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

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 to treat fungal infections that involve the CNS, including cerebral blastomycosis; ketoconazole CSF concentrations unpredictable following oral administration and treatment failures or relapses reported.192 263 288 295 384

Candida Infections

Has been used for treatment of certain Candida infections (e.g., oropharyngeal and/or esophageal candidiasis, vulvovaginal candidiasis, candiduria, chronic mucocutaneous candidiasis);292 320 322 323 328 334 no longer recommended and no longer labeled by FDA for Candida infections.263 384

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

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

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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 to treat fungal infections that involve the CNS, including coccidioidal meningitis; ketoconazole CSF concentrations unpredictable following oral administration and treatment failures or relapses reported.263 288 302 384

Histoplasmosis

Alternative for treatment of histoplasmosis caused by Histoplasma capsulatum.234 263 288 291 292 293 384 428 Use only when other effective antifungals not available or not tolerated and potential benefits of oral ketoconazole outweigh potential risks.263 384

Drugs of choice are IV amphotericin B or oral itraconazole428 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 azoles (fluconazole, ketoconazole, posaconazole, voriconazole) considered second-line alternatives to oral itraconazole.428 436

Paracoccidioidomycosis

Alternative for treatment of paracoccidioidomycosis (South American blastomycosis) caused by Paracoccidioides brasiliensis.263 288 291 311 335 384 436 Use only when other effective antifungals not available or not tolerated and potential benefits of oral ketoconazole outweigh potential risks.263 384

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

Sporotrichosis

Has been used for treatment of sporotrichosis caused by Sporothrix schenckii.312 313 335 429 Not recommended since it is less effective and associated with more adverse effects than some other azoles.429 Oral itraconazole is drug of choice for treatment of cutaneous, lymphocutaneous, or mild pulmonary or osteoarticular sporotrichosis and for follow-up therapy in more severe infections after a response has been obtained with IV amphotericin B.429

Dermatophytoses

Has been used orally 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

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

A regimen of oral ketoconazole, rifampin, and co-trimoxazole has been used for treatment of chronic Acanthamoeba meningitis in several immunocompetent children.187 442 (See Meningitis and Other CNS Infections under Cautions.)

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

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

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

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

Ketoconazole Dosage and Administration

Administration

Oral Administration

Administer orally.263 384

To ensure absorption in patients with achlorhydria (see Absorption under Pharmacokinetics), some clinicians suggest administering 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, this strategy may not be adequate in all patients with achlorhydria and patients should be monitored 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 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

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

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 Risk of depressed adrenocortical function at this high dosage should be considered.263 (See Endocrine and Metabolic Effects under Cautions.)

Hypercalcemia
Oral

200–800 mg daily has been used for treatment of hypercalcemia in adults with sarcoidosis.363 365 366

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., alprazolam, oral midazolam, oral triazolam, eplerenone, ergot alkaloids, lovastatin, simvastatin, nisoldipine); 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, dofetilide, pimozide, quinidine); 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.)

Warnings/Precautions

Warnings

Serious Adverse Effects

Serious adverse effects (e.g., hepatotoxicity, adrenal insufficiency) and drug interactions have been reported with oral ketoconazole.263 384 Use only when other effective antifungals not available or not tolerated and potential benefits of oral ketoconazole outweigh potential risks.263 384

Hepatotoxicity

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

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 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 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

During ketoconazole therapy, monitor serum ALT concentrations weekly.263 384 Prompt recognition of liver injury is essential.263 384 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 Repeat liver tests to ensure that values normalize.263 384

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

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

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, angioneurotic edema, alopecia, and xeroderma also reported.263 384

General Precautions

Meningitis and Other CNS Infections

Because CSF concentrations of ketoconazole are unpredictable 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

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

Drugs Metabolized by Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction with drugs metabolized by CYP3A4; possible increased concentrations of the concomitant drug and increased or prolonged therapeutic and/or adverse effects associated with the drugs.263 384

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction with drugs that inhibit CYP3A4; possible increased ketoconazole concentrations and increased risk of adverse effects associated with the antifungal.263 384

Potential pharmacokinetic interaction with drugs that induce CYP3A4; possible decreased ketoconazole concentrations and decreased efficacy of the antifungal.263 384

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

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) have occurred rarely in patients who ingested alcohol 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

Antacids

Because gastric acidity is necessary for dissolution and absorption of ketoconazole, concomitant administration of antacids may decrease absorption of the antifungal263 384

Concomitant use not recommended263 384

Anticoagulants, oral (warfarin)

Possible enhanced anticoagulant effects263 384

Monitor PT or other appropriate tests closely; adjust anticoagulant dosage if necessary263 384

Anticonvulsants (carbamazepine, phenytoin)

Carbamazepine, phenytoin: Possible pharmacokinetic interaction and altered metabolism of one or both drugs263 384

Carbamazepine, phenytoin: Concomitant use not recommended;263 384 if used concomitantly, closely monitor anticonvulsant concentrations and monitor for decreased antifungal efficacy263 384

Antidiabetic agents, sulfonylureas

Increased plasma concentrations of the antidiabetic agent and symptoms of hypoglycemia reported with other azoles (e.g., itraconazole)263 384

Consider the possibility that hypoglycemia may occur when ketoconazole used concomitantly with antidiabetic agents263 384

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

Artemether and 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

Antimalarials

Artemether and 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 and 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 (rifabutin, rifampin, isoniazid)

Rifabutin: Decreased ketoconazole concentrations and possible increased rifabutin concentrations263 384

Rifampin: Decreased ketoconazole concentrations111 141 221 263 384

Isoniazid: May affect ketoconazole concentrations111 263 384

Rifabutin, rifampin, isoniazid: Concomitant use not recommended263 384

Antiretrovirals, HIV entry inhibitors

Maraviroc: Possible increased maraviroc concentrations200

Maraviroc: Reduce maraviroc dosage to 150 mg twice daily200

Antiretrovirals, HIV protease inhibitors (PIs)

Possible pharmacokinetic interactions if ketoconazole used in patients receiving PIs (e.g., ritonavir-boosted darunavir, fosamprenavir [with or without low-dose ritonavir], indinavir, lopinavir/ritonavir, nelfinavir, ritonavir-boosted saquinavir, ritonavir-boosted tipranavir);204 205 206 207 208 210 211 altered concentrations of the PI and/or the antifungal204 205 206 207 208 210 211

Ritonavir-boosted darunavir: Do not exceed ketoconazole dosage of 200 mg daily204

Fosamprenavir (without low-dose ritonavir): May need decreased ketoconazole dosage in those receiving >400 mg of ketoconazole daily

205 Ritonavir-boosted fosamprenavir: Do not exceed ketoconazole dosage of 200 mg daily205

Indinavir (without low-dose ritonavir): Use indinavir dosage of 600 mg every 8 hours206

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

Ritonavir-boosted saquinavir: Do not exceed ketoconazole dosage of 200 mg daily210

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

Antiretrovirals, nonnucleoside reverse transcriptase inhibitors (NNRTIs)

Delavirdine: Possible increased delavirdine concentrations212

Efavirenz: Possible decreased ketoconazole concentrations213

Etravirine: Possible increased etravirine concentrations and decreased ketoconazole concentrations214

Nevirapine: Possible decreased ketoconazole concentrations and decreased efficacy of the antifungal263

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

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

Nevirapine: Concomitant use not recommended263

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

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 drugs263 384

Alprazolam, oral midazolam, oral triazolam: Concomitant use with ketoconazole contraindicated263 384

Parenteral midazolam: Special precaution and patient monitoring required263 384

Bosentan

Increased bosentan concentrations and AUC263 384

Dosage adjustment of bosentan not needed; monitor closely for increased bosentan-associated adverse effects263 384

Buspirone

Increased buspirone concentrations263 384

Careful monitoring, with possible dosage adjustment, recommended;263 384 use low initial buspirone dosage and adjust subsequent dosage as needed based on clinical assessment263 384

Busulfan

Decreased busulfan clearance and increased systemic exposure263 384

Careful monitoring, with possible dosage adjustment, recommended263 384

Calcium-channel blockers

Amlodipine, felodipine, nicardipine, nifedipine, verapamil: Increased concentrations of the calcium-channel blocker263 384

Nisoldipine: Pretreatment with and concomitant use of ketoconazole increases nisoldipine concentrations and AUC263 384

Amlodipine, felodipine, nicardipine, nifedipine, verapamil: Use concomitantly with caution and careful monitoring; dosage adjustment may be needed263 384

Nisoldipine: Concomitant use contraindicated263 384

Cilostazol

Increased concentrations and AUC of cilostazol; increased incidence of cilostazol-associated adverse effects (e.g., headache)263 384

Careful monitoring recommended; consider 50% reduction in cilostazol dosage263 384

Cisapride

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

Concomitant use contraindicated263 384

Corticosteroids

Methylprednisolone, prednisolone: Increased corticosteroid concentrations;227 228 232 233 263 384 possible enhancement of adrenal suppressive effects228 233

Methylprednisolone, prednisolone: Carefully monitor; adjustment of corticosteroid dosage may be needed227 228 263 232 233 384

Digoxin

Increased digoxin concentrations reported; causative relationship unclear263 384

Closely monitor digoxin concentrations in patients receiving ketoconazole263 384

Docetaxel

Decreased clearance of docetaxel in cancer patients263 384

Careful monitoring recommended; reduction in docetaxel dosage may be necessary to minimize incidence of docetaxel-associated toxicities263 384

Dofetilide

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

Concomitant use contraindicated263 384

Eplerenone

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

Concomitant use contraindicated263 384

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 contraindicated263 384

HCV protease inhibitors

Boceprevir: Increased boceprevir concentrations and AUC; possible increased ketoconazole concentrations444

Telaprevir: Increased concentrations and AUCs of both drugs443

Boceprevir: If concomitant use required, do not exceed ketoconazole dosage of 200 mg daily444

Telaprevir: If concomitant use required, do not exceed ketoconazole dosage of 200 mg daily443

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

Because gastric acidity is necessary for dissolution and absorption of ketoconazole, concomitant administration of histamine H2-receptor antagonists may decrease absorption of the antifungal 263 384

HMG-CoA reductase inhibitors (statins)

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

Atorvastatin, lovastatin: Concomitant use contraindicated263 384

Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)

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

Sirolimus: Increased concentrations and AUC of sirolimus263 384

Tacrolimus: Increased concentrations of tacrolimus263 372 384

Cyclosporine: 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

Sirolimus: Concomitant use not recommended263 384

Tacrolimus: Careful monitoring, with possible dosage adjustment, recommended263 384

Opiate agonists

Alfentanil, fentanyl, sufentanil: Possible increased concentrations of the opiate agonist263 384

Alfentanil, fentanyl, sufentanil: Careful monitoring, with possible dosage adjustment, recommended263 384

Paclitaxel

In vitro evidence that ketoconazole can inhibit metabolism of paclitaxel269

Clinical importance unclear; use concomitantly with caution269

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: Manufacturer of ketoconazole recommends that initial dose of sildenafil be reduced by 50%;263 384 manufacturer of sildenafil recommends initial sildenafil dosage of 25 mg in those receiving ketoconazole445

Tadalafil: Patients receiving ketoconazole should receive no more than 10 mg of tadalafil once every 72 hours;378 if a once-daily tadalafil regimen is used, those receiving ketoconazole should receive no more than 2.5 mg of tadalafil once daily378

Vardenafil: Patients receiving ketoconazole 400 mg daily should receive no more than a single 2.5-mg dose of vardenafil in a 24-hour period; those receiving ketoconazole 200 mg daily should receive no more than a single 5-mg dose of vardenafil in a 24-hour period379

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 contraindicated263 384

Quinidine

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

Concomitant use contraindicated263 384

Sucralfate

Possible decreased absorption of ketoconazole362

Concomitant use not recommended263 384

Telithromycin

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

Careful monitoring, with possible dosage adjustment, recommended263 384

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

Careful monitoring, with possible dosage adjustment, recommended;263 384 if tolterodine initiated in a patient receiving ketoconazole, reduce initial dosage by 50%263 384

Trazodone

Possible substantially increased plasma trazodone concentrations and potential for adverse effects380

Consider reducing trazodone dosage in patients receiving ketoconazole380

Trimetrexate

Possible inhibition of trimetrexate metabolism263 384

Carefully monitor for trimetrexate-associated toxicities; dosage adjustments may be needed263 384

Vinca alkaloids

Vincristine, vinblastine, vinorelbine: Possible inhibition of metabolism of the vinca alkaloid263 384

Vincristine, vinblastine, vinorelbine: Monitor closely for vinca alkaloid toxicity; dosage adjustments may be needed263 384

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 (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 has generally been considered to be minimal.a

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

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

Plasma concentrations and half-life not substantially affected by renal or hepatic impairment.a

Stability

Storage

Oral

Tablets

15–25°C in tight, light-resistant container; protect from moisture.263 384

Actions and Spectrum

  • Imidazole-derivative azole antifungal.127 222

  • 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

  • Candida: Active in vitro and in vivo against C. albicans,120 121 122 123 124 373 C. dubliniensis,283 and some strains of C. glabrata,120 122 123 124 373 C. lusitaniae,289 C. parapsilosis,373 and C. tropicalis.373

  • Dermatophytes: Active against Epidermophyton floccosum,263 384 a Microsporum canis,a M. gypseum,120 a Trichophyton mentagrophytes,a T. rubrum,a and T. tonsurans.a

  • Other fungi: 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

  • Strains of Candida albicans resistant to ketoconazole have been isolated from patients who received the drug.125 126

  • Ketoconazole-resistant Candida may be cross-resistant to other azole antifungals (e.g., fluconazole, itraconazole).337

  • 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 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

  • Advise patients that oral ketoconazole is not used for treatment of fungal nail infections.263 384

  • 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

Preparations

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

* 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

Nizoral

Janssen

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Ketoconazole 200MG Tablets (TARO): 14/$30.99 or 42/$88.99

Nizoral 200MG Tablets (JANSSEN): 30/$129.99 or 90/$369.95

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 27, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

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

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204. Janssen Pharmaceuticals. Prezista (darunavir) oral suspension and tablets prescribing information. Titusville, NJ; 2013 Apr.

205. ViiV Healthcare. Lexiva (fosamprenavir calcium) tablets and oral suspension prescribing information. Research Triangle Park, NC; Apr 2013.

206. Merck Sharp & Dohme Corp. Crixivan (indinavir sulfate) capsules prescribing information. Whitehouse Station, NJ; 2012 Apr.

207. AbbVie Inc. Kaletra (lopinavir/ritonavir) tablets and oral solution prescribing information. North Chicago, IL; 2013 Jul.

208. ViiV Healthcare. Viracept (nelfinavir mesylate) tablets and oral powder prescribing information. Research Triangle Park, NC; 2013 May.

210. Genentech USA Inc. Invirase (saquinavir mesylate) capsules and tablets prescribing information. South San Francisco, CA; 2012 Nov.

211. Boehringer Ingelheim Pharmaceutics Inc. Aptivus (tipranavir) capsules and oral solution prescribing information. Ridgefield, CT; 2012 Apr.

212. ViiV Healthcare. Rescriptor (delavirdine mesylate) tablets prescribing information. Research Triangle Park, NC; 2012 Apr.

213. Bristol-Myers Squibb. Sustiva (efavirenz) capsules and tablets prescribing information. Princeton, NJ; 2013 May.

214. Janssen. Intelence (etravirine) tablets prescribing information.Titusville, NJ; 2013 Feb.

216. Greene NB, Baughman RP, Kim CK et al. Failure of ketoconazole in an immunosuppressed patient with pulmonary blastomycosis. Chest. 1985; 88:640-1. [IDIS 207498] [PubMed 3899536]

217. Thiele JS, Buechner HA, Cook EW Jr. Failure of ketoconazole in two patients with blastomycosis. Chest. 1985; 88:640-1. [IDIS 207498] [PubMed 3899536]

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444. Merck & Co. Victrelis (boceprevir) capsules prescribing information. Whitehouse Station, NJ; 2013 Feb.

445. Pfizer Laboratories. Viagra (sildenafil citrate) tablets prescribing information. New York, NY; 2010 Jan.

446. Teva Pharmaceuticals. Mefloquine hydrochloride tablets prescribing information. Sellersville, Pa; 2013 Jun.

447. AR Scientific, Inc. Qualaquin (quinine sulfate) capsules, USP for oral use prescribing information. Philadelphia, PA; 2011 Apr.

448. Novartis Pharmaceutics Corporation. Coartem (artemether/lumefantrine) tablets prescribing information. East Hanover, NJ; 2013 Apr.

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