effects and reduce haloperidol dosage if needed384

HCV polymerase inhibitors

Fixed combination of ombitasvir, paritaprevir and ritonavir (ombitasvir/paritaprevir/ritonavir) with dasabuvir: Increased ketoconazole AUC455

Ombitasvir/paritaprevir/ritonavir with dasabuvir: Do not exceed ketoconazole dosage of 200 mg daily455

HCV protease inhibitors

Ombitasvir/paritaprevir/ritonavir with dasabuvir: Increased ketoconazole AUC454 455

Simeprevir: Possible increased simeprevir concentrations451

Ombitasvir/paritaprevir/ritonavir with or without dasabuvir: Do not exceed ketoconazole dosage of 200 mg daily454 455

Simeprevir: Concomitant use not recommended451

HCV replication complex inhibitors

Daclatasvir: Increased daclatasvir concentrations and AUC452

Elbasvir or grazoprevir: Increased concentrations and AUC of elbasvir or grazoprevir;453 possible increased risk of hepatotoxicity 453

Ombitasvir/paritaprevir/ritonavir with dasabuvir: Increased ketoconazole AUC454 455

Velpatasvir: No clinically important interaction456

Daclatasvir: If used concomitantly with ketoconazole, use daclatasvir dosage of 30 mg once daily452

Fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir): Concomitant use with ketoconazole not recommended453

Ombitasvir/paritaprevir/ritonavir with or without dasabuvir: Do not exceed ketoconazole dosage of 200 mg daily454 455

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

Possible decreased absorption of ketoconazole263 384

Use concomitantly with caution384

Administer ketoconazole with acidic beverage (e.g., non-diet cola) and administer H2-receptor antagonist ≥1 hour before or ≥2 hours after ketoconazole;384 monitor antifungal activity and adjust ketoconazole dosage if needed384

HMG-CoA reductase inhibitors (statins)

Atorvastatin, lovastatin, simvastatin: Increased statin concentrations; increased statin effects and increased risk of statin-associated adverse effects (e.g., myopathy, rhabdomyolysis)263 384

Atorvastatin: Use concomitantly with caution;384 monitor for increased or prolonged atorvastatin effects and reduce atorvastatin dosage if needed384

Lovastatin, simvastatin: Concomitant use contraindicated;263 384 in addition, do not use for up to 1 week after completion of ketoconazole treatment384

Imatinib

Possible increased imatinib concentrations384

Use concomitantly with caution;384 monitor for increased or prolonged imatinib effects and reduce imatinib dosage if needed384

Immunosuppressive agents (cyclosporine, everolimus, sirolimus, tacrolimus)

Cyclosporine: Increased cyclosporine concentrations;142 143 144 263 384 increased Scr142 143 144

Everolimus: Possible increased everolimus concentrations384

Sirolimus: Increased concentrations and AUC of sirolimus263 384

Tacrolimus: Increased tacrolimus concentrations263 372 384

Cyclosporine: Use concomitantly with caution;384 careful monitoring, with possible dosage adjustment, recommended;263 384 monitor renal function and cyclosporine concentrations;146 consider reduced cyclosporine dosage or use of another immunosuppressive agent;146 patients stabilized on both drugs may require an increase in cyclosporine dosage when ketoconazole discontinued146

Everolimus: Concomitant use not recommended;384 avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of adverse effects;384 if concomitant use cannot be avoided, monitor for increased or prolonged everolimus effects and reduce or interrupt everolimus dosage if needed384

Sirolimus: Concomitant use not recommended;263 384 avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of adverse effects;384 if concomitant use cannot be avoided, monitor for increased or prolonged sirolimus effects and reduce or interrupt sirolimus dosage if needed384

Tacrolimus: Use concomitantly with caution;384 monitor for increased or prolonged tacrolimus effects and reduce tacrolimus dosage if needed384

Irinotecan

Possible increased irinotecan concentrations;384 possible increased risk of fatal adverse effects384

Concomitant use contraindicated;384 in addition, do not use for up to 1 week after completion of ketoconazole treatment384

Ixabepilone

Possible increased ixabepilone concentrations384

Use concomitantly with caution;384 monitor for increased or prolonged ixabepilone effects and reduce ixabepilone dosage if needed384

Lapatinib

Possible increased lapatinib concentrations384

Concomitant use not recommended;384 avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of adverse effects;384 if concomitant use cannot be avoided, monitor for increased or prolonged lapatinib effects and reduce or interrupt lapatinib dosage if needed384

Lurasidone

Possible increased lurasidone concentrations384

Concomitant use contraindicated;384 in addition, do not use for up to 1 week after completion of ketoconazole treatment384

Nadolol

Possible increased nadolol concentrations384

Use concomitantly with caution;384 monitor for increased or prolonged nadolol effects and reduce nadolol dosage if needed384

Nilotinib

Possible increased nilotinib concentrations384

Concomitant use not recommended;384 avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of adverse effects;384 if concomitant use cannot be avoided, monitor for increased or prolonged nilotinib effects and reduce or interrupt nilotinib dosage if needed384

Opiate agonists or partial agonists

Alfentanil, fentanyl, sufentanil: Possible increased opiate agonist concentrations;263 384 possible increased risk of potentially fatal respiratory depression384

Buprenorphine: Possible increased buprenorphine concentrations384

Methadone: Possible increased methadone concentrations and increased risk of serious adverse cardiovascular effects, including QT interval prolongation384

Oxycodone: Possible increased oxycodone concentrations384

Alfentanil, fentanyl, sufentanil: Use concomitantly with caution;384 monitor for increased or prolonged opiate effects and reduce opiate agonist dosage if needed384

Buprenorphine: Use concomitantly with caution;384 monitor for increased or prolonged buprenorphine effects and reduce buprenorphine dosage if needed384

Methadone: Concomitant use contraindicated;384 in addition, do not use for up to 1 week after completion of ketoconazole treatment384

Oxycodone: Use concomitantly with caution;384 monitor for increased or prolonged oxycodone effects and reduce oxycodone dosage if needed384

Paclitaxel

In vitro evidence that ketoconazole can inhibit metabolism of paclitaxel269

Clinical importance unclear;384 use concomitantly with caution;384 monitor for increased or prolonged paclitaxel effects and reduce paclitaxel dosage if needed384

Phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil, vardenafil)

Increased concentrations of the PDE5 inhibitor and increased risk of PDE5 inhibitor-associated adverse effects (e.g., hypotension, syncope, visual changes, prolonged erection)263 376 378 379 384

Sildenafil: Use concomitantly with caution;384 monitor for increased or prolonged sildenafil effects and reduce sildenafil dosage if needed;384 manufacturer of sildenafil states consider initial sildenafil dosage of 25 mg in those receiving ketoconazole445

Tadalafil: Use concomitantly with caution;384 monitor for increased or prolonged tadalafil effects and reduce tadalafil dosage if needed;384 manufacturer of tadalafil recommends no more than 10 mg of tadalafil once every 72 hours in those receiving ketoconazole;378 if a once-daily tadalafil regimen is used, no more than 2.5 mg of tadalafil once daily recommended378

Vardenafil: Use concomitantly with caution;384 monitor for increased or prolonged vardenafil effects and reduce vardenafil dosage if needed;384 manufacturer of vardenafil recommends no more than a single 5-mg dose of vardenafil in a 24-hour period in those receiving ketoconazole 200 mg daily and no more than a single 2.5-mg dose of vardenafil in a 24-hour period in those receiving ketoconazole 400 mg daily379

Pimozide

Possible increased pimozide concentrations; may result in QTc interval prolongation, sometimes resulting in life-threatening ventricular tachyarrhythmias such as torsades de pointes263 384

Concomitant use contraindicated;263 384 in addition, do not use for up to 1 week after completion of ketoconazole treatment384

Praziquantel

Possible increased praziquantel concentrations384

Use concomitantly with caution;384 monitor for increased or prolonged praziquantel effects and reduce praziquantel dosage if needed384

Proton-pump inhibitors

Possible decreased absorption of ketoconazole384

Use concomitantly with caution384

Administer ketoconazole with acidic beverage (e.g., non-diet cola) and administer proton-pump inhibitor ≥1 hour before or ≥2 hours after ketoconazole;384 monitor antifungal activity and adjust ketoconazole dosage if needed384

Quetiapine

Possible increased quetiapine concentrations384

Use concomitantly with caution;384 monitor for increased or prolonged quetiapine effects and reduce quetiapine dosage if needed384

Ramelteon

Possible increased ramelteon concentrations384

Use concomitantly with caution;384 monitor for increased or prolonged ramelteon effects and reduce ramelteon dosage if needed384

Ranolazine

Possible increased ranolazine concentrations and increased risk of serious adverse cardiovascular effects, including QT interval prolongation384

Concomitant use contraindicated;384 in addition, do not use for up to 1 week after completion of ketoconazole treatment384

Risperidone

Possible increased risperidone concentrations384

Use concomitantly with caution;384 monitor for increased or prolonged risperidone effects and reduce risperidone dosage if needed384

Salmeterol

Possible increased salmeterol concentrations384

Concomitant use not recommended;384 avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of adverse effects;384 if concomitant use cannot be avoided, monitor for increased or prolonged salmeterol effects and reduce or interrupt salmeterol dosage if needed384

Solifenacin

Possible increased solifenacin concentrations384

Use concomitantly with caution;384 monitor for increased or prolonged solifenacin effects and reduce solifenacin dosage if needed384

Tamsulosin

Possible increased tamsulosin concentrations384

Concomitant use not recommended;384 avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of adverse effects;384 if concomitant use cannot be avoided, monitor for increased or prolonged tamsulosin effects and reduce or interrupt tamsulosin dosage if needed384

Telithromycin

Possible increased AUC of telithromycin; increased risk of telithromycin-associated adverse events263 384

Use concomitantly with caution;384 monitor for increased or prolonged telithromycin effects and reduce telithromycin dosage if needed384

Temsirolimus

Possible increased temsirolimus concentrations384

Concomitant use not recommended;384 avoid during and for up to 1 week after completion of ketoconazole treatment, unless benefits outweigh potential increased risk of adverse effects;384 if concomitant use cannot be avoided, monitor for increased or prolonged temsirolimus effects and reduce or interrupt temsirolimus dosage if needed384

Theophylline

Conflicting data;147 150 possible decreased theophylline concentrations147

Pending further accumulation of data, monitor theophylline concentrations and adjust theophylline dosage if necessary when ketoconazole is initiated or discontinued in patients receiving theophylline147

Tolterodine

Decreased apparent oral clearance of tolterodine and increased tolterodine concentrations263 384

Use concomitantly with caution;384 monitor for increased or prolonged tolterodine effects and reduce tolterodine dosage if needed384

Tolvaptan

Increased tolvaptan exposures;384 increased ketoconazole dosage expected to produce larger increases in tolvaptan exposures384

Concomitant use contraindicated;384 in addition, do not use for up to 1 week after completion of ketoconazole treatment;384 data insufficient to define safe tolvaptan dosage adjustment if used concomitantly with potent CYP3A inhibitors384

Trazodone

Possible substantially increased plasma trazodone concentrations and potential for adverse effects380

Consider reduced trazodone dosage in patients receiving ketoconazole380

Trimetrexate

Possible inhibition of trimetrexate metabolism263 and increased trimetrexate concentrations384

Use concomitantly with caution;384 monitor for increased or prolonged trimetrexate effects and reduce trimetrexate dosage if needed384

Vinca alkaloids

Vincristine, vinblastine, vinorelbine: Possible inhibition of metabolism of the vinca alkaloid263 and increased vinca alkaloid concentrations384

Use concomitantly with caution;384 monitor for increased or prolonged vinca alkaloid effects and reduce vinca alkaloid dosage if needed384

Ketoconazole Pharmacokinetics

Absorption

Bioavailability

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

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

Food

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

Plasma Concentrations

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

Special Populations

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

Distribution

Extent

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

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

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

Plasma Protein Binding

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

Elimination

Metabolism

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

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

Elimination Route

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

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

Half-life

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

Special Populations

Pharmacokinetics not substantially affected by renal or hepatic impairment.384

Stability

Storage

Oral

Tablets

20–25°C;384 protect from moisture.384

Actions and Spectrum

  • Imidazole-derivative azole antifungal.127 384

  • Usually fungistatic in action.119 121 127 129 130 131 132 133

  • Presumably exerts its antifungal activity by altering cellular membranes resulting in increased membrane permeability, leakage of essential elements (e.g., amino acids, potassium), and impaired uptake of precursor molecules (e.g., purine and pyrimidine precursors to DNA).127 128 130 131 Inhibits cytochrome P-450 14-α-desmethylase in susceptible fungi, which leads to accumulation of C-14 methylated sterols (e.g., lanosterol) and decreased concentrations of ergosterol.128 129 130 151

  • Spectrum of antifungal activity includes many fungi, including yeasts and dermatophytes.263 384 a Has some in vitro activity against some gram-positive bacteria (e.g., staphylococci, Nocardia) and some protozoa (e.g., Acanthamoeba, Leishmania).134 135 136 a

  • Active against Blastomyces dermatitidis,263 371 384 Coccidioides immitis,263 384 Cryptococcus neoformans,263 373 384 Histoplasma capsulatum,263 384 Paracoccidioides brasiliensis,263 384 Penicillium marneffei,389 390 and Phialophoa.263 384 Also active against Actinomadura madurae, Aspergillus flavus,120 122 124 A. fumigatus,122 124 Malassezia furfur (Pityrosporum orbiculare),a Petriellidium boydii,120 122 and Sporothrix schenckii.120 122 124 May be active against some strains of Exophiala castellanii275 and Scopulariopsis, including some strains of S. acremonium and S. brevicaulis.374

  • In vitro and in vivo studies indicate ketoconazole can directly inhibit synthesis of adrenal steroids and testosterone.109 110 112 113 114 115 116 117 148 151 154 156 157 158 159 160 161 171 172 173 174 175 176 Appears to inhibit steroid synthesis principally by blocking several P-450 enzyme systems (e.g., 11β-hydroxylase, C-17,20-lyase, cholesterol side-chain cleavage enzyme).112 114 117 151 152 154 155 157 158 159 171 172 173 174 175 176 201

  • Inhibits cortisol synthesis in a dose-dependent manner in individuals with normal adrenocortical function and in patients with Cushing’s syndrome (hypercortisolism).109 112 113 114 151 154 156 157 158 159 166 173

Advice to Patients

  • Advise patients that oral ketoconazole is used only for treatment of certain serious systemic fungal infections and is prescribed only when other effective antifungals not available or not tolerated and potential benefits of the drug outweigh potential risks.263 384 449 450

  • Advise patients that oral ketoconazole is not used for treatment of fungal infections of the skin or nails.263 384 449 450

  • Risk of hepatotoxicity; importance of reporting any signs or symptoms of possible hepatic dysfunction (e.g., unusual fatigue, anorexia, nausea and/or vomiting, abdominal pain, jaundice, dark urine, pale feces) to their clinician.167 168 188 189 263 384

  • Risk of QT interval prolongation, especially if certain medications are used concomitantly.263 384 Importance of informing their clinicians if they have had an abnormal ECG or have a family member with a history of congenital long QT syndrome.263 384 Importance of contacting their clinicians if symptoms of QT interval prolongation occur (e.g., feeling faint, lightheaded, dizzy, irregular or fast heart beat).263 384

  • Risk of adrenal insufficiency if high dosage is used.263 384 Importance of informing their clinicians if they have a history of adrenal insufficiency.263 384 Importance of contacting their clinicians if symptoms of adrenal insufficiency occur (e.g., tiredness, weakness, dizziness, nausea, vomiting).263 384

  • Risk of hypersensitivity reactions.263 384 Importance of discontinuing ketoconazole and immediately contacting their clinicians if signs of an allergic reaction occur (e.g., rash, itching, hives, fever, swelling of lips or tongue, chest pain, trouble breathing).263 384

  • Advise patients not to consume alcohol during ketoconazole therapy.263 384

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.384

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.384

  • Importance of advising patients of other important precautionary information.384 (See Cautions.)

Preparations

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

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

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

Ketoconazole

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

200 mg*

Ketoconazole Tablets

AHFS DI Essentials. © Copyright 2017, 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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Only references cited for selected revisions after 1984 are available electronically.

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