Ketoconazole, a synthetic imidazole derivative, is an azole antifungal agent.263, 384
Oral ketoconazole has been used as an alternative for the treatment of blastomycosis,220, 234, 263, 288, 291, 292, 299, 300, 384, 424 chromomycosis (chromoblastomycosis),263, 288, 335, 384 coccidioidomycosis,263, 303, 304, 305, 384, 426 histoplasmosis,234, 263, 288, 291, 292, 293, 384, 428 and paracoccidioidomycosis.263, 288, 291, 292, 335, 384 Because ketoconazole has been associated with serious adverse effects (e.g., hepatotoxicity, adrenal insufficiency) and drug interactions, the drug should be used for the treatment of these systemic fungal infections only when they are serious or life-threatening, other effective antifungals are not available or not tolerated, and the potential benefits of oral ketoconazole outweigh potential risks of the drug. 263, 384, 449, 450 (See Cautions: Precautions and Contraindications.)
Although oral ketoconazole has been used in the past for the treatment of certain Candida infections† (e.g., oropharyngeal and/or esophageal candidiasis†, vulvovaginal candidiasis†, candiduria†, chronic mucocutaneous candidiasis†)292, 320, 322, 323, 334 and the treatment of dermatophyte infections† (e.g., tinea capitis†, tinea corporis†, tinea pedis†, tinea unguium† [onychomycosis†]),291, 324, 325, 384 the drug is no longer recommended and no longer labeled by FDA for these uses.263, 384 449, 450 Because skin and nail fungal infections in otherwise healthy individuals are not life-threatening, risks associated with oral ketoconazole outweigh benefits of the drug in patients with these infections. 450 Therefore, oral ketoconazole should not be used for the treatment of mucocutaneous or skin infections caused by Candida and should not be used for the treatment of dermatophyte infections of the skin or nails.449, 450 For use of ketoconazole in the topical treatment of dermatophytoses and superficial mycoses, see Ketoconazole 84:04.08.
Oral ketoconazole has been used for the 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 Based on ketoconazole's endocrine effects, 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 Oral ketoconazole also has been used in the treatment of hypercalcemia in patients with sarcoidosis†363, 364, 365, 366, 394, 395 and the treatment of tuberculosis-associated hypercalcemia†367 and idiopathic infantile hypercalcemia and hypercalciuria†.392
Oral ketoconazole has been used as an alternative for the treatment of blastomycosis caused by Blastomyces dermatitidis .220, 234, 263, 288, 291, 292, 299, 300, 384, 424 Ketoconazole should be used for the treatment of blastomycosis only if the infection is serious or life-threatening, other effective antifungals are not available or not tolerated, and the potential benefits of oral ketoconazole outweigh potential risks of the drug.263, 384, 424, 449, 450
IV amphotericin B and oral itraconazole usually are the drugs of choice for the treatment of blastomycosis;288, 292, 296, 297, 298, 299, 332, 333, 424, 436 oral fluconazole is an alternative.288, 292, 297, 299, 424, 436
In initial clinical studies, ketoconazole was effective when used in immunocompetent individuals with mild to moderate pulmonary or extrapulmonary blastomycosis (response rate 70-100%);220, 234, 291, 292, 297, 424 however, the relapse rate with the drug was 10-14%.424 Because CSF concentrations of ketoconazole are unpredictable and may be negligible following oral administration and because treatment failures or relapses have been reported, the drug should not be used to treat fungal infections that involve the CNS, including cerebral blastomycosis.192, 263, 288, 295, 384
For additional information on management of blastomycosis, the current clinical practice guidelines from the Infectious Diseases Society of America (IDSA) available at [Web] should be consulted.424
Oral ketoconazole has been used as an alternative for the treatment of chromomycosis (chromoblastomycosis) caused by Phialophora spp.263, 288, 335, 384 Ketoconazole should be used for the treatment of chromomycosis only if the infection is serious or life-threatening, other effective antifungals are not available or not tolerated, and the potential benefits of oral ketoconazole outweigh potential risks of the drug.263, 384, 449, 450
A response to ketoconazole has been obtained in some patients with mild to moderate infections, but not in those with more extensive disease.335 While optimum regimens for the treatment of chromomycosis have not been identified, other antifungals (e.g., flucytosine alone or in conjunction with amphotericin B or itraconazole) are recommended.288, 335
Oral ketoconazole has been used as an alternative for the treatment of coccidioidomycosis caused by Coccidioides immitis .263, 288, 303, 304, 305, 384, 426 Ketoconazole should be used for the treatment of coccidioidomycosis only if the infection is serious or life-threatening, other effective antifungals are not available or not tolerated, and the potential benefits of oral ketoconazole outweigh potential risks of the drug.263, 384, 449, 450
IDSA and others state that an oral azole (fluconazole or itraconazole) usually is recommended for initial treatment of symptomatic pulmonary coccidioidomycosis and chronic fibrocavitary or disseminated (extrapulmonary) coccidioidomycosis, including in individuals with human immunodeficiency virus (HIV) infection.426, 436, 440 IV amphotericin B is recommended as an alternative and is preferred for initial treatment of severely ill patients who have hypoxia or rapidly progressing disease, for immunocompromised individuals, or when azole antifungals have been ineffective or cannot be used (e.g., pregnant women).426, 440 Because CSF concentrations of ketoconazole are unpredictable and may be negligible following oral administration and because treatment failures or relapses have been reported, the drug should not be used to treat fungal infections that involve the CNS, including coccidioidal meningitis.263, 288, 302, 384
For additional information on management of coccidioidomycosis, the current clinical practice guidelines from IDSA available at [Web]426 and the current clinical practice guidelines from the US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and IDSA on the prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web]440, 441 should be consulted.
Oral ketoconazole has been used as an alternative for the treatment of histoplasmosis caused by Histoplasma capsulatum .234, 263, 288, 291, 292, 293, 384, 428 Ketoconazole should be used for the treatment of histoplasmosis only if the infection is serious or life-threatening, other effective antifungals are not available or not tolerated, and the potential benefits of oral ketoconazole outweigh potential risks of the drug.263, 384, 449, 450
The drugs of choice for the treatment of histoplasmosis are IV amphotericin B or oral itraconazole.428, 436, 440 IV amphotericin B is preferred for initial treatment of severe, life-threatening histoplasmosis, especially in immunocompromised patients such as those with HIV infection.428, 436, 440 Oral itraconazole generally is used for initial treatment of less severe disease (e.g., mild to moderate acute pulmonary histoplasmosis, chronic cavitary pulmonary histoplasmosis) and as follow-up therapy in the treatment of severe infections after a response has been obtained with IV amphotericin B.428, 436, 440 Other azole antifungals (fluconazole, ketoconazole, posaconazole, voriconazole) are considered second-line alternatives to oral itraconazole.428, 436
For additional information on management of histoplasmosis, the current clinical practice guidelines from IDSA available at [Web]428 and the current clinical practice guidelines from CDC, NIH, and IDSA on the prevention and treatment of opportunistic infections in HIV-infected individuals available at [Web]440, 441 should be consulted.
Oral ketoconazole has been used as an alternative for the treatment of paracoccidioidomycosis (South American blastomycosis) caused by Paracoccidioides brasiliensis .263, 288, 291, 311, 335, 384 Ketoconazole should be used for the treatment of paracoccidioidomycosis only if the infection is serious or life-threatening, other effective antifungals are not available or not tolerated, and the potential benefits of oral ketoconazole outweigh potential risks of the drug.263, 384, 449, 450
IV amphotericin B is the drug of choice for initial treatment of severe paracoccidioidomycosis.288, 291, 293, 310, 311, 335, 436 Oral itraconazole is the drug of choice for the treatment of less severe or localized paracoccidioidomycosis and for follow-up therapy of more severe infections after initial treatment with IV amphotericin B.288, 291, 335, 436
Ketoconazole has been used effectively for the 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 Ketoconazole has been used in a limited number of geriatric patients 75 years or older for the treatment of corticotropin-dependent Cushing's syndrome, and some clinicians suggest that the drug may provide an effective alternative in patients who cannot tolerate surgical treatment.342
Safety and efficacy of ketoconazole for the treatment of Cushing's syndrome have not been established and the drug is not labeled by FDA for this use. 263, 384
Hirsutism and Precocious Puberty
Although safety and efficacy have not been established, ketoconazole has been used with some success in a limited number of patients for the treatment of dysfunctional hirsutism†115, 370 and in a limited number of boys for the treatment of precocious puberty†.116, 185, 186
Safety and efficacy of ketoconazole for treatment of hirsutism and precocious puberty have not been established and the drug is not labeled by FDA for these uses. 263, 384
Although safety and efficacy have not been established, ketoconazole has been used with some success for the treatment of hypercalcemia in adults with sarcoidosis†.363, 364, 365, 366, 394, 395 By competitively inhibiting synthesis of 1,25-dihydroxyvitamin D, ketoconazole may reduce elevated serum concentrations of the vitamin that apparently may contribute to sarcoidosis-associated hypercalcemia.364, 365 Ketoconazole has been shown to produce a dose-dependent decrease in serum 1,25-dihydroxyvitamin D concentrations in healthy individuals and hypercalcemic patients with primary hyperparathyroidism.364, 365, 366 However, while ketoconazole generally decreases serum concentrations of the vitamin, the drug has reduced serum calcium concentrations in some, but not all, patients with sarcoidosis-associated hypercalcemia.364, 365, 366 In addition, hypercalcemia and increased serum 1,25-dihydroxyvitamin D concentrations may recur when ketoconazole dosage is decreased or the drug discontinued.365, 366 Corticosteroids generally are considered first-line treatment of sarcoidosis-associated hypercalcemia; ketoconazole is considered an alternative in patients who fail to respond to or cannot tolerate corticosteroids.363, 365, 393, 394, 395
Ketoconazole has been effective in a few adolescents for the treatment of tuberculosis-associated hypercalcemia†.367 Ketoconazole also has been effective in a few infants† for the treatment of idiopathic infantile hypercalcemia and hypercalciuria†.392
Safety and efficacy of ketoconazole for treatment of hypercalcemia have not been established and the drug is not labeled by FDA for this use. 263, 384
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 Ketoconazole has been used as a first-line agent in a few patients, but usually has been used as second-line hormonal therapy in patients with stage IV recurrent prostatic cancer.284, 286 A limited number of patients with androgen-independent prostatic cancer have received ketoconazole in conjunction with doxorubicin.368, 369 Ketoconazole has been used effectively as an adjunct in the acute management of disseminated intravascular coagulation (DIC) associated with prostatic carcinoma† in a limited number of patients.152, 178
Safety and efficacy of ketoconazole for the treatment of advanced prostate cancer have not been established and the drug is not labeled by FDA for this use. 263, 384
Oral ketoconazole has been used in conjunction with topical anti-infective agents (e.g., miconazole, neomycin, metronidazole, propamidine isethionate) in the treatment of Acanthamoeba keratitis†.134, 135, 136, 137, 138, 139, 140, 225, 442 Optimum therapy for Acanthamoeba keratitis remains to be clearly established, but prolonged local and systemic therapy with multiple anti-infective agents and, often, surgical treatment (e.g., penetrating keratoplasty) are usually required.134, 135, 136, 137, 138, 139, 140, 442
Ketoconazole is administered orally.263, 384
If used in patients receiving a drug that decreases gastric acid output or increases gastric pH, ketoconazole tablets should be administered with an acidic beverage (e.g., non-diet cola) and the acid-reducing drug should be administered at least 1 hour before or 2 hours after ketoconazole.384 (See Drug Interactions: Drugs Affecting Gastric Acidity.)
To ensure absorption in patients with achlorhydria (see Pharmacokinetics: Absorption), some clinicians have suggested that each 200-mg dose of oral ketoconazole should be administered with an acidic beverage (e.g., Coca-Cola®, Pepsi®) or the dose dissolved 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
The usual initial adult dosage of oral ketoconazole recommended by the manufacturer for the treatment of fungal infections is 200 mg once daily.263, 384 If the expected clinical response is not achieved, the manufacturer states that oral ketoconazole dosage may be increased to 400 mg once daily.263, 384 The manufacturer states that the recommended dosage (i.e., 200-400 mg daily in adults) should not be exceeded.263, 384 Higher dosage is associated with increased toxicity.234, 263, 288, 290, 384 (See Cautions.)
Although data are limited regarding use of ketoconazole in children, a dosage of 3.3-6.6 mg/kg once daily has been used for the treatment of fungal infections in some children older than 2 years of age.263, 384 (See Cautions: Pediatric Precautions.)
The manufacturer states that the usual duration of treatment for systemic fungal infections is 6 months and treatment should be continued until the active fungal infection subsides.263, 384
If ketoconazole is used for the treatment of blastomycosis, an initial ketoconazole dosage of 400 mg daily has been recommended; if the response is inadequate, some clinicians suggest that a dosage of 800 mg daily can be considered.220, 234, 288, 424 The risk of toxicity should be considered if ketoconazole dosage exceeds 400 mg daily.263, 384 (See Cautions.)
Blastomycosis usually is treated for 6-12 months.424
A ketoconazole dosage of 200-400 mg daily has been recommended for the treatment of chromomycosis.335
For the treatment of coccidioidomycosis, ketoconazole has been given in a dosage of 400 mg once daily.426 Long-term treatment (months to years) is required.426
HIV-infected individuals who have been adequately treated for coccidioidomycosis should receive long-term (usually life-long) suppressive or maintenance therapy (secondary prophylaxis) with oral itraconazole or oral fluconazole to prevent recurrence or relapse.440, 441
For the treatment of histoplasmosis, some clinicians recommend that ketoconazole be administered in a dosage of 400-800 mg daily.234, 288 The risk of toxicity should be considered if ketoconazole dosage exceeds 400 mg daily.263, 384 (See Cautions.) Histoplasmosis usually is treated for 6-12 weeks, but more prolonged treatment (at least 12 months) may be necessary for chronic cavitary pulmonary disease or disseminated histoplasmosis.428
HIV-infected individuals who have been adequately treated for histoplasmosis should receive long-term suppressive or maintenance therapy (secondary prophylaxis) with oral itraconazole to prevent recurrence or relapse.440, 441
A ketoconazole dosage of 200-400 mg once daily has been recommended for the treatment of paracoccidioidomycosis.335
Although safety and efficacy have not been established for the treatment of hypercalcemia, ketoconazole has been given in a dosage of 200-800 mg daily for the treatment of hypercalcemia† in adults with sarcoidosis.363, 365, 366 The risk of toxicity should be considered if ketoconazole dosage exceeds 400 mg daily.384 (See Cautions.)
For the treatment of idiopathic infantile hypercalcemia and hypercalciuria†, a few infants 4 days to 17 months of age† have received ketoconazole in a dosage of 3-9 mg/kg daily.392
For the treatment of tuberculosis-associated hypercalcemia†, a few adolescents have received ketoconazole in a dosage of 3 mg/kg every 8 hours.367
Although safety and efficacy have not been established for the treatment of prostatic carcinoma†106, 108, 180, 181, 182, 183, 285 or for use as an adjunct in the management of disseminated intravascular coagulation (DIC) associated with prostatic carcinoma†, 152, 178 ketoconazole has been given in a dosage of 400 mg every 8 hours. The risk of toxicity should be considered if ketoconazole dosage exceeds 400 mg daily.263, 384 (See Cautions.)
Transient increases in serum AST, ALT, and alkaline phosphatase concentrations may occur during ketoconazole therapy.50, 61, 165, 167, 170, 188, 189, 190, 191, 193, 263, 384
Serious hepatotoxicity, including cases that were fatal or required liver transplantation, has occurred in patients receiving oral ketoconazole.263, 384, 449 Hepatotoxicity may be hepatocellular (in most cases), cholestatic, or a mixed pattern of injury.50, 61, 164, 167, 170, 188, 189, 190, 191, 193, 263, 384 Although ketoconazole-induced hepatotoxicity usually is reversible following discontinuance of the drug,50, 164, 165, 166, 167, 188, 189, 190, 191, 263, 384 recovery may take several months164, 165, 167, 188, 190 and, in some cases, has not been reversible and deaths have occurred.164, 165, 167, 168, 169, 170, 191, 193, 263, 384 Symptomatic hepatotoxicity usually is apparent within the first few months of ketoconazole therapy,50, 61, 164, 167, 168, 169, 170, 188, 189, 190, 191 but occasionally may be apparent within the first week of therapy.164, 166, 167, 191 (See Cautions: Precautions and Contraindications.)
Some patients with ketoconazole-induced hepatotoxicity had no obvious risk factors for liver disease.263, 384, 449 Serious hepatotoxicity has been reported in patients receiving high oral ketoconazole dosage for short treatment durations and in patients receiving low oral dosage of the drug for long durations.263, 384, 449 Many of the reported cases of hepatotoxicity occurred in patients who received the drug for the treatment of tinea unguium† (onychomycosis)50, 167, 168, 169, 188, 189, 190, 191, 193, 263, 384 or the treatment of chronic, refractory dermatophytoses†.167, 191
Ketoconazole-induced hepatitis has been reported in some children.165, 167, 189, 191, 263, 384
Ketoconazole can prolong the QT interval.263, 384 Data from clinical studies and drug interaction studies indicate that an oral ketoconazole dosage of 200 mg twice daily for 3-7 days can increase the corrected QT (QTc) interval; a mean maximum increase of about 6-12 msec has been reported approximately 1-4 hours after a dose.263, 384
Hypertension has been reported in some patients receiving high-dose ketoconazole therapy (e.g., 400 mg every 6-8 hours) for metastatic prostatic carcinoma.201 Although not clearly established, it has been suggested that ketoconazole-induced increases in mineralocorticoid activity may have caused the increase in blood pressure observed in these patients.201
Peripheral edema and orthostatic hypotension also have been reported.263, 384
Endocrine and Metabolic Effects
Ketoconazole dosages of 400 mg or higher decrease adrenal corticosteroid secretion.263, 384 The drug can inhibit cortisol synthesis, particularly in patients receiving relatively high daily dosages or divided daily dosing of the drug.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 can occur during therapy with the drug;109, 110, 112, 113, 114, 151, 154, 156, 157, 158, 159, 166, 173 adrenocortical insufficiency has been reported rarely.109, 159, 160, 166, 173, 229 (See Cautions: Precautions and Contraindications.)
In a clinical trial in 350 patients receiving high-dose ketoconazole therapy (i.e., 1.2 g daily) for metastatic prostatic carcinoma†, 11 deaths occurred within 2 weeks after the drug was initiated.263, 384 Since these patients had serious underlying disease, it is not possible to ascertain from the available information whether these deaths were related to ketoconazole therapy or adrenocortical insufficiency.263, 384 When adrenocortical hypofunction does occur in patients receiving ketoconazole, the condition generally is reversible following discontinuance of the drug154, 156, 157, 166 but rarely may be persistent.159 (See Cautions: Precautions and Contraindications.)
Gynecomastia has been reported in patients receiving ketoconazole.263, 384 Bilateral gynecomastia with breast tenderness has occurred in some men during ketoconazole therapy. In some patients, gynecomastia and breast pain abated after several weeks of continued treatment with the drug. In other patients, gynecomastia persisted until ketoconazole was discontinued. Limited data suggest that gynecomastia occurs because ketoconazole decreases serum testosterone concentrations and to a lesser extent serum estradiol concentrations, resulting in an increased estradiol: testosterone ratio.117 Although it has been suggested that gynecomastia may be caused by a direct effect on breast tissue since serum hormone concentrations were normal in several patients, ketoconazole only transiently inhibits testosterone synthesis and testosterone concentrations may have returned to baseline values depending on when the serum samples were obtained.112
Dermatologic and Sensitivity Reactions
Anaphylaxis has been reported after the first dose of ketoconazole.102, 263, 384
Other hypersensitivity reactions, including anaphylactoid reaction, erythema multiforme, rash, dermatitis, erythema, urticaria, and pruritus, have been reported in patients receiving ketoconazole.263, 384 Acute generalized exanthematous pustulosis, photosensitivity, angioedema, alopecia, and xeroderma also have been reported.263, 384
Headache,263, 384 dizziness,263, 384 somnolence,263, 384 asthenia,263, 384 fatigue,263, 384 malaise,263, 384 nervousness,263, 384 insomnia,263, 384 and paresthesia263, 384 have been reported in patients receiving ketoconazole.
Reversible increased intracranial pressure (e.g., papilledema, bulging fontanelles in infants) has occurred in patients receiving ketoconazole.263, 384
Vomiting, nausea, diarrhea, constipation, abdominal or upper abdominal pain, anorexia, increased appetite, dry mouth, dysgeusia, dyspepsia, flatulence, and tongue discoloration have been reported in patients receiving ketoconazole.263, 384
Arthralgia,263, 384 myalgia,263, 384 fever,263, 384 chills,263, 384 hot flush,263, 384 photophobia,263, 384 epistaxis,263, 384 menstrual disorder,263, 384 impotence,263, 384 and thrombocytopenia263, 384 have been reported in patients receiving ketoconazole.
Alcohol intolerance has been reported in patients receiving ketoconazole.263, 384 (See Drug Interactions: Alcohol.)
Precautions and Contraindications
Ketoconazole is contraindicated in patients with known hypersensitivity to the drug.263, 384
Ketoconazole is contraindicated in patients with acute or chronic liver disease.263, 384
Concomitant use of ketoconazole and certain drugs that are metabolized by cytochrome P-450 (CYP) isoenzyme 3A4 (e.g., eplerenone, ergot alkaloids, irinotecan, lurasidone, lovastatin, simvastatin, felodipine, nisoldipine, tolvaptan, colchicine) is contraindicated because elevated plasma concentrations of these drugs may occur and may result in increased or prolonged therapeutic and adverse effects.263, 384 (See Drug Interactions.)
Concomitant use with some drugs (e.g., cisapride, disopyramide, dofetilide, dronedarone, methadone, pimozide, quinidine, ranolazine) is contraindicated since 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 Drug Interactions.)
Concomitant use of ketoconazole and certain benzodiazepines (e.g., alprazolam, oral midazolam, oral triazolam) is contraindicated because elevated plasma concentrations of these drugs may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic use.384 (See Drug Interactions.)
Since oral ketoconazole may interact with various drugs resulting in serious and potentially life-threatening adverse effects, all drugs that the patient is receiving should be reviewed to assess for possible interactions with ketoconazole.449 (See Drug Interactions.)
Because ketoconazole has been associated with serious adverse effects (e.g., hepatotoxicity, adrenal insufficiency) and drug interactions, the drug should be used only for the treatment of certain serious or life-threatening fungal infections when other effective antifungals are not available or not tolerated and the potential benefits of oral ketoconazole outweigh potential risks of the drug. 263, 384, 449, 450
Ketoconazole has been associated with serious hepatotoxicity, which has resulted in death or required liver transplantation.164, 165, 166, 167, 168, 169, 170, 191, 193, 263, 384 (See Cautions: Hepatotoxicity.) Patients receiving oral ketoconazole should be informed of the risk of hepatotoxicity and should be instructed to report 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 Patients should be advised to avoid alcohol consumption during ketoconazole therapy.263, 384, 449 In addition, concomitant use of other potentially hepatotoxic drugs should be avoided.263, 384, 449 (See Drug Interactions.)
Prior to initiation of oral ketoconazole therapy, liver function tests, including determinations of serum AST, ALT, alkaline phosphatase, γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP), and total bilirubin, as well as prothrombin time, international normalized ratio (INR), and tests for viral hepatitides should be performed.164, 166, 167, 169, 170, 188, 189, 190, 193, 263, 384, 449 During ketoconazole therapy, serum ALT concentrations should be monitored weekly.263, 384, 449 Prompt recognition of liver injury is essential.263, 384, 449 If ALT concentrations increase above the upper limit of normal or 30% above baseline or if the patient develops symptoms, ketoconazole should be interrupted and a full set of liver tests performed.263, 384, 449 Liver tests should then be repeated 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 a decision is made to restart oral ketoconazole, the patient should be monitored frequently to detect any recurring liver injury since hepatotoxicity has been reported following reinitiation of the drug (rechallenge).263, 384, 449
Because ketoconazole can cause adrenal insufficiency, adrenal function should be monitored 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 The possibility that ketoconazole may depress adrenocortical function should be considered, particularly in patients receiving relatively high dosages of the drug.109, 112, 113, 114, 151, 154, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 173, 263, 384 (See Cautions: Endocrine and Metabolic Effects.) Similarly, the possibility that the drug may reduce serum testosterone concentrations should be considered.109, 110, 151, 174 To minimize the risk of these endocrine effects, the recommended ketoconazole dosage (i.e., 200-400 mg daily in adults) should not be exceeded.263, 384
Because CSF concentrations of ketoconazole are unpredictable and may be negligible following oral administration and because treatment failures or relapses have been reported, the drug should not be used to treat fungal infections that involve the CNS, including cerebral blastomycosis or coccidioidal meningitis.192, 263, 288, 291, 295, 302, 306, 384, 384, 449
Ketoconazole has not been systematically studied in children of any age, and there is essentially no information available regarding use of the drug in children younger than 2 years of age.263, 384
Although ketoconazole has been used in a limited number of children older than 2 years of age, the drug should be used in pediatric patients only when potential benefits outweigh risks.263, 384
Mutagenicity and Carcinogenicity
Ketoconazole did not show any signs of mutagenic potential when evaluated using the dominant lethal mutation test or the Ames Salmonella microsomal activator assay.263, 384
Ketoconazole was not carcinogenic in long-term studies in mice and rats using oral dosages of 5, 20, and 80 mg/kg daily.263, 384 Based on a mg/m2 comparison, the high dosage used in these mice and rats was approximately equal to or twofold higher, respectively, than the usual human dosage.263, 384
Pregnancy, Fertility, and Lactation
Ketoconazole should be used during pregnancy only when potential benefits justify possible risks to the fetus.263, 384
Ketoconazole has been teratogenic (syndactylia and oligodactylia) when given orally to pregnant rats in a dosage of 80 mg/kg daily (2 times the maximum recommended human oral dosage based on body surface area comparisons).263, 384 The drug has also been embryotoxic in rats when given orally during the first trimester of gestation in dosages exceeding 80 mg/kg daily and has caused dystocia in rats when given orally during the third trimester of pregnancy in dosages exceeding 10 mg/kg (approximately 25% of the maximum human dosage based on body surface area comparisons).263, 384 Although these effects may be a reflection of the particular sensitivity of female rats to ketoconazole (maternal toxicity), there are no adequate and controlled studies to date using ketoconazole in pregnant women.263, 384
Oligospermia and, rarely, azoospermia have been reported in adult males receiving ketoconazole dosages greater than 400 mg daily†.109, 263, 384 Ketoconazole dosages of 800 mg daily decrease serum testosterone concentrations; clinical manifestations of these decreased concentrations may include gynecomastia, impotence, and oligospermia.263, 384 (See Mechanism of Action: Endocrine Effects.)
Because ketoconazole is distributed into human milk, lactating women receiving the drug should not breast-feed.263, 384
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Ketoconazole is a substrate for and potent inhibitor of cytochrome P-450 (CYP) isoenzyme 3A4.263, 384
Concomitant use of ketoconazole with drugs that are metabolized by CYP3A4 may increase plasma concentrations of these drugs and may increase or prolong therapeutic and/or adverse effects associated with these drugs.263, 384
Concomitant use of ketoconazole with drugs that inhibit CYP3A4 may increase plasma concentrations of ketoconazole and increase the risk of adverse effects associated with the antifungal.263, 384
Concomitant use of ketoconazole with drugs that induce CYP3A4 may decrease plasma concentrations of ketoconazole and may decrease efficacy of the antifungal.263, 384
Drugs Affecting or Affected by P-glycoprotein Transport
Ketoconazole is an inhibitor of the P-glycoprotein (P-gp) transport system.384
Concomitant use of ketoconazole with drugs that are P-gp substrates may result in increased plasma concentrations of such drugs.384
Drugs that Prolong the QT Interval
Concomitant use of ketoconazole and drugs that are CYP3A4 substrates that prolong the QT interval (e.g., cisapride, disopyramide, dofetilide, dronedarone, methadone, pimozide, quinidine, ranolazine) may increase plasma concentrations of the concomitantly administered CYP3A4 substrate, which can lead to QT interval prolongation, sometimes resulting in life-threatening ventricular arrhythmias such as torsades de pointes.263, 384 Concomitant use of ketoconazole and these drugs that prolong the QT interval is contraindicated;263, 384 in addition, such drugs should not be used for up to 1 week after completion of ketoconazole treatment.384
Drugs Affecting Gastric Acidity
Because gastric acidity is necessary for the dissolution and absorption of ketoconazole, concomitant use of drugs that decrease gastric acid output or increase gastric pH (e.g., antacids, histamine H2-receptor antagonists, proton-pump inhibitors) may decrease absorption of ketoconazole resulting in decreased plasma concentrations of the antifungal.263, 384
In one study, administration of oral cimetidine 2 hours prior to administration of oral ketoconazole had no effect on ketoconazole absorption when the antifungal was administered as an acidified solution. In another study in healthy adults, concomitant administration of a single 400-mg dose of oral ketoconazole within 2 hours of a 150-mg dose of oral ranitidine was associated with a 95% reduction in ketoconazole bioavailability; ranitidine had been administered in a dosage of 150 mg every 12 hours for 2 days prior to administration of ketoconazole.
Caution is advised if an antacid, histamine H2-receptor antagonist, or proton-pump inhibitor (e.g., omeprazole, lansoprazole) is used in patients receiving ketoconazole.263, 384
If ketoconazole is used concomitantly with a drug that decreases gastric acid output or increases gastric pH, ketoconazole tablets should be administered with an acidic beverage (e.g., non-diet cola), the acid-reducing drug should be administered at least 1 hour before or 2 hours after ketoconazole, and antifungal activity should be monitored and ketoconazole dosage adjusted if necessary.384
Because ketoconazole can cause serious hepatotoxicity, concomitant use with other potentially hepatotoxic drugs should be avoided if possible.263, 384
Disulfiram reactions, including flushing, rash, peripheral edema, nausea, and headache, have occurred rarely in patients who ingested alcohol while receiving ketoconazole therapy;263, 267, 268, 384 symptoms usually resolved within a few hours.263, 384
Patients should be advised to avoid alcohol consumption during ketoconazole therapy.263, 384 Some clinicians recommend that alcohol be avoided during and for 48 hours after discontinuance of ketoconazole.267
Concomitant use of aliskiren and ketoconazole may result in increased plasma concentrations of aliskiren.384
Caution is advised if aliskiren is used concomitantly with ketoconazole.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of aliskiren and dosage of aliskiren should be reduced if necessary.384
Disopyramide, Dofetilide, Dronedarone, and Quinidine
Concomitant use of ketoconazole and certain antiarrhythmic agents (disopyramide, dofetilide, dronedarone, quinidine) may result in increased plasma concentrations of the antiarrhythmic agent and increase the risk of serious adverse cardiovascular effects, including QT interval prolongation or serious, life-threatening ventricular arrhythmias such as torsades de pointes.384
Concomitant use of ketoconazole and disopyramide, dofetilide, dronedarone, or quinidine is contraindicated;384 in addition, these antiarrhythmic agents should not be used for up to 1 week after completion of ketoconazole treatment.384
Ketoconazole may increase plasma concentrations of coumarin anticoagulants resulting in enhanced anticoagulant effects.263, 384
Ketoconazole and coumarin anticoagulants should be used concomitantly with caution;263, 384 the anticoagulant effect should be carefully monitored and dosage of the anticoagulant adjusted accordingly.263, 384
Concomitant use of dabigatran and ketoconazole may result in increased dabigatran plasma concentrations.384
Dabigatran and ketoconazole should be used concomitantly with caution.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of dabigatran.384 If dabigatran and ketoconazole are used concomitantly in patients with moderate renal impairment (creatinine clearance 50-80 mL/minute), a decreased dabigatran dosage of 75 mg twice daily should be considered.384
Concomitant use of rivaroxaban and ketoconazole may result in increased rivaroxaban concentrations.384
Concomitant use of rivaroxaban and ketoconazole is not recommended.384 Rivaroxaban should be avoided during and for up to 1 week after completion of ketoconazole treatment.384 If concomitant use cannot be avoided, the patient should be monitored for signs and symptoms of increased or prolonged rivaroxaban effects;384 dosage of rivaroxaban should be reduced or interrupted if necessary.384
Concomitant use of carbamazepine and ketoconazole may increase plasma concentrations of the anticonvulsant and may also decrease plasma concentrations of ketoconazole and decrease efficacy of the antifungal.263, 384
Concomitant use of carbamazepine and ketoconazole is not recommended.263, 384 Carbamazepine should be avoided for 2 weeks prior to and during treatment with ketoconazole, unless the benefits outweigh the risk of potentially reduced ketoconazole efficacy.263, 384 Carbamazepine also should be avoided for up to 1 week after completion of ketoconazole treatment, unless the benefits outweigh the potentially increased risk of carbamazepine adverse effects.384 If concomitant use cannot be avoided, the patient should be monitored for signs and symptoms of increased or prolonged carbamazepine effects;384 dosage of carbamazepine should be reduced or interrupted if necessary.384 In addition, antifungal activity should be monitored and dosage of ketoconazole increased if necessary.384
Concomitant use of phenytoin and ketoconazole may decrease plasma concentrations of ketoconazole and decrease efficacy of the antifungal.384
Concomitant use of phenytoin and ketoconazole is not recommended.384 Phenytoin should be avoided for 2 weeks prior to and during ketoconazole treatment, unless the benefits outweigh the risk of potentially reduced ketoconazole efficacy.384 If concomitant use cannot be avoided, antifungal activity should be monitored and ketoconazole dosage increased if necessary.384
Concomitant use of ketoconazole and repaglinide or saxagliptin may result in increased plasma concentrations of the antidiabetic agent.384 Caution is advised if ketoconazole is used concomitantly with repaglinide or saxagliptin.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of repaglinide or saxagliptin and dosage of the antidiabetic agent should be reduced if necessary.384
Concomitant use of the fixed combination of artemether and lumefantrine (artemether/lumefantrine) and ketoconazole increases peak plasma concentrations and area under the plasma concentration-time curve (AUC) of artemether, the active metabolite of artemether (dihydroartemisinin; DHA), and lumefantrine.448
Although adjustment of artemether/lumefantrine dosage is not necessary if ketoconazole is used concomitantly, ketoconazole and artemether/lumefantrine should be used concomitantly with caution because of the potential for increased lumefantrine concentrations and increased risk of QT interval prolongation.448
Concomitant use of mefloquine (single 500-mg dose) and ketoconazole (400 mg once daily for 10 days) in healthy adults increased the mean peak plasma concentration and AUC of mefloquine by 64 and 79%, respectively, and increased the mean elimination half-life of mefloquine from 322 hours to 448 hours.446
Because of the risk of a potentially fatal prolongation of the corrected QT (QTc) interval, the manufacturer of mefloquine states that ketoconazole should not be used concomitantly with mefloquine or within 15 weeks after the last mefloquine dose.446
In a crossover study in healthy individuals, concomitant use of oral quinine sulfate (single 500-mg dose; not commercially available in the US) and ketoconazole (100 mg twice daily for 3 days) increased the mean AUC of quinine by 45% and decreased clearance of quinine by 31% compared with administration of the antimalarial alone.447
Dosage adjustment of quinine is not needed in patients receiving ketoconazole; however, patients should be monitored closely for adverse effects associated with quinine.447
Concomitant use of isoniazid and ketoconazole may result in decreased plasma concentrations of ketoconazole and decreased efficacy of the antifungal.384
Concomitant use of isoniazid and ketoconazole is not recommended.263, 384 Isoniazid should be avoided for 2 weeks prior to and during ketoconazole treatment, unless the benefits outweigh the risk of potentially reduced ketoconazole efficacy.384 If concomitant use cannot be avoided, antifungal activity should be monitored and ketoconazole dosage increased if necessary.384
Concomitant use of rifabutin and ketoconazole may result in increased plasma concentrations of rifabutin and also may result in decreased plasma concentrations of ketoconazole and decreased efficacy of the antifungal.263, 384
Concomitant use of rifabutin and ketoconazole is not recommended.384 Rifabutin should be avoided for 2 weeks prior to and during ketoconazole treatment, unless the benefits outweigh the risk of potentially reduced ketoconazole efficacy.384 Rifabutin also should be avoided for up to 1 week after completion of ketoconazole treatment, unless the benefits outweigh the potentially increased risk of rifabutin adverse effects.384 If concomitant use cannot be avoided, the patient should be monitored for signs and symptoms of increased or prolonged rifabutin effects;384 dosage of rifabutin should be reduced or interrupted if necessary.384 In addition, antifungal activity should be monitored and ketoconazole dosage increased if necessary.384
Concomitant use of rifampin and ketoconazole results in decreased plasma concentrations of ketoconazole111, 141, 221, 263, 384 and may decrease efficacy of the antifungal.384 In one patient receiving ketoconazole concomitantly with rifampin and isoniazid, serum concentrations of both rifampin and ketoconazole were decreased.111 Although administration of ketoconazole 12 hours after the rifampin dose resulted in therapeutic serum concentrations of rifampin, serum concentrations of ketoconazole were subtherapeutic regardless of when the doses were given.111 In addition, isoniazid and rifampin appeared to have an additive effect in reducing serum ketoconazole concentrations.111
Concomitant use of rifampin and ketoconazole is not recommended.263, 384 Rifampin should be avoided for 2 weeks prior to and during ketoconazole treatment, unless the benefits outweigh the risk of potentially reduced ketoconazole efficacy.384 If concomitant use cannot be avoided, antifungal activity should be monitored and ketoconazole dosage increased if necessary.384
Bortezomib, Erlotinib, and Imatinib
Concomitant use of ketoconazole and bortezomib, erlotinib, or imatinib may result in increased plasma concentrations of the antineoplastic agent.384
Caution is advised if ketoconazole is used concomitantly with bortezomib, erlotinib, or imatinib.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of the antineoplastic agent and dosage of the antineoplastic agent should be reduced if necessary.384
Concomitant use of ketoconazole may decrease clearance of busulfan resulting in increased systemic exposure to the antineoplastic agent.263, 384
Caution is advised if busulfan and ketoconazole are used concomitantly.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of busulfan and dosage of the antineoplastic agent should be reduced if necessary.384
Dasatinib, Lapatinib, and Nilotinib
Concomitant use of ketoconazole and dasatinib, lapatinib, or nilotinib may result in increased plasma concentrations of the antineoplastic agent.384
Concomitant use of ketoconazole and dasatinib, lapatinib, or nilotinib is not recommended.384 These antineoplastic agents should be avoided during and for up to 1 week after completion of ketoconazole treatment, unless the benefits of the antineoplastic agent outweigh the potentially increased risk of adverse effects.384 If concomitant use cannot be avoided, the patient should be monitored for signs and symptoms of increased or prolonged effects of the antineoplastic agent and dosage of the antineoplastic agent should be reduced or interrupted if necessary.384
Clearance of docetaxel in cancer patients is decreased by 50% in the presence of ketoconazole.263, 384
Caution is advised if docetaxel and ketoconazole are used concomitantly.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of docetaxel and dosage of the antineoplastic agent should be reduced if necessary.384
Concomitant use of irinotecan and ketoconazole may result in increased plasma concentrations of irinotecan and may increase the risk of potentially fatal adverse effects associated with the antineoplastic agent.384
Concomitant use of irinotecan and ketoconazole is contraindicated;384 in addition, irinotecan should not be used for up to 1 week after completion of ketoconazole treatment.384
Concomitant use of ixabepilone and ketoconazole may result in increased plasma concentrations of the antineoplastic agent.384
Caution is advised if ixabepilone and ketoconazole are used concomitantly.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of ixabepilone and dosage of the antineoplastic agent should be reduced if necessary.384
In vitro studies indicate that ketoconazole can inhibit the metabolism of paclitaxel;269 this potential pharmacokinetic interaction has not been evaluated in humans.269
Caution is advised if paclitaxel and ketoconazole are used concomitantly.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of paclitaxel and dosage of the antineoplastic agent should be reduced if necessary.384
Concomitant use of temsirolimus and ketoconazole may result in increased plasma concentrations of the antineoplastic agent.384
Concomitant use of temsirolimus and ketoconazole is not recommended.384 Temsirolimus should be avoided during and for up to 1 week after completion of ketoconazole treatment, unless the benefits of the antineoplastic agent outweigh the potentially increased risk of adverse effects.384 If concomitant use cannot be avoided, the patient should be monitored for signs and symptoms of increased or prolonged effects of temsirolimus and dosage of the antineoplastic agent should be reduced or interrupted if necessary.384
In vitro data suggest that trimetrexate is extensively metabolized by CYP3A4 and in vitro animal models have demonstrated that ketoconazole potently inhibits metabolism of trimetrexate.263 Concomitant use of trimetrexate and ketoconazole may result in increased plasma concentrations of trimetrexate.384
Caution is advised if trimetrexate and ketoconazole are used concomitantly.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of trimetrexate and dosage of the antineoplastic agent should be reduced if necessary.384
Ketoconazole may inhibit metabolism of vinca alkaloids metabolized by CYP3A4 (e.g., vincristine, vinblastine, vinorelbine)263 and concomitant use of the drugs may result in increased plasma concentrations of the vinca alkaloid.384
Caution is advised if ketoconazole is used concomitantly with a vinca alkaloid.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of the vinca alkaloid and dosage of the vinca alkaloid should be reduced if necessary.384
Concomitant use of ketoconazole (200 mg daily for 14 days) and aripiprazole (single 15-mg dose) resulted in increases of 63 and 77% in the AUCs of aripiprazole and its active metabolite, respectively.384 The effect of higher ketoconazole dosages on aripiprazole exposures has not been evaluated.384
Caution is advised if aripiprazole and ketoconazole are used concomitantly.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of aripiprazole and dosage of aripiprazole should be reduced to 50% of the recommended dosage.384
Concomitant use of haloperidol and ketoconazole may result in increased plasma concentrations of haloperidol.384
Caution is advised if haloperidol is used concomitantly with ketoconazole.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of haloperidol and dosage of haloperidol should be reduced if necessary.384
Concomitant use of lurasidone and ketoconazole may result in increased plasma concentrations of lurasidone.384
Concomitant use of lurasidone and ketoconazole is contraindicated;384 in addition, lurasidone should not be used for up to 1 week after completion of ketoconazole treatment.384
Concomitant use of pimozide and ketoconazole may increase pimozide plasma concentrations and lead to QTc interval prolongation, sometimes resulting in serious life-threatening ventricular tachyarrhythmias such as torsades de pointes.263, 384
Concomitant use of pimozide and ketoconazole is contraindicated;263, 384 in addition, pimozide should not be used for up to 1 week after completion of ketoconazole treatment.384
Concomitant use of quetiapine and ketoconazole may result in increased plasma concentrations of quetiapine.384
Caution is advised if quetiapine is used concomitantly with ketoconazole.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of quetiapine and dosage of quetiapine should be reduced if necessary.384
Concomitant use of risperidone and ketoconazole may result in increased plasma concentrations of risperidone.384
Caution is advised if risperidone is used concomitantly with ketoconazole.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of risperidone and dosage of risperidone should be reduced if necessary.384
Concomitant use of maraviroc and ketoconazole may result in increased plasma concentrations of maraviroc.384
Caution is advised if maraviroc and ketoconazole are used concomitantly.384 The patient should be carefully monitored for signs or symptoms of maraviroc-associated adverse effects and dosage of the antiretroviral agent should be reduced if necessary.384
HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Concomitant use of ketoconazole and delavirdine may result in increased trough plasma concentrations of delavirdine.212
Concomitant use of efavirenz and ketoconazole may result in decreased ketoconazole plasma concentrations and may decrease efficacy of the antifungal.213, 384
Concomitant use of efavirenz and ketoconazole is not recommended.384 Efavirenz should be avoided for 2 weeks prior to and during ketoconazole treatment, unless the benefits outweigh the risk of potentially reduced ketoconazole efficacy.384 If concomitant use cannot be avoided, antifungal activity should be monitored and ketoconazole dosage should be increased if necessary.384
Concomitant use of etravirine and ketoconazole may result in increased etravirine plasma concentrations and decreased ketoconazole plasma concentrations.214 Dosage adjustment of ketoconazole may be needed depending on other concomitantly administered drugs.214
Concomitant use of nevirapine and ketoconazole results in decreased plasma concentrations and AUC of ketoconazole263 and may decrease efficacy of the antifungal.384
Concomitant use of nevirapine and ketoconazole is not recommended.263, 384 Nevirapine should be avoided for 2 weeks prior to and during ketoconazole treatment, unless the benefits outweigh the risk of potentially reduced ketoconazole efficacy.384 If concomitant use cannot be avoided, antifungal activity should be monitored and ketoconazole dosage should be increased if necessary.384
Concomitant use of ketoconazole and rilpivirine has resulted in increased rilpivirine plasma concentrations and AUC and decreased ketoconazole plasma concentrations and AUC.226
Rilpivirine dosage adjustments are not needed when the drug is used concomitantly with ketoconazole;226 however, patients should be monitored for breakthrough fungal infections.226
Clinically important changes in atazanavir plasma concentrations or AUC do not occur if unboosted atazanavir (i.e., without low-dose ritonavir or cobicistat) is used concomitantly with ketoconazole.203
Concomitant use of ketoconazole and ritonavir-boosted or cobicistat-boosted atazanavir may result in increased plasma concentrations of ketoconazole, atazanavir, and cobicistat.203, 238
Caution is advised if high ketoconazole dosage (exceeding 200 mg daily) is used in patients receiving ritonavir-boosted atazanavir.203 Specific dosage recommendations are not available for concomitant use of ketoconazole and cobicistat-boosted atazanavir.238
Concomitant use of ritonavir-boosted darunavir and ketoconazole increases darunavir and ketoconazole concentrations.204 Pharmacokinetic interactions are possible if ketoconazole is used concomitantly with cobicistat-boosted darunavir (increased ketoconazole, darunavir, and cobicistat concentrations).237
Caution is advised if ketoconazole is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir.204, 237, 384 The patient should be closely monitored for increased ketoconazole-, darunavir-, and ritonavir- or cobicistat-associated adverse effects.204, 237, 384 Decreased ketoconazole dosage should be considered and ketoconazole plasma concentrations should be monitored if necessary.384
Ketoconazole dosage should not exceed 200 mg daily in patients receiving ritonavir-boosted darunavir.204 Specific dosage recommendations are not available for concomitant use of ketoconazole and cobicistat-boosted darunavir.237
Concomitant use of ketoconazole and ritonavir-boosted fosamprenavir results in increased plasma concentrations and AUC of the antifungal.205
Caution is advised if ketoconazole is used concomitantly with ritonavir-boosted fosamprenavir.384 The patient should be closely monitored for ketoconazole-associated adverse effects and decreased ketoconazole dosage should be considered.384 Ketoconazole plasma concentrations should be monitored if necessary.384
Ketoconazole dosage should not exceed 200 mg daily in patients receiving ritonavir-boosted fosamprenavir.205 In patients receiving fosamprenavir (without low-dose ritonavir), reduced antifungal dosage may be needed in those receiving ketoconazole dosages exceeding 400 mg daily.205
Concomitant use of ketoconazole and indinavir can increase indinavir concentrations.206
Caution is advised if indinavir is used concomitantly with ketoconazole.384 Dosage of indinavir should be reduced to 600 mg every 8 hours in patients receiving ketoconazole206 and the patient should be carefully monitored for signs or symptoms of indinavir-associated adverse effects.384
Concomitant use of the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) and ketoconazole results in increased plasma concentrations of the antifungal.207
Ketoconazole dosage should not exceed 200 mg daily in patients receiving lopinavir/ritonavir.207
Concomitant use of ketoconazole (400 mg once daily for 7 days) and nelfinavir (500 mg 3 times daily for 5-6 days) resulted in a 35% increase in the AUC and a 25% increase in peak plasma concentrations of nelfinavir.208
Concomitant use of ritonavir-boosted saquinavir and ketoconazole increases concentrations of ketoconazole, but does not appear to affect saquinavir pharmacokinetics.210
Caution is advised and the patient should be carefully monitored if saquinavir is used concomitantly with ketoconazole.384 Ketoconazole dosage should not exceed 200 mg daily in patients receiving ritonavir-boosted saquinavir.210
Concomitant use of ritonavir-boosted tipranavir and ketoconazole may result in increased ketoconazole concentrations.211
Ketoconazole and ritonavir-boosted tipranavir should be used concomitantly with caution and ketoconazole dosage should not exceed 200 mg daily.211
Concomitant use of aprepitant and ketoconazole may result in increased plasma concentrations of aprepitant.384
Caution is advised if aprepitant is used concomitantly with ketoconazole.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of aprepitant and dosage of aprepitant should be reduced if necessary.384
Concomitant use of ketoconazole and alprazolam, midazolam, or triazolam increases peak plasma concentrations of these benzodiazepines and may result in potentiated and prolonged hypnotic and sedative effects, especially in patients receiving repeated or chronic therapy with the drugs.263, 384
Concomitant use of ketoconazole and alprazolam, oral midazolam, or triazolam is contraindicated;263, 384 in addition, these benzodiazepines should not be used for up to 1 week after completion of ketoconazole treatment.384
Caution is advised if parenteral midazolam is used concomitantly with ketoconazole.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of midazolam and dosage of the benzodiazepine should be reduced if necessary.384
Concomitant use of bosentan (125 mg twice daily) and ketoconazole increased peak plasma concentrations and AUC of bosentan approximately twofold in healthy individuals.263, 384
Caution is advised if bosentan is used concomitantly with ketoconazole.384 Although dosage adjustment of bosentan is not needed in patients receiving ketoconazole, the patient should be carefully monitored for increased bosentan-associated pharmacologic and adverse effects.263, 384
Concomitant use of buspirone with ketoconazole is expected to result in clinically important increases in plasma concentrations of buspirone.263, 384
Caution is advised if buspirone is used concomitantly with ketoconazole.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of buspirone and dosage of the drug should be reduced if necessary.384 In patients who have been titrated to a stable dosage of buspirone, dosage reduction may be necessary to avoid buspirone-associated adverse effects or diminished anxiolytic activity.384
Calcium-channel Blocking Agents
Concomitant use of ketoconazole and amlodipine, felodipine, nicardipine, nifedipine, or verapamil results in increased plasma concentrations of the calcium-channel blocker.263 Calcium-channel blockers have a negative inotropic effect which may be additive to that of ketoconazole.384 The potential increase in plasma concentrations of calcium-channel blockers may increase the risk of edema and congestive heart failure.384
Concomitant use of ketoconazole and felodipine or nisoldipine is contraindicated;384 in addition, felodipine or nisoldipine should not be used for up to 1 week after completion of ketoconazole treatment.384
Caution is advised if ketoconazole is used concomitantly with other dihydropyridines (e.g., amlodipine, nicardipine, nifedipine).384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of the calcium-channel blocker and dosage should be reduced if necessary.384
Caution is advised if verapamil and ketoconazole are used concomitantly.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of verapamil and dosage of the calcium-channel blocker should be reduced if necessary.384
Concomitant use of cilostazol and ketoconazole increases peak plasma concentrations and AUC of cilostazol approximately twofold and may alter (increase or decrease) concentrations of the active cilostazol metabolite.384
Caution is advised if cilostazol is used concomitantly with ketoconazole.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of cilostazol and dosage of the drug should be reduced if necessary.384
Concomitant use of cinacalcet and ketoconazole may result in increased plasma concentrations of cinacalcet.384
Caution is advised if cinacalcet and ketoconazole are used concomitantly.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of cinacalcet and dosage of cinacalcet should be reduced if necessary.384
Ketoconazole potentially inhibits metabolism of cisapride (available in the US only under a limited-use protocol).263, 384 Concomitant use of ketoconazole and cisapride has resulted in increased cisapride plasma concentrations and AUC;263, 276, 384 QT interval prolongation and serious cardiovascular effects, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes, have been reported rarely.276
Concomitant use of cisapride and ketoconazole is contraindicated;384 in addition, cisapride should not be used for up to 1 week after completion of ketoconazole treatment.384
Concomitant use of colchicine and ketoconazole may increase colchicine plasma concentrations and increase the risk of potentially fatal adverse effects.384
In patients with renal or hepatic impairment, concomitant use of colchicine and ketoconazole is contraindicated;384 in addition, colchicine should not be used for up to 1 week after completion of ketoconazole treatment in these patients.384
In patients without renal or hepatic impairment, concomitant use of colchicine and ketoconazole is not recommended.384 Colchicine should be avoided during and for up to 1 week after completion of ketoconazole treatment, unless the benefits of the drug outweigh the potential increased risk of adverse effects.384 If concomitant use cannot be avoided, the patient should be monitored clinically for signs and symptoms of increased or prolonged effects of colchicine and dosage of colchicine should be reduced or interrupted if necessary.384
Concomitant use of ketoconazole and budesonide,384 ciclesonide,384 dexamethasone,384 fluticasone,384 methylprednisolone,227, 228, 263, 384 or prednisolone232, 233 may increase plasma concentrations of the corticosteroid,227, 228, 263, 384 possibly due to decreased clearance.227, 228, 232, 233 Ketoconazole may enhance the adrenal suppressive effects of corticosteroids.228, 233
Concomitant use of fluticasone propionate and ketoconazole is not recommended, unless potential benefits outweigh potential risks of systemic corticosteroid adverse effects.384
Caution is advised if ketoconazole is used concomitantly with budesonide, ciclesonide, dexamethasone, or methylprednisolone.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of the corticosteroid and dosage of the corticosteroid should be reduced if necessary.227, 228, 232, 233, 263, 384
Elevated plasma concentrations of digoxin have been reported in patients receiving ketoconazole.263, 384 Although it is unclear whether concomitant use of ketoconazole caused these increased plasma concentrations, digoxin and ketoconazole should be used concomitantly with caution and digoxin concentrations should be monitored.263, 384
Concomitant use of eletriptan and ketoconazole may result in increased plasma concentrations of eletriptan.384
Eletriptan should be avoided for 72 hours after completion of ketoconazole treatment.384 Caution is advised if eletriptan is used concomitantly with ketoconazole.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of eletriptan and dosage of eletriptan should be reduced if necessary.384
Concomitant use of eplerenone and ketoconazole increases the AUC of eplerenone approximately fivefold and increases the risk of hyperkalemia and hypotension.263, 384
Concomitant use of eplerenone and ketoconazole is contraindicated;384 in addition, eplerenone should not be used for up to 1 week after completion of ketoconazole treatment.384
Concomitant use of ergot alkaloids (e.g., ergotamine, dihydroergotamine, methylergonovine) and ketoconazole may increase concentrations of the ergot alkaloid resulting in ergotism (i.e., risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities).263, 384
Concomitant use of ketoconazole and ergot alkaloids is contraindicated;384 in addition, ergot alkaloids should not be used for up to 1 week after completion of ketoconazole treatment.384
Concomitant use of fesoterodine and ketoconazole may result in increased plasma concentrations of fesoterodine.384
Caution is advised if fesoterodine is used concomitantly with ketoconazole.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of fesoterodine and dosage of fesoterodine should be reduced if necessary.384
Concomitant use of ketoconazole (400 mg once daily) and the fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) with dasabuvir sodium results in a twofold increase in ketoconazole AUC.455
If ketoconazole is used concomitantly with ombitasvir/paritaprevir/ritonavir with dasabuvir, dosage of the antifungal should not exceed 200 mg daily.455
Concomitant use of ketoconazole (400 mg once daily) and ombitasvir/paritaprevir/ritonavir with or without dasabuvir results in a twofold increase in ketoconazole AUC.454, 455
If ketoconazole is used concomitantly with ombitasvir/paritaprevir/ritonavir with or without dasabuvir, dosage of the antifungal should not exceed 200 mg daily.454, 455
Concomitant use of simeprevir and ketoconazole may result in increased plasma concentrations of simeprevir.451
Concomitant use of simeprevir and ketoconazole is not recommended.451
HCV Replication Complex Inhibitors
Concomitant use of ketoconazole (400 mg once daily) and daclatasvir (single 10-mg dose) results in increased daclatasvir plasma concentrations and AUC due to potent CYP3A inhibition by ketoconazole.452
If daclatasvir and ketoconazole are used concomitantly, daclatasvir should be given in a dosage of 30 mg once daily.452
Concomitant use of ketoconazole (400 mg once daily) and elbasvir (single 50-mg dose) or grazoprevir (single 100-mg dose) results in increased plasma concentrations and AUCs of elbasvir and grazoprevir, which may increase the overall risk of hepatotoxicity.453
Concomitant use of ketoconazole and the fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir) is not recommended.453
Concomitant use of ketoconazole (400 mg once daily) and ombitasvir/paritaprevir/ritonavir with or without dasabuvir results in a twofold increase in ketoconazole AUC.454, 455
If ketoconazole is used concomitantly with ombitasvir/paritaprevir/ritonavir with or without dasabuvir, dosage of the antifungal should not exceed 200 mg daily.454, 455
Concomitant use of ketoconazole (200 mg twice daily) and velpatasvir (single 100-mg dose) does not result in clinically important pharmacokinetic interactions.456
Concomitant use of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) metabolized by CYP3A (e.g., atorvastatin, lovastatin, simvastatin) and ketoconazole may increase plasma concentrations of the statin resulting in increased effects and increased risk of statin-associated adverse effects, including myopathy and rhabdomyolysis.263, 384
Concomitant use of ketoconazole and lovastatin or simvastatin is contraindicated;384 in addition, lovastatin or simvastatin should not be used for up to 1 week after completion of ketoconazole treatment.384
Caution is advised if atorvastatin is used concomitantly with ketoconazole.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of atorvastatin and dosage of atorvastatin should be reduced if necessary.384
Concomitant use of ketoconazole and cyclosporine has been reported to increase plasma concentrations of cyclosporine142, 143, 144, 263, 384 and serum creatinine concentrations.142, 143, 144 It has been suggested that ketoconazole may interfere with the metabolism of cyclosporine via hepatic microsomal enzyme inhibition,142, 144, 146 although other mechanisms may also be involved.145, 146
Caution is advised if cyclosporine is used concomitantly with ketoconazole.384 Careful monitoring, with possible dosage adjustment, is recommended if ketoconazole and cyclosporine are used concomitantly.263, 384 When ketoconazole is initiated in a patient receiving cyclosporine, renal function and blood or plasma cyclosporine concentrations should be monitored;146 reduction in cyclosporine dosage or replacement of cyclosporine with another immunosuppressive agent should be considered.146 Patients stabilized on both drugs may require an increase in cyclosporine dosage when ketoconazole is discontinued.146
Concomitant use of everolimus and ketoconazole may result in increased plasma concentrations of everolimus.384
Concomitant use of everolimus and ketoconazole is not recommended.384 Everolimus should be avoided during and for up to 1 week after completion of ketoconazole treatment, unless the benefits of the immunosuppressive agent outweigh the potentially increased risk of adverse effects.384 If concomitant use cannot be avoided, the patient should be monitored for signs and symptoms of increased or prolonged effects of everolimus and dosage of the immunosuppressive agent should be reduced or interrupted if necessary.384
In healthy individuals, concomitant use of sirolimus (single 5-mg dose) and ketoconazole (200 mg daily for 10 days) increases the peak plasma concentration and AUC of sirolimus approximately 4-fold and 11-fold, respectively.263, 384
Concomitant use of sirolimus and ketoconazole is not recommended.384 Sirolimus should be avoided during and for up to 1 week after completion of ketoconazole treatment, unless the benefits of the immunosuppressive agent outweigh the potentially increased risk of adverse effects.384 If concomitant use cannot be avoided, the patient should be monitored for signs and symptoms of increased or prolonged effects of sirolimus and dosage of sirolimus should be reduced or interrupted if necessary.384
Concomitant use of ketoconazole and tacrolimus may affect metabolism of tacrolimus resulting in increased plasma concentrations of the immunosuppressive agent.263, 372
Caution is advised if tacrolimus is used concomitantly with ketoconazole.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of tacrolimus and dosage of the immunosuppressive agent should be reduced if necessary.384
In a limited number of individuals receiving ketoconazole dosages of 200 mg twice daily, concomitant administration of a single 20-mg dose of loratadine resulted in a 302% average increase of loratadine's AUC, a 251% average increase in peak loratadine plasma concentrations, a 155% average increase of descarboethoxyloratadine's (an active metabolite of loratadine) AUC, and a 141% average increase in peak descarboethoxyloratadine plasma concentrations compared with those achieved in individuals receiving loratadine and placebo.263, 384 No changes in the QTc intervals were reported 2, 6, and 24 hours after concomitant administration of the drugs and adverse effects were similar in individuals receiving loratadine concomitantly with ketoconazole and in those receiving loratadine and placebo.263, 384
Concomitant use of nadolol and ketoconazole may result in increased plasma concentrations of nadolol.384
Caution is advised if nadolol and ketoconazole are used concomitantly.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of nadolol and dosage of nadolol should be reduced if necessary.384
Alfentanil, Fentanyl, and Sufentanil
In vitro data suggest that alfentanil, fentanyl, and sufentanil are metabolized by CYP3A4.263, 384 Therefore, concomitant use of ketoconazole may increase plasma concentrations of these opiate agonists263, 384 and increase the risk of potentially fatal respiratory depression.384
Caution is advised if ketoconazole is used concomitantly with alfentanil, fentanyl, or sufentanil.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of the opiate agonist and dosage of the opiate agonist should be reduced if necessary.384
Concomitant use of buprenorphine and ketoconazole may result in increased plasma concentrations of buprenorphine.384
Caution is advised if buprenorphine (IV or sublingual) is used concomitantly with ketoconazole.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of buprenorphine and dosage of buprenorphine should be reduced if necessary.384
Concomitant use of methadone and ketoconazole may increase methadone plasma concentrations and may increase the risk of serious adverse effects (e.g., cardiovascular events including QT interval prolongation and torsades de pointes, respiratory depression, CNS depression).384
Concomitant use of methadone and ketoconazole is contraindicated;384 in addition, methadone should not be used for up to 1 week after completion of ketoconazole treatment.384
Concomitant use of oxycodone and ketoconazole may result in increased plasma concentrations of oxycodone.384
Caution is advised if oxycodone is used concomitantly with ketoconazole.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of oxycodone and dosage of the opiate agonist should be reduced if necessary.384
Phosphodiesterase Type 5 Inhibitors
Ketoconazole is a potent inhibitor of CYP3A4, and concomitant use in patients receiving a phosphodiesterase type 5 (PDE5) inhibitor (sildenafil, tadalafil, vardenafil) can substantially increase plasma concentrations of the PDE5 inhibitor and may increase the risk of adverse effects (e.g., hypotension, visual changes, priapism) associated with these agents.263, 376, 378, 379, 384
Caution is advised if sildenafil is used concomitantly with ketoconazole.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of sildenafil and dosage of sildenafil should be reduced if necessary.384 The manufacturer of sildenafil states that an initial sildenafil dose of 25 mg should be considered in patients receiving ketoconazole.445
Concomitant use of ketoconazole (400 mg daily) and tadalafil (20 mg) results in a 312% increase in the tadalafil AUC and a 22% increase in peak tadalafil plasma concentrations; concomitant use of ketoconazole (200 mg daily) and tadalafil (10 mg) results in a 107% increase in the tadalafil AUC and a 15% increase in peak tadalafil plasma concentrations.378
Caution is advised if tadalafil is used concomitantly with ketoconazole.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of tadalafil and dosage of tadalafil should be reduced if necessary.384 The manufacturer of tadalafil recommends that patients receiving ketoconazole 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 daily.378
Concomitant use of ketoconazole (200 mg once daily) and vardenafil (5 mg) results in a tenfold increase in the AUC of vardenafil and a fourfold increase in peak plasma concentrations of vardenafil.379
Caution is advised if vardenafil is used concomitantly with ketoconazole.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of vardenafil and dosage of vardenafil should be reduced if necessary.384 The manufacturer of vardenafil recommends that patients receiving ketoconazole in a dosage of 400 mg daily should receive no more than a single 2.5-mg dose of vardenafil in a 24-hour period and those receiving ketoconazole in a dosage of 200 mg daily should receive no more than a single 5-mg dose of vardenafil in a 24-hour period.379
Concomitant use of praziquantel and ketoconazole may result in increased plasma concentrations of praziquantel.384
Caution is advised if praziquantel is used concomitantly with ketoconazole.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of praziquantel and dosage of praziquantel should be reduced if necessary.384
Concomitant use of ramelteon and ketoconazole may result in increased plasma concentrations of ramelteon.384
Caution is advised if ramelteon is used concomitantly with ketoconazole.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of ramelteon and dosage of ramelteon should be reduced if necessary.384
Concomitant use of ranolazine and ketoconazole may increase plasma concentrations of ranolazine and increase the risk of serious cardiovascular effects, including QT interval prolongation.384
Concomitant use of ranolazine and ketoconazole is contraindicated;384 in addition, ranolazine should not be used for up to 1 week after completion of ketoconazole treatment.384
Concomitant use of salmeterol and ketoconazole may result in increased plasma concentrations of salmeterol.384
Concomitant use of salmeterol and ketoconazole is not recommended.384 Salmeterol should be avoided during and for up to 1 week after completion of ketoconazole treatment, unless the benefits outweigh the potentially increased risk of adverse effects.384 If concomitant use cannot be avoided, the patient should be monitored for signs and symptoms of increased or prolonged effects of salmeterol and dosage of salmeterol should be reduced or interrupted if necessary.384
Concomitant use of solifenacin and ketoconazole may result in increased plasma concentrations of solifenacin.384
Caution is advised if solifenacin is used concomitantly with ketoconazole.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of solifenacin and dosage of solifenacin should be reduced if necessary.384
Concomitant use of tamsulosin and ketoconazole may result in increased plasma concentrations of tamsulosin.384
Concomitant use of tamsulosin and ketoconazole is not recommended.384 Tamsulosin should be avoided during and for up to 1 week after completion of ketoconazole treatment, unless the benefits of the drug outweigh the potentially increased risk of adverse effects.384 If concomitant use cannot be avoided, the patient should be monitored for signs and symptoms of increased or prolonged tamsulosin effects and dosage of tamsulosin should be reduced or interrupted if necessary.384
Concomitant use of telithromycin and ketoconazole increases peak plasma concentrations and AUC of telithromycin and may increase the risk for telithromycin-associated adverse events.263, 384
Telithromycin and ketoconazole should be used concomitantly with caution.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of telithromycin and dosage of the macrolide should be reduced if necessary.384
Concomitant use of ketoconazole and theophylline has resulted in decreased serum theophylline concentrations in a limited number of patients.147 Data from a study in healthy adults, however, indicate that single or multiple oral doses of ketoconazole may not substantially alter the plasma clearance of single IV doses of theophylline (as aminophylline).150 Pending further accumulation of data, serum theophylline concentrations and the patient should be monitored closely and theophylline dosage adjusted accordingly when ketoconazole is initiated or discontinued in patients receiving theophylline.147
Ketoconazole decreases apparent oral clearance of tolterodine resulting in at least a twofold increase in tolterodine concentrations.263, 384
Caution is advised if tolterodine is used concomitantly with ketoconazole.384 The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of tolterodine and dosage of tolterodine should be reduced if necessary.384
Concomitant use of ketoconazole (200 mg) and tolvaptan results in a fivefold increase in tolvaptan exposures.384 Larger doses of ketoconazole are expected to produce larger increases in tolvaptan exposures.384 Data are not adequate to define a safe dosage adjustment for tolvaptan if the drug is used concomitantly with potent CYP3A inhibitors like ketoconazole.384
Concomitant use of tolvaptan and ketoconazole is contraindicated;384 in addition, tolvaptan should not be used for up to 1 week after completion of ketoconazole treatment.384
Because ketoconazole is a potent inhibitor of CYP34A,380, 381 concomitant use with trazodone may result in substantially increased plasma trazodone concentrations with the potential for adverse effects.380 If trazodone is used in patients receiving ketoconazole, consider reducing trazodone dosage.380
Although there have been no reports to date of the acute toxicity associated with overdosage of ketoconazole, the manufacturer states that in the event of overdosage supportive measures, including gastric lavage with sodium bicarbonate, should be employed.
Ketoconazole usually is fungistatic in action, but may be fungicidal at high concentrations after prolonged incubation or against very susceptible organisms.119, 121, 127, 129, 130, 131, 132, 133
Like other azole antifungals, ketoconazole presumably exerts its antifungal activity by altering cellular membranes, resulting in increased membrane permeability, secondary metabolic effects, and growth inhibition.127, 128, 130, 131 Although the exact mechanism of action of ketoconazole has not been fully determined, it has been suggested that the fungistatic activity of the drug may result from interference with ergosterol synthesis, probably via inhibition of C-14 demethylation of sterol intermediates (e.g., lanosterol).128, 129, 130, 151 The fungicidal activity of ketoconazole at high concentrations may result from a direct physiochemical effect of the drug on the fungal cell membrane.133
In vitro, ketoconazole concentrations as low as 0.01 mcg/mL prevent Candida albicans from forming pseudohyphae. This effect enhances phagocytosis of the fungi when polymorphonuclear leukocytes are added to the cultures because the leukocytes can phagocytize yeast phase cells more easily than mycelial phase cells.
Further study is needed to fully elucidate the effects of ketoconazole on steroid synthesis in humans, but the drug apparently directly inhibits synthesis of adrenal steroids and testosterone in vitro and in vivo.109, 110, 112, 113, 114, 115, 116, 117, 148, 151, 154, 156, 157, 158, 159, 160, 161, 171, 172, 173, 174, 175, 176 Ketoconazole 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
Usual dosages (i.e., 200-400 mg daily) of ketoconazole have been reported to transiently (for 2-12 hours) inhibit testicular testosterone synthesis.109, 110, 151, 174 A compensatory increase in serum luteinizing hormone (LH) concentrations may occur.110, 151, 174 Dosages of 800-1200 mg daily have been reported to have a more prolonged effect on testosterone synthesis;109, 151 in one study in males receiving these high dosages, serum testosterone concentrations remained at a subnormal level (i.e., less than 300 ng/dL) throughout the day in about 30% of those receiving 800 mg daily and in all of those receiving 1200 mg daily.109 Oligospermia, decreased libido, and impotence often occurred in these males and azoospermia occurred rarely.109, 151
Ketoconazole 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 In patients receiving ketoconazole, particularly those receiving relatively high dosages (e.g., greater than 400 mg daily) or divided daily dosing of the drug, the adrenocortical response to stimulation by corticotropin (ACTH) may be at least transiently diminished and urinary free and serum cortisol concentrations may be reduced.109, 110, 112, 113, 114, 151, 154, 156, 157, 158, 159, 166, 173
Ketoconazole is active against most pathogenic fungi, including dermatophytes. The drug also has in vitro activity against some gram-positive bacteria, including Staphylococcus aureus , S. epidermidis , enterococci, Nocardia , and Actinomadura . Although the clinical importance is unknown, ketoconazole appears to have some in vitro activity against herpes simplex virus types 1 and 2 (HSV-1 and -2).118 In addition, limited in vitro studies indicate that ketoconazole may have some activity against protozoa, including Acanthamoeba 134, 135, 136 and Leishmania and also may have some activity against chloroquine-sensitive and -resistant Plasmodium falciparum .
In Vitro Susceptibility Testing
Results of in vitro ketoconazole susceptibility tests are method dependent, and MIC values vary substantially depending on the culture medium used, pH,119, 148, 202 the presence of serum, and the concentration of fungi used in the test inoculum. In addition, currently available in vitro tests may not necessarily reflect the in vivo susceptibility of some fungi (especially Candida ).148, 202
In vitro, ketoconazole concentrations of 0.1-2 mcg/mL generally inhibit most susceptible strains of Blastomyces dermatitidis ,371 Coccidioides immitis , Cryptococcus neoformans ,373 Epidermophyton floccosum , Histoplasma capsulatum , Malassezia furfur ( Pityrosporum orbiculare ), Microsporum canis , M. gypseum ,120 Trichophyton mentagrophytes , T. rubrum , and T. tonsurans . Paracoccidioides brasiliensis is generally inhibited in vitro by ketoconazole concentrations of 0.002-0.1 mcg/mL. Ketoconazole concentrations of 1-25 mcg/mL generally are required in vitro to inhibit Actinomadura madurae , Aspergillus flavus ,120, 122, 124 A. fumigatus ,122, 124 Nocardia , Petriellidium boydii ,120, 122 and Sporothrix schenckii .120, 122, 124
A wide range of ketoconazole MIC values has been reported for Candida .120, 121, 122, 123, 124, 373 In some in vitro studies, the MIC90 of ketoconazole for C. albicans ,373 C. glabrata ,120, 122, 123, 124, 373 C. parapsilosis ,373 and C. tropicalis 373 was 0.125-16 mcg/mL; however, in other studies, these organisms required ketoconazole concentrations of 25 mcg/mL or greater for in vitro inhibition.120, 121, 122, 123, 124 In a study evaluating in vitro susceptibility of clinical isolates of C. dubliniensis obtained from patients with or without human immunodeficiency virus (HIV) infection, these strains were inhibited by ketoconazole concentrations of 0.03-0.25 mcg/mL.283 Some strains of C. lusitaniae are inhibited in vitro by ketoconazole concentrations of 0.03-0.12 mcg/mL.289
Exophiala castellanii has been inhibited in vitro by a ketoconazole concentration of 0.4 mcg/mL.275 Some strains of Scopulariopsis , including some strains of S. acremonium and S. brevicaulis , are inhibited in vitro by ketoconazole concentrations of 1-8 mcg/mL, but the MIC reported for other strains is greater than 16 mcg/mL.374
Penicillium marneffei has been inhibited in vitro by ketoconazole concentrations of 0.002-1 mcg/mL.389, 390
Limited in vitro studies indicate that ketoconazole concentrations of 6.25-10 mcg/mL may be amebistatic and concentrations of 25 mcg/mL may be amebicidal against Acanthamoeba .134, 135, 136
Strains of Candida albicans resistant to ketoconazole have been isolated from patients who received the drug.125, 126 C. albicans resistant to ketoconazole may also be cross-resistant to other azole antifungals (e.g., fluconazole, itraconazole).337
Ketoconazole is rapidly absorbed from the GI tract.162, 163 Following oral administration, ketoconazole is dissolved in gastric secretions and converted to the hydrochloride salt prior to absorption from the stomach.
The bioavailability of oral ketoconazole depends on the pH of the gastric contents in the stomach; an increase in the pH results in decreased absorption of the drug.384 Decreased bioavailability of ketoconazole has been reported in patients with acquired immunodeficiency syndrome (AIDS),198 probably because of gastric hypochlorhydria associated with this condition;198 concomitant administration of dilute hydrochloric acid solution normalized absorption of the drug in these patients.198 Concomitant administration of an acidic beverage may increase bioavailability of oral ketoconazole in some individuals with achlorhydria.273 In one cross-over study in healthy, fasting adults with achlorhydria (induced by administration of 60 mg of oral omeprazole 6-8 hours prior to ketoconazole), the peak plasma concentration and area under the plasma concentration-time curve (AUC) of the drug averaged 0.8 mcg/mL and 3.46 mcg/mL per hour, respectively, when the dose was administered with 240 mL of water and averaged 2.44 mcg/mL and 11.22 mcg/mL per hour, respectively, when the dose was administered with 240 mL of Coca-Cola Classic (pH 2.5).273 Concomitant administration of drugs which increase gastric pH decreases absorption of ketoconazole.384 (See Drug Interactions: Drugs Affecting Gastric Acidity.)
The effect of food on the rate and extent of GI absorption of ketoconazole has not been clearly determined.162 Some clinicians have reported that administration of ketoconazole to fasting individuals results in higher plasma concentrations of the drug than does administration with food. However, the manufacturer states that administration of ketoconazole with food increases the extent of absorption and results in more consistent plasma concentrations of the drug. The manufacturer suggests that food increases absorption of ketoconazole by increasing the rate and/or extent of dissolution of ketoconazole (e.g., by increasing bile secretions) or by delaying stomach emptying.
In healthy, fasting adults, peak plasma ketoconazole concentrations of approximately 4.2 mcg/mL occurred 1-2 hours following oral administration of a single 200-mg dose as tablets.149, 162 Following oral administration of a single 200-mg dose of ketoconazole as tablets to nonfasting adults in another study, peak plasma concentrations of the drug were attained within 1-4 hours and ranged from 1.5-4.5 mcg/mL; plasma concentrations of the drug were usually less than 0.05 mcg/mL after 24 hours. In one study in adults, a single 200-mg dose of ketoconazole as tablets given with a meal resulted in average plasma concentrations of the drug of 3.2 mcg/mL at 1 hour, 2.4 mcg/mL at 2 hours, 1.2 mcg/mL at 4 hours, and 0.6 mcg/mL at 6 hours.
Only limited data are available regarding the pharmacokinetics of ketoconazole in pediatric patients.384 In one study in a limited number of children 4-12 years of age, a single 100-mg oral dose of ketoconazole as tablets resulted in plasma concentrations of the drug ranging from 0.6-2.5 mcg/mL 2 hours after the dose. There is some evidence that ketoconazole absorption is greater when administered as a suspension (not commercially available in the US) than when administered as a crushed tablet mixed with applesauce.163, 384
Considerable interindividual variations in peak plasma concentrations attained and areas under the concentration-time curves (AUCs) have been reported with a specific oral dose of ketoconazole. In one cross-over study in adults who received single oral doses of ketoconazole of 100 mg, 200 mg, and 400 mg, a comparison of dose versus AUC suggested that ketoconazole undergoes saturable first pass elimination since bioavailability of the lower dose was relatively poor.
Ketoconazole has been detected in urine, bile, saliva, sebum, cerumen, and synovial fluid following oral administration of a single 200-mg dose of the drug in adults.
CNS penetration of ketoconazole is unpredictable and CSF concentrations of the drug generally have been considered to be negligible.384 In 2 adults with meningitis caused by Coccidioides immitis , a single 400-mg oral dose of ketoconazole resulted in CSF concentrations of the drug of 0.14 mcg/mL and 0.21 mcg/mL 4 hours after the dose; serum concentrations of ketoconazole in these patients were 2-4 mcg/mL 1-2 hours after the dose. In one study in adults with inflamed meninges, CSF concentrations of ketoconazole ranged from 0-0.24 mcg/mL at 1-2 hours after a single 200-mg oral dose of the drug and 0-0.85 mcg/mL at 1-3.5 hours after a single 400-mg oral dose of the drug. In several other adults with coccidioidal CNS infections, lumbar CSF concentrations of ketoconazole averaged 0.25 mcg/mL at 8 hours after an 800-mg oral dose and ranged from 0.27-1.65 mcg/mL at 4 hours after a 1.2-g oral dose; ventricular CSF concentrations averaged 50-60% of those attained in lumbar CSF.101
In rats, highest concentrations of ketoconazole are attained in the liver, pituitary, and adrenals; moderate concentrations are attained in the lungs, kidneys, bladder, bone marrow, teeth, myocardium, and various glandular tissues; and lowest concentrations are attained in the brain and testes following a single oral dose of the drug.
It is not known if ketoconazole crosses the placenta in humans; however, the drug crosses the placenta in rats. Ketoconazole is distributed into human milk.263, 384
Ketoconazole is 84-99% bound to plasma proteins, primarily albumin.
Plasma concentrations of ketoconazole appear to decline in a biphasic manner with a half-life of approximately 2 hours in the initial phase and approximately 8 hours in the terminal phase. Data indicate that ketoconazole pharmacokinetics are not substantially affected by renal or hepatic impairment.384
Ketoconazole is 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. In vitro studies indicate that the drug is principally metabolized by cytochrome P-450 (CYP) isoenzyme 3A4.384
The major route of elimination of ketoconazole and its metabolites appears to be excretion into the feces via the bile. In one study in fasting adults with normal renal function, approximately 57% of a single 200-mg oral dose of ketoconazole was excreted in the feces within 4 days; 20-65% of this was unchanged drug. In the same study, approximately 13% of the dose was excreted in urine within 4 days; 2-4% of this was unchanged drug.
Ketoconazole, a synthetic azole antifungal agent, is an imidazole derivative structurally related to other imidazoles (e.g., butoconazole, clotrimazole, econazole).384 Ketoconazole occurs as a white to slightly beige powder and is practically insoluble in water. Ketoconazole has pKas of 2.9 and 6.5.
Ketoconazole tablets should be stored at 20-25°C and protected from moisture.384
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 200 mg* | Ketoconazole Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
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