Total Cost
Free shipping on all orders

Powered by GeniusRx

ketoconazole 200 mg tablet

Out of Stock Manufacturer TARO PHARM USA 51672402601
Out of Stock

Uses

Oral ketoconazole has been used as an alternative for the treatment of blastomycosis, chromomycosis (chromoblastomycosis), coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis.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.(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) and the treatment of dermatophyte infections (e.g., tinea capitis, tinea corporis, tinea pedis, tinea unguium [onychomycosis]), the drug is no longer recommended and no longer labeled by FDA for these uses.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. 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. For use of ketoconazole in the topical treatment of dermatophytoses and superficial mycoses,

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. Based on ketoconazole's endocrine effects, the drug has been used in the treatment of advanced prostatic carcinoma. Oral ketoconazole also has been used in the treatment of hypercalcemia in patients with sarcoidosis and the treatment of tuberculosis-associated hypercalcemia and idiopathic infantile hypercalcemia and hypercalciuria.

Blastomycosis

Oral ketoconazole has been used as an alternative for the treatment of blastomycosis caused by Blastomyces dermatitidis. 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.

IV amphotericin B and oral itraconazole usually are the drugs of choice for the treatment of blastomycosis; oral fluconazole is an alternative.

In initial clinical studies, ketoconazole was effective when used in immunocompetent individuals with mild to moderate pulmonary or extrapulmonary blastomycosis (response rate 70-100%); however, the relapse rate with the drug was 10-14%. 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.

For additional information on management of blastomycosis, the current clinical practice guidelines from the Infectious Diseases Society of America (IDSA) available at http://www.idsociety.org should be consulted.

Chromomycosis

Oral ketoconazole has been used as an alternative for the treatment of chromomycosis (chromoblastomycosis) caused by Phialophora spp. 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.

A response to ketoconazole has been obtained in some patients with mild to moderate infections, but not in those with more extensive disease. 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.

Coccidioidomycosis

Oral ketoconazole has been used as an alternative for the treatment of coccidioidomycosis caused by Coccidioides immitis. 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.

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. 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). 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.

For additional information on management of coccidioidomycosis, the current clinical practice guidelines from IDSA available at http://www.idsociety.org 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 http://www.aidsinfo.nih.gov should be consulted.

Histoplasmosis

Oral ketoconazole has been used as an alternative for the treatment of histoplasmosis caused by Histoplasma capsulatum. 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.

The drugs of choice for the treatment of histoplasmosis are IV amphotericin B or oral itraconazole. IV amphotericin B is preferred for initial treatment of severe, life-threatening histoplasmosis, especially in immunocompromised patients such as those with HIV infection. 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. Other azole antifungals (fluconazole, ketoconazole, posaconazole, voriconazole) are considered second-line alternatives to oral itraconazole.

For additional information on management of histoplasmosis, the current clinical practice guidelines from IDSA available at http://www.idsociety.org 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 http://www.aidsinfo.nih.gov should be consulted.

Paracoccidioidomycosis

Oral ketoconazole has been used as an alternative for the treatment of paracoccidioidomycosis (South American blastomycosis) caused by Paracoccidioides brasiliensis. 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.

IV amphotericin B is the drug of choice for initial treatment of severe paracoccidioidomycosis. 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.

Cushing's Syndrome

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. 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.

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.

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 and in a limited number of boys for the treatment of precocious puberty.

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.

Hypercalcemia

Although safety and efficacy have not been established, ketoconazole has been used with some success for the treatment of hypercalcemia in adults with sarcoidosis. 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. 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. 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. In addition, hypercalcemia and increased serum 1,25-dihydroxyvitamin D concentrations may recur when ketoconazole dosage is decreased or the drug discontinued. 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.

Ketoconazole has been effective in a few adolescents for the treatment of tuberculosis-associated hypercalcemia. Ketoconazole also has been effective in a few infants for the treatment of idiopathic infantile hypercalcemia and hypercalciuria.

Safety and efficacy of ketoconazole for treatment of hypercalcemia have not been established and the drug is not labeled by FDA for this use.

Prostate Cancer

Because of ketoconazole's ability to inhibit testicular and adrenal steroid synthesis, the drug has been used in the treatment of advanced prostatic carcinoma. 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. A limited number of patients with androgen-independent prostatic cancer have received ketoconazole in conjunction with doxorubicin. 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.

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.

Protozoal Infections

Acanthamoeba Infections

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. 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.

Dosage and Administration

Administration

Ketoconazole is administered orally.

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.(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.

Dosage

Fungal Infections

General Dosage

The usual initial adult dosage of oral ketoconazole recommended by the manufacturer for the treatment of fungal infections is 200 mg once daily. If the expected clinical response is not achieved, the manufacturer states that oral ketoconazole dosage may be increased to 400 mg once daily. The manufacturer states that the recommended dosage (i.e., 200-400 mg daily in adults) should not be exceeded. Higher dosage is associated with increased toxicity. (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.(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.

Blastomycosis

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. The risk of toxicity should be considered if ketoconazole dosage exceeds 400 mg daily.(See Cautions.)

Blastomycosis usually is treated for 6-12 months.

Chromomycosis

A ketoconazole dosage of 200-400 mg daily has been recommended for the treatment of chromomycosis.

Coccidioidomycosis

For the treatment of coccidioidomycosis, ketoconazole has been given in a dosage of 400 mg once daily. Long-term treatment (months to years) is required.

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.

Histoplasmosis

For the treatment of histoplasmosis, some clinicians recommend that ketoconazole be administered in a dosage of 400-800 mg daily. The risk of toxicity should be considered if ketoconazole dosage exceeds 400 mg daily.(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.

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.

Paracocciodioidomycosis

A ketoconazole dosage of 200-400 mg once daily has been recommended for the treatment of paracoccidioidomycosis.

Hypercalcemia

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. The risk of toxicity should be considered if ketoconazole dosage exceeds 400 mg daily.(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.

For the treatment of tuberculosis-associated hypercalcemia, a few adolescents have received ketoconazole in a dosage of 3 mg/kg every 8 hours.

Prostate Cancer

Although safety and efficacy have not been established for the treatment of prostatic carcinoma or for use as an adjunct in the management of disseminated intravascular coagulation (DIC) associated with prostatic carcinoma, 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.(See Cautions.)

Cautions

Hepatotoxicity

Transient increases in serum AST, ALT, and alkaline phosphatase concentrations may occur during ketoconazole therapy.

Serious hepatotoxicity, including cases that were fatal or required liver transplantation, has occurred in patients receiving oral ketoconazole. Hepatotoxicity may be hepatocellular (in most cases), cholestatic, or a mixed pattern of injury. Although ketoconazole-induced hepatotoxicity usually is reversible following discontinuance of the drug, recovery may take several months and, in some cases, has not been reversible and deaths have occurred. Symptomatic hepatotoxicity usually is apparent within the first few months of ketoconazole therapy, but occasionally may be apparent within the first week of therapy.(See Cautions: Precautions and Contraindications.)

Some patients with ketoconazole-induced hepatotoxicity had no obvious risk factors for liver disease. 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. Many of the reported cases of hepatotoxicity occurred in patients who received the drug for the treatment of tinea unguium (onychomycosis) or the treatment of chronic, refractory dermatophytoses.

Ketoconazole-induced hepatitis has been reported in some children.

Cardiovascular Effects

Ketoconazole can prolong the QT interval. 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.

Hypertension has been reported in some patients receiving high-dose ketoconazole therapy (e.g., 400 mg every 6-8 hours) for metastatic prostatic carcinoma. 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.

Peripheral edema and orthostatic hypotension also have been reported.

Endocrine and Metabolic Effects

Ketoconazole dosages of 400 mg or higher decrease adrenal corticosteroid secretion. The drug can inhibit cortisol synthesis, particularly in patients receiving relatively high daily dosages or divided daily dosing of the drug. 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; adrenocortical insufficiency has been reported rarely.(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. 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. When adrenocortical hypofunction does occur in patients receiving ketoconazole, the condition generally is reversible following discontinuance of the drug but rarely may be persistent.(See Cautions: Precautions and Contraindications.)

Gynecomastia has been reported in patients receiving ketoconazole. 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. 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.

Dermatologic and Sensitivity Reactions

Anaphylaxis has been reported after the first dose of ketoconazole.

Other hypersensitivity reactions, including anaphylactoid reaction, erythema multiforme, rash, dermatitis, erythema, urticaria, and pruritus, have been reported in patients receiving ketoconazole. Acute generalized exanthematous pustulosis, photosensitivity, angioedema, alopecia, and xeroderma also have been reported.

Nervous System Effects

Headache, dizziness, somnolence, asthenia, fatigue, malaise, nervousness, insomnia, and paresthesia have been reported in patients receiving ketoconazole.

Reversible increased intracranial pressure (e.g., papilledema, bulging fontanelles in infants) has occurred in patients receiving ketoconazole.

GI Effects

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.

Other Adverse Effects

Arthralgia, myalgia, fever, chills, hot flush, photophobia, epistaxis, menstrual disorder, impotence, and thrombocytopenia have been reported in patients receiving ketoconazole.

Alcohol intolerance has been reported in patients receiving ketoconazole.(See Drug Interactions: Alcohol.)

Precautions and Contraindications

Ketoconazole is contraindicated in patients with known hypersensitivity to the drug.

Ketoconazole is contraindicated in patients with acute or chronic liver disease.

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.(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.(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.(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.(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.

Ketoconazole has been associated with serious hepatotoxicity, which has resulted in death or required liver transplantation.(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. Patients should be advised to avoid alcohol consumption during ketoconazole therapy. In addition, concomitant use of other potentially hepatotoxic drugs should be avoided.(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. During ketoconazole therapy, serum ALT concentrations should be monitored weekly. Prompt recognition of liver injury is essential. 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. Liver tests should then be repeated to ensure that values normalize. Minor, asymptomatic elevations in liver function test results may return to pretreatment concentrations during continued ketoconazole therapy. 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).

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). The possibility that ketoconazole may depress adrenocortical function should be considered, particularly in patients receiving relatively high dosages of the drug.(See Cautions: Endocrine and Metabolic Effects.) Similarly, the possibility that the drug may reduce serum testosterone concentrations should be considered. To minimize the risk of these endocrine effects, the recommended ketoconazole dosage (i.e., 200-400 mg daily in adults) should not be exceeded.

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.

Pediatric Precautions

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.

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.

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.

Ketoconazole was not carcinogenic in long-term studies in mice and rats using oral dosages of 5, 20, and 80 mg/kg daily. Based on a mg/m comparison, the high dosage used in these mice and rats was approximately equal to or twofold higher, respectively, than the usual human dosage.

Pregnancy, Fertility, and Lactation

Pregnancy

Ketoconazole should be used during pregnancy only when potential benefits justify possible risks to the fetus.

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). 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). 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.

Fertility

Oligospermia and, rarely, azoospermia have been reported in adult males receiving ketoconazole dosages greater than 400 mg daily. Ketoconazole dosages of 800 mg daily decrease serum testosterone concentrations; clinical manifestations of these decreased concentrations may include gynecomastia, impotence, and oligospermia.(See Mechanism of Action: Endocrine Effects.)

Lactation

Because ketoconazole is distributed into human milk, lactating women receiving the drug should not breast-feed.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Ketoconazole is a substrate for and potent inhibitor of cytochrome P-450 (CYP) isoenzyme 3A4.

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.

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.

Concomitant use of ketoconazole with drugs that induce CYP3A4 may decrease plasma concentrations of ketoconazole and may decrease efficacy of the antifungal.

Drugs Affecting or Affected by P-glycoprotein Transport

Ketoconazole is an inhibitor of the P-glycoprotein (P-gp) transport system.

Concomitant use of ketoconazole with drugs that are P-gp substrates may result in increased plasma concentrations of such drugs.

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. Concomitant use of ketoconazole and these drugs that prolong the QT interval is contraindicated; in addition, such drugs should not be used for up to 1 week after completion of ketoconazole treatment.

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.

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.

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.

Hepatotoxic Drugs

Because ketoconazole can cause serious hepatotoxicity, concomitant use with other potentially hepatotoxic drugs should be avoided if possible.

Alcohol

Disulfiram reactions, including flushing, rash, peripheral edema, nausea, and headache, have occurred rarely in patients who ingested alcohol while receiving ketoconazole therapy; symptoms usually resolved within a few hours.

Patients should be advised to avoid alcohol consumption during ketoconazole therapy. Some clinicians recommend that alcohol be avoided during and for 48 hours after discontinuance of ketoconazole.

Aliskiren

Concomitant use of aliskiren and ketoconazole may result in increased plasma concentrations of aliskiren.

Caution is advised if aliskiren is used concomitantly with ketoconazole. 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.

Antiarrhythmic Agents

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.

Concomitant use of ketoconazole and disopyramide, dofetilide, dronedarone, or quinidine is contraindicated; in addition, these antiarrhythmic agents should not be used for up to 1 week after completion of ketoconazole treatment.

Anticoagulants

Coumarin Anticoagulants

Ketoconazole may increase plasma concentrations of coumarin anticoagulants resulting in enhanced anticoagulant effects.

Ketoconazole and coumarin anticoagulants should be used concomitantly with caution; the anticoagulant effect should be carefully monitored and dosage of the anticoagulant adjusted accordingly.

Dabigatran

Concomitant use of dabigatran and ketoconazole may result in increased dabigatran plasma concentrations.

Dabigatran and ketoconazole should be used concomitantly with caution. The patient should be carefully monitored for signs or symptoms of increased or prolonged effects of dabigatran. 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.

Rivaroxaban

Concomitant use of rivaroxaban and ketoconazole may result in increased rivaroxaban concentrations.

Concomitant use of rivaroxaban and ketoconazole is not recommended. Rivaroxaban should be avoided during and for up to 1 week after completion of ketoconazole treatment. If concomitant use cannot be avoided, the patient should be monitored for signs and symptoms of increased or prolonged rivaroxaban effects; dosage of rivaroxaban should be reduced or interrupted if necessary.

Anticonvulsants

Carbamazepine

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.

Concomitant use of carbamazepine and ketoconazole is not recommended. 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. 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. If concomitant use cannot be avoided, the patient should be monitored for signs and symptoms of increased or prolonged carbamazepine effects; dosage of carbamazepine should be reduced or interrupted if necessary. In addition, antifungal activity should be monitored and dosage of ketoconazole increased if necessary.

Phenytoin

Concomitant use of phenytoin and ketoconazole may decrease plasma concentrations of ketoconazole and decrease efficacy of the antifungal.

Concomitant use of phenytoin and ketoconazole is not recommended. Phenytoin should be avoided for 2 weeks prior to and during ketoconazole treatment, unless the benefits outweigh the risk of potentially reduced ketoconazole efficacy. If concomitant use cannot be avoided, antifungal activity should be monitored and ketoconazole dosage increased if necessary.

Antidiabetic Agents

Concomitant use of ketoconazole and repaglinide or saxagliptin may result in increased plasma concentrations of the antidiabetic agent. Caution is advised if ketoconazole is used concomitantly with repaglinide or saxagliptin. 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.

Antimalarials

Artemether and Lumefantrine

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.

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.

Mefloquine

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.

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.

Quinine

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.

Dosage adjustment of quinine is not needed in patients receiving ketoconazole; however, patients should be monitored closely for adverse effects associated with quinine.

Antimycobacterial Agents

Isoniazid

Concomitant use of isoniazid and ketoconazole may result in decreased plasma concentrations of ketoconazole and decreased efficacy of the antifungal.

Concomitant use of isoniazid and ketoconazole is not recommended. Isoniazid should be avoided for 2 weeks prior to and during ketoconazole treatment, unless the benefits outweigh the risk of potentially reduced ketoconazole efficacy. If concomitant use cannot be avoided, antifungal activity should be monitored and ketoconazole dosage increased if necessary.

Rifabutin

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.

Concomitant use of rifabutin and ketoconazole is not recommended. Rifabutin should be avoided for 2 weeks prior to and during ketoconazole treatment, unless the benefits outweigh the risk of potentially reduced ketoconazole efficacy. 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. If concomitant use cannot be avoided, the patient should be monitored for signs and symptoms of increased or prolonged rifabutin effects; dosage of rifabutin should be reduced or interrupted if necessary. In addition, antifungal activity should be monitored and ketoconazole dosage increased if necessary.

Rifampin

Concomitant use of rifampin and ketoconazole results in decreased plasma concentrations of ketoconazole and may decrease efficacy of the antifungal. In one patient receiving ketoconazole concomitantly with rifampin and isoniazid, serum concentrations of both rifampin and ketoconazole were decreased. 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. In addition, isoniazid and rifampin appeared to have an additive effect in reducing serum ketoconazole concentrations.

Concomitant use of rifampin and ketoconazole is not recommended. Rifampin should be avoided for 2 weeks prior to and during ketoconazole treatment, unless the benefits outweigh the risk of potentially reduced ketoconazole efficacy. If concomitant use cannot be avoided, antifungal activity should be monitored and ketoconazole dosage increased if necessary.

Antineoplastic Agents

Bortezomib, Erlotinib, and Imatinib

Concomitant use of ketoconazole and bortezomib, erlotinib, or imatinib may result in increased plasma concentrations of the antineoplastic agent.

Caution is advised if ketoconazole is used concomitantly with bortezomib, erlotinib, or imatinib. 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.

Busulfan

Concomitant use of ketoconazole may decrease clearance of busulfan resulting in increased systemic exposure to the antineoplastic agent.

Caution is advised if busulfan and ketoconazole are used concomitantly. 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.

Dasatinib, Lapatinib, and Nilotinib

Concomitant use of ketoconazole and dasatinib, lapatinib, or nilotinib may result in increased plasma concentrations of the antineoplastic agent.

Concomitant use of ketoconazole and dasatinib, lapatinib, or nilotinib is not recommended. 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. 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.

Docetaxel

Clearance of docetaxel in cancer patients is decreased by 50% in the presence of ketoconazole.

Caution is advised if docetaxel and ketoconazole are used concomitantly. 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.

Irinotecan

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.

Concomitant use of irinotecan and ketoconazole is contraindicated; in addition, irinotecan should not be used for up to 1 week after completion of ketoconazole treatment.

Ixabepilone

Concomitant use of ixabepilone and ketoconazole may result in increased plasma concentrations of the antineoplastic agent.

Caution is advised if ixabepilone and ketoconazole are used concomitantly. 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.

Paclitaxel

In vitro studies indicate that ketoconazole can inhibit the metabolism of paclitaxel; this potential pharmacokinetic interaction has not been evaluated in humans.

Caution is advised if paclitaxel and ketoconazole are used concomitantly. 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.

Temsirolimus

Concomitant use of temsirolimus and ketoconazole may result in increased plasma concentrations of the antineoplastic agent.

Concomitant use of temsirolimus and ketoconazole is not recommended. 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. 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.

Trimetrexate

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. Concomitant use of trimetrexate and ketoconazole may result in increased plasma concentrations of trimetrexate.

Caution is advised if trimetrexate and ketoconazole are used concomitantly. 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.

Vinca Alkaloids

Ketoconazole may inhibit metabolism of vinca alkaloids metabolized by CYP3A4 (e.g., vincristine, vinblastine, vinorelbine) and concomitant use of the drugs may result in increased plasma concentrations of the vinca alkaloid.

Caution is advised if ketoconazole is used concomitantly with a vinca alkaloid. 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.

Antipsychotic Agents

Aripiprazole

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. The effect of higher ketoconazole dosages on aripiprazole exposures has not been evaluated.

Caution is advised if aripiprazole and ketoconazole are used concomitantly. 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.

Haloperidol

Concomitant use of haloperidol and ketoconazole may result in increased plasma concentrations of haloperidol.

Caution is advised if haloperidol is used concomitantly with ketoconazole. 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.

Lurasidone

Concomitant use of lurasidone and ketoconazole may result in increased plasma concentrations of lurasidone.

Concomitant use of lurasidone and ketoconazole is contraindicated; in addition, lurasidone should not be used for up to 1 week after completion of ketoconazole treatment.

Pimozide

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.

Concomitant use of pimozide and ketoconazole is contraindicated; in addition, pimozide should not be used for up to 1 week after completion of ketoconazole treatment.

Quetiapine

Concomitant use of quetiapine and ketoconazole may result in increased plasma concentrations of quetiapine.

Caution is advised if quetiapine is used concomitantly with ketoconazole. 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.

Risperidone

Concomitant use of risperidone and ketoconazole may result in increased plasma concentrations of risperidone.

Caution is advised if risperidone is used concomitantly with ketoconazole. 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.

Antiretroviral Agents

HIV Entry Inhibitors

Concomitant use of maraviroc and ketoconazole may result in increased plasma concentrations of maraviroc.

Caution is advised if maraviroc and ketoconazole are used concomitantly. 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.

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Delavirdine

Concomitant use of ketoconazole and delavirdine may result in increased trough plasma concentrations of delavirdine.

Efavirenz

Concomitant use of efavirenz and ketoconazole may result in decreased ketoconazole plasma concentrations and may decrease efficacy of the antifungal.

Concomitant use of efavirenz and ketoconazole is not recommended. Efavirenz should be avoided for 2 weeks prior to and during ketoconazole treatment, unless the benefits outweigh the risk of potentially reduced ketoconazole efficacy. If concomitant use cannot be avoided, antifungal activity should be monitored and ketoconazole dosage should be increased if necessary.

Etravirine

Concomitant use of etravirine and ketoconazole may result in increased etravirine plasma concentrations and decreased ketoconazole plasma concentrations. Dosage adjustment of ketoconazole may be needed depending on other concomitantly administered drugs.

Nevirapine

Concomitant use of nevirapine and ketoconazole results in decreased plasma concentrations and AUC of ketoconazole and may decrease efficacy of the antifungal.

Concomitant use of nevirapine and ketoconazole is not recommended. Nevirapine should be avoided for 2 weeks prior to and during ketoconazole treatment, unless the benefits outweigh the risk of potentially reduced ketoconazole efficacy. If concomitant use cannot be avoided, antifungal activity should be monitored and ketoconazole dosage should be increased if necessary.

Rilpivirine

Concomitant use of ketoconazole and rilpivirine has resulted in increased rilpivirine plasma concentrations and AUC and decreased ketoconazole plasma concentrations and AUC.

Rilpivirine dosage adjustments are not needed when the drug is used concomitantly with ketoconazole; however, patients should be monitored for breakthrough fungal infections.

HIV Protease Inhibitors (PIs)

Atazanavir

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.

Concomitant use of ketoconazole and ritonavir-boosted or cobicistat-boosted atazanavir may result in increased plasma concentrations of ketoconazole, atazanavir, and cobicistat.

Caution is advised if high ketoconazole dosage (exceeding 200 mg daily) is used in patients receiving ritonavir-boosted atazanavir. Specific dosage recommendations are not available for concomitant use of ketoconazole and cobicistat-boosted atazanavir.

Darunavir

Concomitant use of ritonavir-boosted darunavir and ketoconazole increases darunavir and ketoconazole concentrations. Pharmacokinetic interactions are possible if ketoconazole is used concomitantly with cobicistat-boosted darunavir (increased ketoconazole, darunavir, and cobicistat concentrations).

Caution is advised if ketoconazole is used concomitantly with ritonavir-boosted or cobicistat-boosted darunavir. The patient should be closely monitored for increased ketoconazole-, darunavir-, and ritonavir- or cobicistat-associated adverse effects. Decreased ketoconazole dosage should be considered and ketoconazole plasma concentrations should be monitored if necessary.

Ketoconazole dosage should not exceed 200 mg daily in patients receiving ritonavir-boosted darunavir. Specific dosage recommendations are not available for concomitant use of ketoconazole and cobicistat-boosted darunavir.

Fosamprenavir

Concomitant use of ketoconazole and ritonavir-boosted fosamprenavir results in increased plasma concentrations and AUC of the antifungal.

Caution is advised if ketoconazole is used concomitantly with ritonavir-boosted fosamprenavir. The patient should be closely monitored for ketoconazole-associated adverse effects and decreased ketoconazole dosage should be considered. Ketoconazole plasma concentrations should be monitored if necessary.

Ketoconazole dosage should not exceed 200 mg daily in patients receiving ritonavir-boosted fosamprenavir. In patients receiving fosamprenavir (without low-dose ritonavir), reduced antifungal dosage may be needed in those receiving ketoconazole dosages exceeding 400 mg daily.

Indinavir

Concomitant use of ketoconazole and indinavir can increase indinavir concentrations.

Caution is advised if indinavir is used concomitantly with ketoconazole. Dosage of indinavir should be reduced to 600 mg every 8 hours in patients receiving ketoconazole and the patient should be carefully monitored for signs or symptoms of indinavir-associated adverse effects.

Lopinavir

Concomitant use of the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) and ketoconazole results in increased plasma concentrations of the antifungal.

Ketoconazole dosage should not exceed 200 mg daily in patients receiving lopinavir/ritonavir.

Nelfinavir

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.

Saquinavir

Concomitant use of ritonavir-boosted saquinavir and ketoconazole increases concentrations of ketoconazole, but does not appear to affect saquinavir pharmacokinetics.

Caution is advised and the patient should be carefully monitored if saquinavir is used concomitantly with ketoconazole. Ketoconazole dosage should not exceed 200 mg daily in patients receiving ritonavir-boosted saquinavir.

Tipranavir

Concomitant use of ritonavir-boosted tipranavir and ketoconazole may result in increased ketoconazole concentrations.

Ketoconazole and ritonavir-boosted tipranavir should be used concomitantly with caution and ketoconazole dosage should not exceed 200 mg daily.

Aprepitant

Concomitant use of aprepitant and ketoconazole may result in increased plasma concentrations of aprepitant.

Caution is advised if aprepitant is used concomitantly with ketoconazole. 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.

Benzodiazepines

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.

Concomitant use of ketoconazole and alprazolam, oral midazolam, or triazolam is contraindicated; in addition, these benzodiazepines should not be used for up to 1 week after completion of ketoconazole treatment.

Caution is advised if parenteral midazolam is used concomitantly with ketoconazole. 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.

Bosentan

Concomitant use of bosentan (125 mg twice daily) and ketoconazole increased peak plasma concentrations and AUC of bosentan approximately twofold in healthy individuals.

Caution is advised if bosentan is used concomitantly with ketoconazole. 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.

Buspirone

Concomitant use of buspirone with ketoconazole is expected to result in clinically important increases in plasma concentrations of buspirone.

Caution is advised if buspirone is used concomitantly with ketoconazole. 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. 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.

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. Calcium-channel blockers have a negative inotropic effect which may be additive to that of ketoconazole. The potential increase in plasma concentrations of calcium-channel blockers may increase the risk of edema and congestive heart failure.

Concomitant use of ketoconazole and felodipine or nisoldipine is contraindicated; in addition, felodipine or nisoldipine should not be used for up to 1 week after completion of ketoconazole treatment.

Caution is advised if ketoconazole is used concomitantly with other dihydropyridines (e.g., amlodipine, nicardipine, nifedipine). 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.

Caution is advised if verapamil and ketoconazole are used concomitantly. 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.

Cilostazol

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.

Caution is advised if cilostazol is used concomitantly with ketoconazole. 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.

Cinacalcet

Concomitant use of cinacalcet and ketoconazole may result in increased plasma concentrations of cinacalcet.

Caution is advised if cinacalcet and ketoconazole are used concomitantly. 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.

Cisapride

Ketoconazole potentially inhibits metabolism of cisapride (available in the US only under a limited-use protocol). Concomitant use of ketoconazole and cisapride has resulted in increased cisapride plasma concentrations and AUC; QT interval prolongation and serious cardiovascular effects, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes, have been reported rarely.

Concomitant use of cisapride and ketoconazole is contraindicated; in addition, cisapride should not be used for up to 1 week after completion of ketoconazole treatment.

Colchicine

Concomitant use of colchicine and ketoconazole may increase colchicine plasma concentrations and increase the risk of potentially fatal adverse effects.

In patients with renal or hepatic impairment, concomitant use of colchicine and ketoconazole is contraindicated; in addition, colchicine should not be used for up to 1 week after completion of ketoconazole treatment in these patients.

In patients without renal or hepatic impairment, concomitant use of colchicine and ketoconazole is not recommended. 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. 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.

Corticosteroids

Concomitant use of ketoconazole and budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, or prednisolone may increase plasma concentrations of the corticosteroid, possibly due to decreased clearance. Ketoconazole may enhance the adrenal suppressive effects of corticosteroids.

Concomitant use of fluticasone propionate and ketoconazole is not recommended, unless potential benefits outweigh potential risks of systemic corticosteroid adverse effects.

Caution is advised if ketoconazole is used concomitantly with budesonide, ciclesonide, dexamethasone, or methylprednisolone. 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.

Digoxin

Elevated plasma concentrations of digoxin have been reported in patients receiving ketoconazole. 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.

Eletriptan

Concomitant use of eletriptan and ketoconazole may result in increased plasma concentrations of eletriptan.

Eletriptan should be avoided for 72 hours after completion of ketoconazole treatment. Caution is advised if eletriptan is used concomitantly with ketoconazole. 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.

Eplerenone

Concomitant use of eplerenone and ketoconazole increases the AUC of eplerenone approximately fivefold and increases the risk of hyperkalemia and hypotension.

Concomitant use of eplerenone and ketoconazole is contraindicated; in addition, eplerenone should not be used for up to 1 week after completion of ketoconazole treatment.

Ergot Alkaloids

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).

Concomitant use of ketoconazole and ergot alkaloids is contraindicated; in addition, ergot alkaloids should not be used for up to 1 week after completion of ketoconazole treatment.

Fesoterodine

Concomitant use of fesoterodine and ketoconazole may result in increased plasma concentrations of fesoterodine.

Caution is advised if fesoterodine is used concomitantly with ketoconazole. 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.

HCV Antivirals

HCV Polymerase Inhibitors

Dasabuvir

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.

If ketoconazole is used concomitantly with ombitasvir/paritaprevir/ritonavir with dasabuvir, dosage of the antifungal should not exceed 200 mg daily.

HCV Protease Inhibitors

Paritaprevir

Concomitant use of ketoconazole (400 mg once daily) and ombitasvir/paritaprevir/ritonavir with or without dasabuvir results in a twofold increase in ketoconazole AUC.

If ketoconazole is used concomitantly with ombitasvir/paritaprevir/ritonavir with or without dasabuvir, dosage of the antifungal should not exceed 200 mg daily.

Simeprevir

Concomitant use of simeprevir and ketoconazole may result in increased plasma concentrations of simeprevir.

Concomitant use of simeprevir and ketoconazole is not recommended.

HCV Replication Complex Inhibitors

Daclatasvir

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.

If daclatasvir and ketoconazole are used concomitantly, daclatasvir should be given in a dosage of 30 mg once daily.

Elbasavir and Grazoprevir

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.

Concomitant use of ketoconazole and the fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir) is not recommended.

Ombitasvir

Concomitant use of ketoconazole (400 mg once daily) and ombitasvir/paritaprevir/ritonavir with or without dasabuvir results in a twofold increase in ketoconazole AUC.

If ketoconazole is used concomitantly with ombitasvir/paritaprevir/ritonavir with or without dasabuvir, dosage of the antifungal should not exceed 200 mg daily.

Velpatasvir

Concomitant use of ketoconazole (200 mg twice daily) and velpatasvir (single 100-mg dose) does not result in clinically important pharmacokinetic interactions.

HMG-CoA Reductase Inhibitors

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.

Concomitant use of ketoconazole and lovastatin or simvastatin is contraindicated; in addition, lovastatin or simvastatin should not be used for up to 1 week after completion of ketoconazole treatment.

Caution is advised if atorvastatin is used concomitantly with ketoconazole. 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.

Immunosuppressive Agents

Cyclosporine

Concomitant use of ketoconazole and cyclosporine has been reported to increase plasma concentrations of cyclosporine and serum creatinine concentrations. It has been suggested that ketoconazole may interfere with the metabolism of cyclosporine via hepatic microsomal enzyme inhibition, although other mechanisms may also be involved.

Caution is advised if cyclosporine is used concomitantly with ketoconazole. Careful monitoring, with possible dosage adjustment, is recommended if ketoconazole and cyclosporine are used concomitantly. When ketoconazole is initiated in a patient receiving cyclosporine, renal function and blood or plasma cyclosporine concentrations should be monitored; reduction in cyclosporine dosage or replacement of cyclosporine with another immunosuppressive agent should be considered. Patients stabilized on both drugs may require an increase in cyclosporine dosage when ketoconazole is discontinued.

Everolimus

Concomitant use of everolimus and ketoconazole may result in increased plasma concentrations of everolimus.

Concomitant use of everolimus and ketoconazole is not recommended. 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. 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.

Sirolimus

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.

Concomitant use of sirolimus and ketoconazole is not recommended. 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. 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.

Tacrolimus

Concomitant use of ketoconazole and tacrolimus may affect metabolism of tacrolimus resulting in increased plasma concentrations of the immunosuppressive agent.

Caution is advised if tacrolimus is used concomitantly with ketoconazole. 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.

Loratadine

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. 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.

Nadolol

Concomitant use of nadolol and ketoconazole may result in increased plasma concentrations of nadolol.

Caution is advised if nadolol and ketoconazole are used concomitantly. 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.

Opiate Agonists

Alfentanil, Fentanyl, and Sufentanil

In vitro data suggest that alfentanil, fentanyl, and sufentanil are metabolized by CYP3A4. Therefore, concomitant use of ketoconazole may increase plasma concentrations of these opiate agonists and increase the risk of potentially fatal respiratory depression.

Caution is advised if ketoconazole is used concomitantly with alfentanil, fentanyl, or sufentanil. 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.

Buprenorphine

Concomitant use of buprenorphine and ketoconazole may result in increased plasma concentrations of buprenorphine.

Caution is advised if buprenorphine (IV or sublingual) is used concomitantly with ketoconazole. 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.

Methadone

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).

Concomitant use of methadone and ketoconazole is contraindicated; in addition, methadone should not be used for up to 1 week after completion of ketoconazole treatment.

Oxycodone

Concomitant use of oxycodone and ketoconazole may result in increased plasma concentrations of oxycodone.

Caution is advised if oxycodone is used concomitantly with ketoconazole. 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.

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.

Sildenafil

Caution is advised if sildenafil is used concomitantly with ketoconazole. 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. The manufacturer of sildenafil states that an initial sildenafil dose of 25 mg should be considered in patients receiving ketoconazole.

Tadalafil

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.

Caution is advised if tadalafil is used concomitantly with ketoconazole. 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. The manufacturer of tadalafil recommends that patients receiving ketoconazole receive no more than 10 mg of tadalafil once every 72 hours. If a once-daily tadalafil regimen is used, those receiving ketoconazole should receive no more than 2.5 mg of tadalafil once daily.

Vardenafil

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.

Caution is advised if vardenafil is used concomitantly with ketoconazole. 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. 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.

Praziquantel

Concomitant use of praziquantel and ketoconazole may result in increased plasma concentrations of praziquantel.

Caution is advised if praziquantel is used concomitantly with ketoconazole. 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.

Ramelteon

Concomitant use of ramelteon and ketoconazole may result in increased plasma concentrations of ramelteon.

Caution is advised if ramelteon is used concomitantly with ketoconazole. 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.

Ranolazine

Concomitant use of ranolazine and ketoconazole may increase plasma concentrations of ranolazine and increase the risk of serious cardiovascular effects, including QT interval prolongation.

Concomitant use of ranolazine and ketoconazole is contraindicated; in addition, ranolazine should not be used for up to 1 week after completion of ketoconazole treatment.

Salmeterol

Concomitant use of salmeterol and ketoconazole may result in increased plasma concentrations of salmeterol.

Concomitant use of salmeterol and ketoconazole is not recommended. 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. 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.

Solifenacin

Concomitant use of solifenacin and ketoconazole may result in increased plasma concentrations of solifenacin.

Caution is advised if solifenacin is used concomitantly with ketoconazole. 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.

Tamsulosin

Concomitant use of tamsulosin and ketoconazole may result in increased plasma concentrations of tamsulosin.

Concomitant use of tamsulosin and ketoconazole is not recommended. 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. 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.

Telithromycin

Concomitant use of telithromycin and ketoconazole increases peak plasma concentrations and AUC of telithromycin and may increase the risk for telithromycin-associated adverse events.

Telithromycin and ketoconazole should be used concomitantly with caution. 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.

Theophylline

Concomitant use of ketoconazole and theophylline has resulted in decreased serum theophylline concentrations in a limited number of patients. 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). 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.

Tolterodine

Ketoconazole decreases apparent oral clearance of tolterodine resulting in at least a twofold increase in tolterodine concentrations.

Caution is advised if tolterodine is used concomitantly with ketoconazole. 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.

Tolvaptan

Concomitant use of ketoconazole (200 mg) and tolvaptan results in a fivefold increase in tolvaptan exposures. Larger doses of ketoconazole are expected to produce larger increases in tolvaptan exposures. Data are not adequate to define a safe dosage adjustment for tolvaptan if the drug is used concomitantly with potent CYP3A inhibitors like ketoconazole.

Concomitant use of tolvaptan and ketoconazole is contraindicated; in addition, tolvaptan should not be used for up to 1 week after completion of ketoconazole treatment.

Trazodone

Because ketoconazole is a potent inhibitor of CYP34A, concomitant use with trazodone may result in substantially increased plasma trazodone concentrations with the potential for adverse effects. If trazodone is used in patients receiving ketoconazole, consider reducing trazodone dosage.

Pharmacokinetics

Absorption

Ketoconazole is rapidly absorbed from the GI tract. 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. Decreased bioavailability of ketoconazole has been reported in patients with acquired immunodeficiency syndrome (AIDS), probably because of gastric hypochlorhydria associated with this condition; concomitant administration of dilute hydrochloric acid solution normalized absorption of the drug in these patients. Concomitant administration of an acidic beverage may increase bioavailability of oral ketoconazole in some individuals with achlorhydria. 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). Concomitant administration of drugs which increase gastric pH decreases absorption of ketoconazole.(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. 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. 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. 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.

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.

Distribution

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. 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.

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.

Ketoconazole is 84-99% bound to plasma proteins, primarily albumin.

Elimination

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.

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.

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.

Write Your Own Review

Your meds on autopilot. Forever.