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  • CLASSES

    Azole Antifungals
    Topical Dermatological Antifungals
    Topical Scalp Antifungals

    BOXED WARNING

    Ethanol ingestion, hepatic disease, hepatitis, hepatotoxicity

    Orally administered ketoconazole is contraindicated in patients with acute or chronic hepatic disease. Serious hepatotoxicity, including cases with a fatal outcome or requiring liver transplantation, has occurred with the use of oral ketoconazole. These cases were reported both by patients receiving high doses for short treatment durations and by patients receiving low doses for long durations. Some patients had no obvious risk factors for hepatic disease. The hepatic injury has usually, but not always, been reversible upon discontinuation of treatment. Cases of hepatitis have been reported in pediatric patients. Due to the risk of hepatotoxicity and other serious adverse effects, oral ketoconazole should only be used to treat serious fungal infections when no other antifungal therapies are available. Patients should be informed of the risk and closely monitored if systemic ketoconazole therapy is to be given. At baseline, obtain laboratory tests (such as SGGT, alkaline phosphatase, ALT, AST, total bilirubin, prothrombin time (PT), International Normalized Ratio (INR), and testing for viral hepatitides). Advise patients against ethanol ingestion while on treatment. If possible, coadministration with potentially hepatotoxic drugs should be avoided. Prompt recognition of liver injury is critical. During the course of treatment, monitor serum ALT weekly for the duration of treatment. If ALT values increase to a level above the upper limit of normal or 30 percent above baseline, or if the patient develops symptoms, ketoconazole treatment should be interrupted and a full set of liver tests should be obtained. Repeat liver tests to ensure normalization of values. Hepatotoxicity has been reported upon rechallenge. If it is decided to restart oral ketoconazole, monitor the patient frequently to detect any recurring hepatic injury from the drug.

    Bradycardia, cardiac arrhythmias, diabetes mellitus, females, heart failure, hypocalcemia, hypokalemia, hypomagnesemia, ketoconazole coadministration with other drugs, long QT syndrome, QT prolongation, torsade de pointes, ventricular arrhythmias

    Due to its potent inhibition of the hepatic isoenzyme CYP3A4, oral ketoconazole coadministration with other drugs metabolized by CYP3A4 should be done with extreme caution, if at all. Ketoconazole can cause elevated plasma concentrations of selected drugs metabolized via CYP3A4 which may prolong the QT interval, sometimes resulting in life-threatening ventricular arrhythmias such as torsade de pointes; use of ketoconazole with such drugs is contraindicated. Oral ketoconazole may also inhibit the metabolism of many other drugs, which could result in serious and potentially life-threatening adverse reactions, and use with selected drugs is also contraindicated. Due to the potential for harmful drug interactions and other serious adverse effects, oral ketoconazole should only be used to treat serious fungal infections when no other antifungal therapies are available. Systemic ketoconazole can prolong the QT interval. Use ketoconazole tablets with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, older adult patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation.

    DEA CLASS

    Rx, OTC

    DESCRIPTION

    Imidazole antifungal
    Used topically for fungal skin and skin structure infections; used orally for serious fungal infections only when no other antifungal therapies available
    Oral use associated with fatal hepatotoxicity, adrenal gland suppression, and harmful drug interactions

    COMMON BRAND NAMES

    Extina, Ketodan, Kuric, Nizoral, Nizoral A-D, Xolegel

    HOW SUPPLIED

    Extina/Ketoconazole/Ketodan Topical Foam: 2%
    Ketoconazole/Kuric/Nizoral Topical Cream: 2%
    Ketoconazole/Nizoral Oral Tab: 200mg
    Ketoconazole/Nizoral/Nizoral A-D Topical Shampoo: 1%, 2%
    Xolegel Topical Gel: 2%

    DOSAGE & INDICATIONS

    For the treatment of chromomycosis in patients who have failed or who are intolerant to other therapies.
    NOTE: Due to the potential for serious adverse events (i.e., fatal hepatotoxicity, adrenal insufficiency, harmful drug interactions), oral ketoconazole should only be used to treat serious fungal infections when no other antifungal therapies are available.
    Oral dosage
    Adults

    200 mg PO once daily. Serious infection may require 400 mg PO once daily.

    Children 2 years and older and Adolescents

    3.3 to 6.6 mg/kg PO once daily. Do not to exceed adult doses.

    For the treatment of blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis in patients who have failed or who are intolerant to other therapies.
    NOTE: Due to the potential for serious adverse events (i.e., fatal hepatotoxicity, adrenal insufficiency, harmful drug interactions), oral ketoconazole should only be used to treat serious fungal infections when no other antifungal therapies are available.
    Oral dosage
    Adults

    200 to 400 mg PO once daily. For blastomycosis, doses of 400 mg PO once daily were successful in 79% of patients and doses of 800 mg PO once daily were successful in 100% of patients, although adverse reactions were more prevalent with the higher dosage. For coccidioidomycosis, 400 mg PO once daily is recommended.

    Children 2 years and older and Adolescents

    3.3 to 6.6 mg/kg PO once daily. Do not to exceed adult doses.

    For treatment of mucocutaneous candidiasis.
    Topical dosage (cream)
    Adults

    Apply a sufficient amount to the affected and surrounding areas once daily for 2 weeks.

    For the treatment of dandruff, to control flaking, scaling, or itching.
    Topical dosage (1% shampoo, OTC product)
    Adults, Adolescents, and Children 12 years and older

    Apply to wet hair; generously lather, rinse thoroughly, and repeat. Apply every 3 to 4 days for up to 8 weeks, if needed, or as directed by a doctor.

    Topical dosage (2% shampoo, Rx-only product)
    Adults

    Apply the shampoo to the damp skin of the affected area and a wide margin surrounding this area. Lather and leave in place for 5 minutes, and then rinse off with water. One application should be sufficient. In a clinical trial, 246 patients with moderate to severe dandruff were randomized to either ketoconazole 2% shampoo or selenium sulfide 2.5% shampoo. Ketoconazole was statistically superior to selenium sulfide at day 8 only. Both products were superior to placebo. Ketoconazole was better tolerated than selenium sulfide.

    For the treatment of seborrheic dermatitis.
    Topical dosage (cream)
    Adults

    Apply to the affected areas twice daily for 4 weeks or until clinical clearing.

    Topical dosage (gel)
    Adults, Adolescents, and Children 12 years and older

    Apply a sufficient amount to the affected areas once daily for 2 weeks.

    Topical dosage (foam)
    Adults, Adolescents, and Children 12 years and older

    Apply a sufficient amount to the affected areas twice daily for 4 weeks.

    For the treatment of tinea corporis or tinea cruris.
    Topical dosage (cream)
    Adults

    Apply a sufficient amount to the affected and surrounding areas once daily for 2 weeks.

    For the treatment of tinea pedis.
    Topical dosage (cream)
    Adults

    Apply a sufficient amount to the affected and surrounding areas once daily for 6 weeks.

    For the treatment of tinea versicolor.
    Topical dosage (cream)
    Adults

    Apply a sufficient amount to the affected and surrounding areas once daily for 2 weeks.

    Topical dosage (2% shampoo)
    Adults

    Apply to damp skin of the affected area and to surrounding area, as a single application. Lather and leave in place for 5 minutes, then rinse off with water.

    For the treatment of advanced prostate cancer†.
    Oral dosage
    Adults

    400 mg PO every 8 hours has been used in a limited number of patients over a 6 month period with measurable success.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    400 mg/day PO; doses up to 1200 mg/day PO have been used off-label for prostate cancer; maximum dosage for topical preparations is dependent on indication and product.

    Elderly

    400 mg/day PO; doses up to 1200 mg/day PO have been used off-label for prostate cancer; maximum dosage for topical preparations is dependent on indication and product.

    Adolescents

    3.3—6.6 mg/kg/day PO (not to exceed 400 mg/day PO); maximum dosage for topical preparations is dependent on indication and product.

    Children

    >= 2 years: 3.3—6.6 mg/kg/day PO (not to exceed 400 mg/day PO); safety and efficacy have not been established for topical products.
    < 2 years: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    The use of ketoconazole tablets in patients with hepatic disease (acute or chronic) is contraindicated. Monitor liver function weekly in other patients receiving systemic therapy.

    Renal Impairment

    No dosage adjustment needed.

    ADMINISTRATION

    Oral Administration

    For patients with achlorhydria, administration with an acidic beverage (i.e., cola) significantly increases the oral bioavailability. .

    Topical Administration
    Cream/Ointment/Lotion Formulations

    Cream should not be administered intravaginally or applied to the eye.
    Rub cream gently into cleansed affected area.

    Other Topical Formulations

    1% Shampoo (OTC) for dandruff
     
    Saturate hair with warm water. Rub shampoo between hands. Use an amount the size of a quarter for long or thick hair and an amount the size of a dime for short hair. Put shampoo on hair and scalp, starting at the back of the head, then the sides, then the top. Use a firm circular movement using the pads of the fingers. Rinse thoroughly.
    The shampoo can be used on permed, bleached, or color-treated hair.
     
    2% Shampoo (Rx) for tinea versicolor
    Apply shampoo to the damp skin of the affected area and a wide margin surrounding this area.
    Lather and leave in place for 5 minutes, then rinse off with water.
    One application should be sufficient.
     
    Gel
    Do not use near the eyes, nose, mouth, or other mucous membranes.
    Rub gel gently into cleansed affected area. Wash hands after use.
    Avoid fire, flame, and smoking during and immediately after use.
     
    Foam
    Do not use near the eyes, nose, mouth, or other mucous membranes.
    Hold can upright and dispense foam into the cap of the can or onto another cool surface; do not dispense directly into hands as the foam will begin to melt.
    Pick up small amounts of foam with fingertips and gently rub into the affected area(s) until the foam disappears.
    For application to areas covered with hair, part the hair so the foam may be applied directly to the skin.
    This product is flammable. Keep away from fire, flame, and smoking during and immediately after use.

    STORAGE

    Extina:
    - Do not refrigerate
    - Do Not Store at Temperatures Above 120 degrees F (49 degrees C)
    - Flammable, keep away from heat and flame
    - Protect from direct sunlight
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Ketodan:
    - Do not refrigerate
    - Do Not Store at Temperatures Above 120 degrees F (49 degrees C)
    - Flammable, keep away from heat and flame
    - Protect from direct sunlight
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Kuric:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Nizoral:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Nizoral A-D:
    - Protect from freezing
    - Protect from light
    - Store between 35 to 86 degrees F
    Xolegel:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Achlorhydria, human immunodeficiency virus (HIV) infection, hypochlorhydria

    Oral ketoconazole requires an acidic environment for dissolution and absorption. Patients with achlorhydria or hypochlorhydria may achieve low plasma ketoconazole concentrations. To increase bioavailability, these patients should take ketoconazole with an acidic beverage (i.e., cola). Hypochlorhydria has been reported in patients with the human immunodeficiency virus (HIV) infection, and the absorption of ketoconazole may be decreased in these patients.

    Ethanol ingestion, hepatic disease, hepatitis, hepatotoxicity

    Orally administered ketoconazole is contraindicated in patients with acute or chronic hepatic disease. Serious hepatotoxicity, including cases with a fatal outcome or requiring liver transplantation, has occurred with the use of oral ketoconazole. These cases were reported both by patients receiving high doses for short treatment durations and by patients receiving low doses for long durations. Some patients had no obvious risk factors for hepatic disease. The hepatic injury has usually, but not always, been reversible upon discontinuation of treatment. Cases of hepatitis have been reported in pediatric patients. Due to the risk of hepatotoxicity and other serious adverse effects, oral ketoconazole should only be used to treat serious fungal infections when no other antifungal therapies are available. Patients should be informed of the risk and closely monitored if systemic ketoconazole therapy is to be given. At baseline, obtain laboratory tests (such as SGGT, alkaline phosphatase, ALT, AST, total bilirubin, prothrombin time (PT), International Normalized Ratio (INR), and testing for viral hepatitides). Advise patients against ethanol ingestion while on treatment. If possible, coadministration with potentially hepatotoxic drugs should be avoided. Prompt recognition of liver injury is critical. During the course of treatment, monitor serum ALT weekly for the duration of treatment. If ALT values increase to a level above the upper limit of normal or 30 percent above baseline, or if the patient develops symptoms, ketoconazole treatment should be interrupted and a full set of liver tests should be obtained. Repeat liver tests to ensure normalization of values. Hepatotoxicity has been reported upon rechallenge. If it is decided to restart oral ketoconazole, monitor the patient frequently to detect any recurring hepatic injury from the drug.

    Bradycardia, cardiac arrhythmias, diabetes mellitus, females, heart failure, hypocalcemia, hypokalemia, hypomagnesemia, ketoconazole coadministration with other drugs, long QT syndrome, QT prolongation, torsade de pointes, ventricular arrhythmias

    Due to its potent inhibition of the hepatic isoenzyme CYP3A4, oral ketoconazole coadministration with other drugs metabolized by CYP3A4 should be done with extreme caution, if at all. Ketoconazole can cause elevated plasma concentrations of selected drugs metabolized via CYP3A4 which may prolong the QT interval, sometimes resulting in life-threatening ventricular arrhythmias such as torsade de pointes; use of ketoconazole with such drugs is contraindicated. Oral ketoconazole may also inhibit the metabolism of many other drugs, which could result in serious and potentially life-threatening adverse reactions, and use with selected drugs is also contraindicated. Due to the potential for harmful drug interactions and other serious adverse effects, oral ketoconazole should only be used to treat serious fungal infections when no other antifungal therapies are available. Systemic ketoconazole can prolong the QT interval. Use ketoconazole tablets with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, older adult patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation.

    Adrenal insufficiency, surgery

    Ketoconazole oral tablets may cause adrenal insufficiency at doses of 400 mg/day and higher in adults. This effect is not shared with other azole antifungals. The recommended dose of 200 to 400 mg daily in adults should not be exceeded. Adrenal function should be monitored in patients with adrenal insufficiency or with borderline adrenal function and in patients under prolonged periods of stress (major surgery, intensive care, etc.). Due to the risk of adrenal insufficiency and other serious adverse effects, oral ketoconazole should only be used to treat serious fungal infections when no other antifungal therapies are available.

    Azole antifungals hypersensitivity

    Ketoconazole should be used with caution in patients with known azole antifungals hypersensitivity. Hypersensitivity reactions may be due to the various vehicles present in the different ketoconazole formulations. Ketoconazole may have a cross sensitivity with other azole derivatives such as itraconazole, fluconazole, clotrimazole, and miconazole. In rare cases, patients receiving ketoconazole have reported hypersensitivity reactions and even anaphylaxis. Ketoconazole is contraindicated in patients who have previously demonstrated these reactions.

    Pregnancy

    Ketoconazole is classified as FDA pregnancy risk category C. Teratogenic effects have been demonstrated in animals using oral ketoconazole doses 10 times the maximum recommended human dose. Animal data are not always predictive of effects in humans. Birth defects have been reported in women who have taken fluconazole, another azole antifungal, for extended periods during pregnancy. The Guidelines for the Prevention of Opportunistic Infections in Patients with HIV recommend that oral azole antifungals, including ketoconazole, not be started during pregnancy and that these agents should be discontinued in HIV-positive women who become pregnant. There are no adequate and well-controlled studies of topical ketoconazole use in pregnant women; however, ketoconazole is not detected in human plasma after chronic shampooing on the scalp. Ketoconazole should be used in pregnant women only when the potential benefits to the mother outweigh the potential risks to the fetus. Women of childbearing potential should use effective contraception during ketoconazole therapy.

    Breast-feeding

    Systemic ketoconazole is excreted in breast milk. In a case report of one mother prescribed 200 mg PO daily for 10 days, ketoconazole milk concentrations of 0.22 micrograms/ml (peak) were observed 3.25 hours post-dose and were undetectable at 24 hours post-dose. Assuming a milk intake of 150 ml/kg/day, the author calculated the daily ketoconazole dose of an exclusively breast-fed infant at 0.01 mg/kg/day or 0.4% of the mother's weight-adjusted dose. The manufacturer recommends mothers refrain from nursing their infants during oral therapy; however, the American Academy of Pediatrics (AAP) considers ketoconazole compatible with breast-feeding. There are no adequate and well-controlled studies of topical use in nursing women; however, ketoconazole is not detected in plasma after chronic shampooing on the scalp. If the topical gel is used during breast-feeding and is applied to the chest, care should be taken to avoid accidental ingestion by the infant. Fluconazole may be a potential alternative to consider during breast-feeding. However, site of infection, patient factors, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative agent. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested or administered drug, health care providers are encouraged to report the adverse effect to the FDA.

    Ocular exposure

    Avoid accidental ocular exposure of topical ketoconazole products. If ocular exposure occurs, treat by immediate flushing the affected eye with cool, clean water. Contact an ophthalmologist if eye irritation persists.

    Tobacco smoking

    Some topical ketoconazole products are flammable. Due to the alcohol content of ketoconazole topical gel (e.g., Xolegel gel) and the alcohol, butane, and proprane content of ketoconazole topical foam (e.g., Extina foam), avoid fire, flame, or tobacco smoking during and immediately after the application of these ketoconazole products.

    Driving or operating machinery

    Dizziness or drowsiness occurs in some patients receiving systemic ketoconazole. Patients should be careful driving or operating machinery if they have these reactions.

    Geriatric

    Due to the risk of severe drug interactions and other serious adverse effects with ketoconazole oral tablets, ketoconazole oral tablets should not be a first-line treatment for any fungal infection in the geriatric patient. Systemic ketoconazole can prolong the QT interval. Geriatric patients may be at increased risk for QT prolongation and for serious drug-drug interactions that may increase the risk QT prolongation risk or may increase the risk for other serious side effects. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, systemic azole antifungals should be used in the lowest possible dose for the shortest possible duration, particularly in patients receiving other medications known to interact with these medications. Increased monitoring may be required to identify and minimize the toxicity of warfarin, phenytoin, theophylline, or sulfonylureas when an azole antifungal is co-administered; other medications such as rifampin and cimetidine may decrease the therapeutic effect of the antifungal. Some drug-drug combinations may be contraindicated. OBRA guidelines caution that azole antifungals may cause hepatotoxicity, headaches, and GI distress.

    Children, infants, neonates

    The safety and efficacy of oral ketoconazole have not been established in neonates, infants, or children under 2 years of age. Topical products (e.g., shampoo, cream) have been used in pediatric patients off-label but are not FDA-approved for use in pediatric patients; the safety and efficacy of ketoconazole topical foam and gel products have not been established in pediatric patients less than 12 years old.

    ADVERSE REACTIONS

    Severe

    keratoconjunctivitis / Early / 0-1.0
    hemolytic anemia / Delayed / 0-1.0
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    papilledema / Delayed / Incidence not known
    increased intracranial pressure / Early / Incidence not known

    Moderate

    impotence (erectile dysfunction) / Delayed / 0-1.0
    photophobia / Early / 0-1.0
    leukopenia / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    erythema / Early / 0-1.0
    jaundice / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    adrenocortical insufficiency / Delayed / Incidence not known
    QT prolongation / Rapid / Incidence not known

    Mild

    vomiting / Early / 3.0-3.0
    nausea / Early / 3.0-3.0
    pruritus / Rapid / 0-1.5
    abdominal pain / Early / 1.2-1.2
    diarrhea / Early / 0-1.0
    gynecomastia / Delayed / 0-1.0
    fever / Early / 0-1.0
    chills / Rapid / 0-1.0
    drowsiness / Early / 0-1.0
    dizziness / Early / 0-1.0
    headache / Early / 0-1.0
    ocular irritation / Rapid / 0-1.0
    paresthesias / Delayed / 0-1.0
    acne vulgaris / Delayed / 0-1.0
    rash (unspecified) / Early / 0-1.0
    xerosis / Delayed / 0-1.0
    nail discoloration / Delayed / 0-1.0
    skin irritation / Early / 0-1.0
    fatigue / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    oligospermia / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    hair discoloration / Delayed / Incidence not known
    photosensitivity / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abarelix: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include abarelix,
    Abemaciclib: (Major) Avoid coadministration of abemaciclib with ketoconazole. Abemaciclib is a CYP3A4 substrate and ketoconazole is a strong CYP3A inhibitor. Ketoconazole is predicted to increase the AUC of abemaciclib up to 16-fold.
    Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and ketoconazole; significantly increased acalabrutinib exposure may occur. If short-term ketoconazole use is unavoidable, interrupt acalabrutinib therapy. Acalabrutinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Ketoconazole has been shown to inhibit the clearance of caffeine by 11 percent. The clinical significance of these interactions has not been determined.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Ketoconazole has been shown to inhibit the clearance of caffeine by 11 percent. The clinical significance of these interactions has not been determined.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Ketoconazole has been shown to inhibit the clearance of caffeine by 11 percent. The clinical significance of these interactions has not been determined. (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Ketoconazole has been shown to inhibit the clearance of caffeine by 11 percent. The clinical significance of these interactions has not been determined.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Ketoconazole has been shown to inhibit the clearance of caffeine by 11 percent. The clinical significance of these interactions has not been determined.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Ketoconazole has been shown to inhibit the clearance of caffeine by 11 percent. The clinical significance of these interactions has not been determined.
    Acetaminophen; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Acetaminophen; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and ketoconazole are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Acetaminophen; Oxycodone: (Major) Oxycodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in oxycodone plasma concentrations, which could increase or prolong adverse effects and may cause potentially fatal respiratory depression. If coadministration of these agents is necessary, patients should be monitored for an extended period of time and dosage adjustments made if warranted.
    Acetaminophen; Propoxyphene: (Moderate) Propoxyphene is a substrate and an inhibitor of CYP3A4. Increased serum concentrations of propoxyphene would be expected from concurrent use of a CYP3A4 inhibitor, such as ketoconazole. A reduced dosage of propoxyphene may be needed. Monitor patients for central nervous system (CNS) and respiratory depression.
    Acetaminophen; Tramadol: (Moderate) Administration of CYP3A4 inhibitors such as ketoconazole with tramadol may affect the metabolism of tramadol leading to altered tramadol exposure. Increased serum tramadol concentrations may occur.
    Acetohexamide: (Moderate) Hypoglycemia, sometimes severe, has been reported when ketoconazole is coadministered with oral hypoglycemic agents. The most likely mechanism for this interaction is inhibition of the CYP450 metabolism of oral hypoglycemics by ketoconazole. Blood glucose concentrations should be monitored during concomitant treatment; patients should be aware of the symptoms of hypoglycemia. In some cases, dosage adjustment of the sulfonylurea may be necessary. There is no evidence that an interaction occurs between oral hypoglycemics and topical or vaginal azole antifungal preparations.
    Ado-Trastuzumab emtansine: (Major) Avoid concomitant use of ado-trastuzumab emtansine with ketoconazole, as plasma exposure to the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, may be increased. Treatment with ado-trastuzumab emtansine should be delayed until ketoconazole is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered. If co-administration is necessary, monitor for an increase in ado-trastuzumab emtansine-related adverse events. Ketoconazole is a strong CYP3A4 inhibitor. While formal drug interaction studies have not been conducted, DM1 is mainly metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro. Coadministration may result in potentially increased DM1 exposure and toxicity.
    Afatinib: (Major) If the concomitant use of ketoconazole and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of ketoconazole . Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and ketoconazole is a P-gp inhibitor in vitro; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Albuterol: (Minor) Coadministration may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists such as albuterol.
    Albuterol; Ipratropium: (Minor) Coadministration may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists such as albuterol.
    Alfentanil: (Moderate) Ketoconazole may decrease the systemic clearance of alfentanill. Prolonged duration of opiate action, increased sedation, respiratory depression or other opiate side effects may occur. Close monitoring of patients is warranted.
    Alfuzosin: (Severe) Concomitant use of alfuzosin and ketoconazole is contraindicated. Both alfuzosin and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with alfuzosin (a CYP3A4 substrate) results in elevated alfuzosin plasma concentrations and may increase the risk for adverse events, including QT prolongation. In one study, repeated doses of ketoconazole (400 mg) increased alfuzosin Cmax by 2.3-fold and AUC by 3.2-fold after a single alfuzosin dose. At a lower ketoconazole dose (200 mg) the Cmax and AUC of alfuzosin were increased by 2.1-fold and 2.5-fold, respectively.
    Aliskiren: (Moderate) Coadmistration of aliskiren with ketoconazole, causes a significant increase in the plasma concentration of aliskiren. When 200 mg of ketoconazole twice daily was administered with aliskiren, the plasma concentrations of aliskiren increased by 80%. Although a 400 mg dose of ketoconazole was not studied, it is expected that the higher dose would further increase plasma concentrations of aliskiren. Blood pressure should be monitored in patients taking both of these medications.
    Aliskiren; Amlodipine: (Moderate) Coadmistration of aliskiren with ketoconazole, causes a significant increase in the plasma concentration of aliskiren. When 200 mg of ketoconazole twice daily was administered with aliskiren, the plasma concentrations of aliskiren increased by 80%. Although a 400 mg dose of ketoconazole was not studied, it is expected that the higher dose would further increase plasma concentrations of aliskiren. Blood pressure should be monitored in patients taking both of these medications. (Moderate) Ketoconazole may decrease the clearance of calcium-channel blockers, including amlodipine, via inhibition of CYP3A4 metabolism.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Coadmistration of aliskiren with ketoconazole, causes a significant increase in the plasma concentration of aliskiren. When 200 mg of ketoconazole twice daily was administered with aliskiren, the plasma concentrations of aliskiren increased by 80%. Although a 400 mg dose of ketoconazole was not studied, it is expected that the higher dose would further increase plasma concentrations of aliskiren. Blood pressure should be monitored in patients taking both of these medications. (Moderate) Ketoconazole may decrease the clearance of calcium-channel blockers, including amlodipine, via inhibition of CYP3A4 metabolism.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Coadmistration of aliskiren with ketoconazole, causes a significant increase in the plasma concentration of aliskiren. When 200 mg of ketoconazole twice daily was administered with aliskiren, the plasma concentrations of aliskiren increased by 80%. Although a 400 mg dose of ketoconazole was not studied, it is expected that the higher dose would further increase plasma concentrations of aliskiren. Blood pressure should be monitored in patients taking both of these medications.
    Aliskiren; Valsartan: (Moderate) Coadmistration of aliskiren with ketoconazole, causes a significant increase in the plasma concentration of aliskiren. When 200 mg of ketoconazole twice daily was administered with aliskiren, the plasma concentrations of aliskiren increased by 80%. Although a 400 mg dose of ketoconazole was not studied, it is expected that the higher dose would further increase plasma concentrations of aliskiren. Blood pressure should be monitored in patients taking both of these medications.
    Almotriptan: (Major) Ketoconazole may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and ketoconazole is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole resulted in an approximately 60% increase in almotriptan exposure.
    Alogliptin; Pioglitazone: (Moderate) Ketoconazole appears to significantly inhibit the metabolism of pioglitazone. It is recommended that patients receiving both pioglitazone and ketoconazole be evaluated more frequently with respect to glycemic control.
    Alosetron: (Moderate) Alosetron is partially metabolized by CYP3A4. Ketoconazole is an inhibitor of CYP3A4. Caution should be used if these drugs are coadministered. In a study of healthy female subjects, ketoconazole increased mean alosetron AUC by 29%.
    Alprazolam: (Severe) Coadministration of ketoconazole and alprazolam is contraindicated. Ketoconazole significantly impairs the CYP3A4 metabolism of alprazolam, resulting in elevated alprazolam concentrations. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with ketoconazole, as these benzodiazepines are not oxidatively metabolized.
    Amiodarone: (Major) Avoid coadministration of amiodarone and ketoconazole due to the potential for increased amiodarone concentrations and additive effects on the QT interval. There have been reports of prolonged QT, with or without torsade de pointes (TdP) with the concomitant use of amiodarone and azole antifungals. Both ketoconazole and amiodarone are associated with QT prolongation. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with amiodarone (a CYP3A4 substrate) may result in elevated amiodarone plasma concentrations and an increased risk for adverse events, including QT prolongation. Per the manufacturer, the need to administer amiodarone with drugs known to prolong the QT interval should be done with a careful assessment of risks versus benefits, especially when the coadministered agent might decrease the metabolism of amiodarone. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amitriptyline: (Minor) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; ketoconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope have occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred. Close clinical monitoring is necessary if concurrent use is medically necessary.
    Amitriptyline; Chlordiazepoxide: (Moderate) CYP3A4 inhibitors, such as ketoconazole, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. (Minor) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; ketoconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope have occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred. Close clinical monitoring is necessary if concurrent use is medically necessary.
    Amlodipine: (Moderate) Ketoconazole may decrease the clearance of calcium-channel blockers, including amlodipine, via inhibition of CYP3A4 metabolism.
    Amlodipine; Atorvastatin: (Major) Atorvastatin is metabolized by CYP3A4, and coadministration with CYP3A4 inhibitors can lead to an increase in plasma concentrations of atorvastatin. The risk of developing myopathy during therapy with atorvastatin is increased if coadministered with ketoconazole, a CYP3A4 inhibitor. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined atorvastatin and ketoconazole therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. In addition, because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends that caution should be exercised when atorvastatin is administered concomitantly with drugs that may decrease the concentrations or activity of endogenous hormones, such as ketoconazole. The clinical relevance of these potential interactions has not been established. (Moderate) Ketoconazole may decrease the clearance of calcium-channel blockers, including amlodipine, via inhibition of CYP3A4 metabolism.
    Amlodipine; Benazepril: (Moderate) Ketoconazole may decrease the clearance of calcium-channel blockers, including amlodipine, via inhibition of CYP3A4 metabolism.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Ketoconazole may decrease the clearance of calcium-channel blockers, including amlodipine, via inhibition of CYP3A4 metabolism.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Ketoconazole may decrease the clearance of calcium-channel blockers, including amlodipine, via inhibition of CYP3A4 metabolism.
    Amlodipine; Olmesartan: (Moderate) Ketoconazole may decrease the clearance of calcium-channel blockers, including amlodipine, via inhibition of CYP3A4 metabolism.
    Amlodipine; Telmisartan: (Moderate) Ketoconazole may decrease the clearance of calcium-channel blockers, including amlodipine, via inhibition of CYP3A4 metabolism.
    Amlodipine; Valsartan: (Moderate) Ketoconazole may decrease the clearance of calcium-channel blockers, including amlodipine, via inhibition of CYP3A4 metabolism.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as clarithromycin. Both clarithromycin and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, both drugs are substrates and inhibitors of CYP3A4. Coadministration may result in increased plasma concentrations of both drugs, thereby further increasing the risk for adverse events. Azithromycin can be considered as an alternative macrolide antimicrobial if appropriate for the clinical circumstance, due to its lack of metabolism via CYP3A4.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as clarithromycin. Both clarithromycin and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, both drugs are substrates and inhibitors of CYP3A4. Coadministration may result in increased plasma concentrations of both drugs, thereby further increasing the risk for adverse events. Azithromycin can be considered as an alternative macrolide antimicrobial if appropriate for the clinical circumstance, due to its lack of metabolism via CYP3A4.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Moderate) Theoretically, azole antifungals could interfere with the action of amphotericin B by depleting polyene binding sites. Whenever possible, azole antifungals should not be coadministered with amphotericin B until more data are available.
    Amphotericin B lipid complex (ABLC): (Moderate) Theoretically, azole antifungals could interfere with the action of amphotericin B by depleting polyene binding sites. Whenever possible, azole antifungals should not be coadministered with amphotericin B until more data are available.
    Amphotericin B liposomal (LAmB): (Moderate) Theoretically, azole antifungals could interfere with the action of amphotericin B by depleting polyene binding sites. Whenever possible, azole antifungals should not be coadministered with amphotericin B until more data are available.
    Amphotericin B: (Moderate) Theoretically, azole antifungals could interfere with the action of amphotericin B by depleting polyene binding sites. Whenever possible, azole antifungals should not be coadministered with amphotericin B until more data are available.
    Amprenavir: (Major) Coadministration of amprenavir with ketoconazole results in clinically significant increases in ketoconazole plasma concentrations. If these drugs are to be coadministered, monitor for adverse events due to ketoconazole and dose reduction may be needed for patients receiving more than 400 mg ketoconazole per day.
    Anagrelide: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include anagrelide.
    Antacids: (Major) Ketoconazole requires an acidic pH for absorption. Medications that increase gastric pH or decrease acid output can cause a notable decrease in the bioavailability of ketoconazole. Medications that have this effect are antacids, antimuscarinics, histamine H2-blockers, and proton pump inhibitors (PPIs). Except for antacids, these medications have a prolonged duration of action, and staggering their time of administration with ketoconazole by several hours may not prevent the drug interaction; ketoconazole should be administered at least 2 hours before or 1 hour after antacids. An alternative imidazole antifungal should be chosen if any of these gastrointestinal medications are required. If these drugs must be coadministered, administer ketoconazole tablets with an acidic beverage and closely monitor for breakthrough infection.
    Apixaban: (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as ketoconazole. Concomitant administration of ketoconazole and apixaban results in increased exposure to apixaban and an increase in the risk of bleeding. If patients are already receiving the reduced dose of 2.5 mg twice daily, avoid concomitant administration of apixaban and ketoconazole.
    Apomorphine: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include apomorphine.
    Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of ketoconazole with aprepitant due to substantially increased exposure of aprepitant; increased ketoconazole exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in ketoconazole- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. Topical ketoconazole is unlikely to interact unless significant systemic absorption occurs. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Ketoconazole is a strong CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of a single oral dose of aprepitant (125 mg) on day 5 of a 10-day ketoconazole regimen increased the aprepitant AUC approximately 5-fold, and increased the mean terminal half-life by approximately 3-fold. Ketoconazole is also a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer; substitution of fosaprepitant 115 mg IV on day 1 of the 3-day regimen may lessen the inhibitory effects of CYP3A4. The AUC of a single dose of another CYP3A4 substrate, midazolam, increased by 2.3-fold and 3.3-fold on days 1 and 5, respectively, when coadministered with a 5-day oral aprepitant regimen. After a 3-day oral aprepitant regimen, the AUC of midazolam increased by 25% on day 4, and decreased by 19% and 4% on days 8 and 15, respectively, when given on days 1, 4, 8, and 15. As a single 40-mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.2-fold; the midazolam AUC increased by 1.5-fold after a single 125-mg dose of oral aprepitant. After single doses of IV fosaprepitant, the midazolam AUC increased by 1.8-fold (150 mg) and 1.6-fold (100 mg); less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Arformoterol: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the beta-agonists. In addition, the long-acting beta agonists (LABAs) indacaterol, vilanterol, salmeterol are CYP3A4 substrates. The coadministration of these LABAs with strong CYP3A4 inhibitors such as ketoconazole may result in elevated LABA plasma concentrations and increased risk for adverse reactions, particularly systemic side effects such as nervousness, tremor, or cardiovascular effects. In a placebo-controlled, drug interaction study of 20 healthy subjects, coadministration of salmeterol (50 mcg twice daily), and ketoconazole (400 mg PO once daily) for 7 days resulted in a 16-fold increase in salmeterol AUC. Three of the 20 subjects were withdrawn from the study due to cardiovascular adverse effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia). An increase in AUC also occurred when ketoconazole was coadministered with indacaterol. Similar interactions may occur when ketoconazole is added to vilanterol, such as umeclidinium; vilanterol.
    Aripiprazole: (Major) Aripiprazole and ketoconazole are both associated with prolongation of the QT interval; caution and close monitoring is recommended. In addition, because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as ketoconazole. Concurrent use of aripiprazole (15 mg single dose) and ketoconazole (200 mg/day for 14 days) resulted in an increase in the AUC of aripiprazole and its active metabolite by 63% and 77%, respectively. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated.
    Armodafinil: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as ketoconazole are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
    Arsenic Trioxide: (Major) Avoid coadministration of ketoconazole and arsenic trioxide. Ketoconazole has been associated with prolongation of the QT interval. If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. If concomitant drug use is unavoidable, frequently monitor electrocardiograms. QT prolongation should be expected with the administration of arsenic trioxide.
    Artemether; Lumefantrine: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as lumefantrine. Both lumefantrine and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with lumefantrine (a CYP3A4 substrate) results in elevated lumefantrine plasma concentrations. No dosage adjustments are required, but patients should be monitored for adverse events, including QT prolongation. (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong the QT interval and are metabolized by CYP3A4, such as artemether. Both artemether and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with artemether (a CYP3A4 substrate) results in elevated artemether plasma concentrations. No dosage adjustments are required, but patients should be monitored for adverse events, including QT prolongation.
    Asenapine: (Major) Avoid coadministration of asenapine and ketoconazole due to the potential for additive effects on the QT interval; increased exposure to asenapine is also possible. Both asenapine and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with asenapine (a CYP3A4 substrate) may result in elevated asenapine plasma concentrations and an increased risk for adverse events, including QT prolongation.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Ketoconazole has been shown to inhibit the clearance of caffeine by 11 percent. The clinical significance of these interactions has not been determined.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Ketoconazole has been shown to inhibit the clearance of caffeine by 11 percent. The clinical significance of these interactions has not been determined. (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Ketoconazole has been shown to inhibit the clearance of caffeine by 11 percent. The clinical significance of these interactions has not been determined.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Aspirin, ASA; Oxycodone: (Major) Oxycodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in oxycodone plasma concentrations, which could increase or prolong adverse effects and may cause potentially fatal respiratory depression. If coadministration of these agents is necessary, patients should be monitored for an extended period of time and dosage adjustments made if warranted.
    Atazanavir: (Major) Atazanavir may interact with selected azole antifungal drugs. Ketoconazole is a substrate and inhibitor of CYP3A4; coadministration with atazanavir may result in increased plasma concentrations of atazanavir (CYP3A4 substrate). Also, serum concentrations of azole antifungal drugs that are substrates for CYP3A4 may be increased by atazanavir (CYP3A4 inhibitor). However, caution and close monitoring of the anticipated responses are recommended when administering atazanavir with these antifungals.
    Atazanavir; Cobicistat: (Major) Atazanavir may interact with selected azole antifungal drugs. Ketoconazole is a substrate and inhibitor of CYP3A4; coadministration with atazanavir may result in increased plasma concentrations of atazanavir (CYP3A4 substrate). Also, serum concentrations of azole antifungal drugs that are substrates for CYP3A4 may be increased by atazanavir (CYP3A4 inhibitor). However, caution and close monitoring of the anticipated responses are recommended when administering atazanavir with these antifungals. (Major) Avoid concurrent use of ketoconazole with regimens containing cobicistat and atazanavir or darunavir. Use of these drugs together may result in increase plasma concentrations of ketoconazole, cobicistat, atazanavir, and darunavir. Specific dosage recommendations have not been determined.
    Atomoxetine: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Atomoxetine is considered a drug with a possible risk of torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with atomoxetine include ketoconazole.
    Atorvastatin: (Major) Atorvastatin is metabolized by CYP3A4, and coadministration with CYP3A4 inhibitors can lead to an increase in plasma concentrations of atorvastatin. The risk of developing myopathy during therapy with atorvastatin is increased if coadministered with ketoconazole, a CYP3A4 inhibitor. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined atorvastatin and ketoconazole therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. In addition, because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends that caution should be exercised when atorvastatin is administered concomitantly with drugs that may decrease the concentrations or activity of endogenous hormones, such as ketoconazole. The clinical relevance of these potential interactions has not been established.
    Atorvastatin; Ezetimibe: (Major) Atorvastatin is metabolized by CYP3A4, and coadministration with CYP3A4 inhibitors can lead to an increase in plasma concentrations of atorvastatin. The risk of developing myopathy during therapy with atorvastatin is increased if coadministered with ketoconazole, a CYP3A4 inhibitor. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined atorvastatin and ketoconazole therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. In addition, because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends that caution should be exercised when atorvastatin is administered concomitantly with drugs that may decrease the concentrations or activity of endogenous hormones, such as ketoconazole. The clinical relevance of these potential interactions has not been established.
    Avanafil: (Major) Concomitant use of avanafil and ketoconazole is not recommended due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a substrate of and primarily metabolized by CYP3A4; ketoconazole is a strong inhibitor of CYP3A4. Ketoconazole increased avanafil AUC and Cmax equal to 13-fold and 3-fold, respectively and prolonged the half-life of avanafil to approximately 9 hours. Likewise, coadministration of ritonavir (strong CYP3A4 inhibitor) with avanafil resulted in an approximate 13-fold increase in AUC and 2.4-fold increase in Cmax of avanafil.
    Axitinib: (Major) Avoid coadministration of axitinib with ketoconazole due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after ketoconazole is discontinued. Axitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Ketoconazole is a strong CYP3A4 inhibitor, as well as a weak, in vitro inhibitor of CYP2C19. Coadministration with ketoconazole significantly increased the plasma exposure of axitinib in healthy volunteers.
    Azelastine: (Minor) Theoretically, systemic exposure of nasally administered azelastine may be increased by coadministration with ketoconazole, although an interaction has not been documented.
    Azelastine; Fluticasone: (Major) Coadministration of ketoconazole and fluticasone may result in increased systemic corticosteroid adverse effects. Per the manufacturer of fluticasone propionate, concurrent use of ketoconazole is not recommended; the manufacturer of fluticasone furoate recommends caution during concurrent use. Coadministration of ketoconazole increases the systemic exposure to fluticasone. Ketoconazole is a strong CYP3A4 inhibitor; fluticasone is a CYP3A4 substrate. (Minor) Theoretically, systemic exposure of nasally administered azelastine may be increased by coadministration with ketoconazole, although an interaction has not been documented.
    Azithromycin: (Moderate) Increased concentrations of azithromycin may occur if it is coadministered with ketoconazole; exercise caution. Ketoconazole is an inhibitor of the efflux transporter P-glycoprotein (P-gp) and azithromycin may be a P-gp substrate.
    Barbiturates: (Minor) Barbiturates induce hepatic CYP enzymes including 3A4, 2C19 and 2C9 and may reduce effective serum concentrations of ketoconazole. Clinicians should be alert for lack of efficacy of these antifungals in concurrent use.
    Bedaquiline: (Major) Avoid prolonged (more than 14 consecutive days) concurrent administration of bedaquiline and ketoconazole unless the benefits outweigh the risks. Coadministration of ketoconazole (a potent CYP3A4 inhibitor) with bedaquiline (a CYP3A4 substrate) results in elevated bedaquiline plasma concentrations and may increase the risk for adverse events, including QT prolongation. One study found the AUC, Cmax, and Cmin of bedaquiline increased by 22%, 9%, and 33%, respectively, when administered with ketoconazole 400 mg PO daily for 4 days. In addition, repeated dosing of this drug combination resulted in additive QT prolongation when compared with repeated dosing of the individual drugs. Both bedaquiline and ketoconazole are associated with QT prolongation; coadministration increases this risk. Monitor ECGs if bedaquiline is coadministered to patients receiving ketoconazole; discontinue bedaquiline if evidence of serious ventricular arrhythmia or QT interval greater than 500 msec.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Severe) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as ketoconazole, is contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, and/or other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
    Bendroflumethiazide; Nadolol: (Moderate) Careful monitoring is recommended when ketoconazole is coadministered with nadolol. If these drugs are administered together, monitor patient for signs or symptoms of increased or prolonged nadolol-related side effects.
    Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving ketoconazole. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving ketoconazole. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; ketoconazole inhibits P-gp.
    Bexarotene: (Moderate) Bexarotene is extensively metabolized by the CYP3A4 hepatic isoenzyme. When significant CYP3A4 inhibitors like ketoconazole are administered concomitantly with bexarotene, the health care professional may need to observe the patient for increased toxicity from bexarotene.
    Bicalutamide: (Moderate) Bicalutamide is metabolized by cytochrome CYP3A4. Substances that are inhibitors of CYP3A4 activity, like ketoconazole, decrease the metabolism of bicalutamide and increase bicalutamide concentrations.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include metronidazole. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include metronidazole. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Boceprevir: (Major) Close clinical monitoring is advised when administering ketoconazole with boceprevir due to an increased potential for serious ketoconazole and boceprevir-related adverse events, such as QT prolongation. When concurrent administration is required, high doses of ketoconazole (> 200 mg/day) are not recommended. If ketoconazole dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Predictions about the interaction can be made based on the metabolic pathways of ketoconazole and boceprevir. Both ketoconazole and boceprevir are substrates and inhibitors of the hepatic isoenzyme CYP3A4. Additionally, ketoconazole is an inhibitor of P-glycoprotein (P-gp), a drug efflux transporter partially responsible for the metabolism of boceprevir. When used in combination, the plasma concentrations of both medications may be elevated.
    Bortezomib: (Moderate) Ketoconazole inhibits CYP3A4 and may increase the exposure to bortezomib and increase the risk for toxicity. Monitor for potential toxicity.
    Bosentan: (Moderate) Coadministration of bosentan with ketoconazole, a potent CYP3A4 inhibitor, increased the plasma concentrations of bosentan by approximately 2-fold. No dosage adjustment of bosentan is needed, however, the potential for increased bosentan effects should be monitored.
    Bosutinib: (Major) Avoid concomitant use of bosutinib, a CYP3A4 substrate, and ketoconazole, a strong CYP3A4 inhibitor, as bosutinib plasma exposure may increase. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, following a single oral dose of bosutinib 100 mg administered after 5 days of oral ketoconazole 400 mg/day.
    Brentuximab vedotin: (Minor) Concomitant administration of brentuximab vedotin and ketoconazole increased the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, by approximately 34%. MMAE is a CYP3A4 substrate and ketoconazole is a potent CYP3A4 inhibitor. Monitor patients for adverse reactions.
    Brexpiprazole: (Major) Because brexpiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the brexpiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as ketoconazole. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. Because brexpiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a moderate to strong CYP3A4 inhibitor and moderate to strong CYP2D6 inhibitor should have their brexpiprazole dose reduced to one-quarter (25%) of the usual dose. If the co-administered CYP inhibitor is discontinued, adjust the brexpiprazole dose to its original level.
    Brigatinib: (Major) Avoid coadministration of brigatinib with ketoconazole if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. Plasma concentrations of ketoconazole may also decrease; monitor for decreased efficacy. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of ketoconazole, resume the brigatinib dose that was tolerated prior to initiation of ketoconazole. Brigatinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. Ketoconazole is also a CYP3A substrate while brigatinib induces CYP3A in vitro; plasma concentrations of ketoconazole may decrease.
    Bromocriptine: (Major) When bromocriptine is used for diabetes, avoid coadministration with ketoconazole ensuring adequate washout before initiating bromocriptine. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may significantly increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; ketoconazole is a strong inhibitor of CYP3A4.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and ketoconazole are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and ketoconazole are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Budesonide: (Moderate) Ketoconazole may increase plasma concentrations of oral budesonide more than 7-fold due to inhibition of the CYP3A4 isoenzyme in the liver, as well as in the gut, and can enhance the cortisol suppression associated with budesonide administered via inhalation. Inhibition of CYP3A4 may be clinically significant for inhaled forms of budesonide, including budesonide nasal spray.
    Budesonide; Formoterol: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the beta-agonists. In addition, the long-acting beta agonists (LABAs) indacaterol, vilanterol, salmeterol are CYP3A4 substrates. The coadministration of these LABAs with strong CYP3A4 inhibitors such as ketoconazole may result in elevated LABA plasma concentrations and increased risk for adverse reactions, particularly systemic side effects such as nervousness, tremor, or cardiovascular effects. In a placebo-controlled, drug interaction study of 20 healthy subjects, coadministration of salmeterol (50 mcg twice daily), and ketoconazole (400 mg PO once daily) for 7 days resulted in a 16-fold increase in salmeterol AUC. Three of the 20 subjects were withdrawn from the study due to cardiovascular adverse effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia). An increase in AUC also occurred when ketoconazole was coadministered with indacaterol. Similar interactions may occur when ketoconazole is added to vilanterol, such as umeclidinium; vilanterol. (Moderate) Ketoconazole may increase plasma concentrations of oral budesonide more than 7-fold due to inhibition of the CYP3A4 isoenzyme in the liver, as well as in the gut, and can enhance the cortisol suppression associated with budesonide administered via inhalation. Inhibition of CYP3A4 may be clinically significant for inhaled forms of budesonide, including budesonide nasal spray.
    Bupivacaine Liposomal: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as ketoconazole, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Bupivacaine: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as ketoconazole, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and ketoconazole may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; ketoconazole inhibits CYP3A4. (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as ketoconazole, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Buprenorphine: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of ketoconazole and buprenorphine is necessary. Buprenorphine and ketoconazole have been associated with QT prolongation and torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a strong CYP3A4 inhibitor such as ketoconazole may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
    Buprenorphine; Naloxone: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of ketoconazole and buprenorphine is necessary. Buprenorphine and ketoconazole have been associated with QT prolongation and torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a strong CYP3A4 inhibitor such as ketoconazole may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
    Buspirone: (Moderate) Pharmacokinetic data suggest that concomitant administration of ketoconazole and buspirone results in significant (up to 19-fold) increases in buspirone AUC; the mechanism is probably reduced buspirone metabolism via CYP3A4. However, a wide interindividual variability in the extent of the interaction has been noted. Some patients receiving these drugs with buspirone concurrently have reported lightheadedness, asthenia, dizziness, and drowsiness. If the two drugs are to be used in combination, a low dose of buspirone (e.g., 2.5 mg PO twice daily) is recommended.
    Busulfan: (Moderate) Ketoconazole may decrease the clearance of busulfan, resulting in elevated serum concentrations of busulfan. Careful monitoring, with possible dose adjustments, is recommended during coadministration.
    Cabazitaxel: (Major) Avoid coadministration of cabazitaxel with ketoconazole if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and ketoconazole is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with ketoconazole increased cabazitaxel exposure by 25%.
    Cabozantinib: (Major) Avoid concomitant use of cabozantinib with ketoconazole due to the risk of increased cabozantinib-related toxicities; if coadministration is necessary, reduce the daily cabozantinib capsule (Cometriq) dose by 40 mg (e.g., 140 mg/day to 100 mg/day; 100 mg/day to 60 mg/day) and the cabozantinib tablet (Cabometyx) dose by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day). Resume the prior cabozantinib dose after 2 to 3 days if ketoconazole is discontinued. Cabozantinib is primarily metabolized by CYP3A4 and ketoconazole is a strong CYP3A4 inhibitor; coadministration of ketoconazole (400 mg daily for 27 days) increased cabozantinib (single dose) exposure by 38%.
    Caffeine: (Moderate) Ketoconazole has been shown to inhibit the clearance of caffeine by 11 percent. The clinical significance of these interactions has not been determined.
    Caffeine; Ergotamine: (Severe) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as ketoconazole, is contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, and/or other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids. (Moderate) Ketoconazole has been shown to inhibit the clearance of caffeine by 11 percent. The clinical significance of these interactions has not been determined.
    Calcifediol: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with ketoconazole. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with ketoconazole. Ketoconazole, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
    Calcitriol: (Moderate) Ketoconazole may inhibit both synthetic and catabolic enzymes of calcitriol. Reductions in endogenous serum calcitriol concentrations have been observed following the the administration of ketoconazole 300 to 1200 mg/day.
    Calcium Carbonate: (Major) By increasing intragastric pH, calcium carbonate can reduce the oral absorption of ketoconazole; administer calcium carbonate and other antacids 2 hours after oral administration of ketoconazole or itraconazole to minimize this interaction.
    Calcium Carbonate; Magnesium Hydroxide: (Major) By increasing intragastric pH, calcium carbonate can reduce the oral absorption of ketoconazole; administer calcium carbonate and other antacids 2 hours after oral administration of ketoconazole or itraconazole to minimize this interaction.
    Calcium Carbonate; Risedronate: (Major) By increasing intragastric pH, calcium carbonate can reduce the oral absorption of ketoconazole; administer calcium carbonate and other antacids 2 hours after oral administration of ketoconazole or itraconazole to minimize this interaction.
    Calcium; Vitamin D: (Major) By increasing intragastric pH, calcium carbonate can reduce the oral absorption of ketoconazole; administer calcium carbonate and other antacids 2 hours after oral administration of ketoconazole or itraconazole to minimize this interaction.
    Canagliflozin: (Moderate) Canagliflozin is a substrate of drug transporter P glycoprotein (P-gp). Ketoconazole is a PGP inhibitor in vitro and may theoretically increase concentrations of canagliflozin. Patients should be monitored for changes in glycemic control.
    Canagliflozin; Metformin: (Moderate) Canagliflozin is a substrate of drug transporter P glycoprotein (P-gp). Ketoconazole is a PGP inhibitor in vitro and may theoretically increase concentrations of canagliflozin. Patients should be monitored for changes in glycemic control.
    Carbamazepine: (Major) Concomitant use of carbamazepine with ketoconazole may result in reduced antifungal activity and is not recommended. Unless the benefits outweigh the risk, these drugs should not be administered within 2 weeks of each other. If administered concurrently, monitor for breakthrough fungal infections. Ketoconazole is a substrate/inhibitor of the hepatic isoenzyme CYP3A4, carbamazepine is a substrate/inducer. Coadministration may result in decreased ketoconazole plasma concentrations and increased carbamazepine concentrations.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and ketoconazole are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and ketoconazole are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. When a strong CYP3A4 inhibitor, such as ketoconazole, is initiated in a patient who is on a stable dose of cariprazine, reduce the cariprazine dosage by half. For adult patients taking cariprazine 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For adult patients taking cariprazine 1.5 mg daily, the dosing frequency should be adjusted to every other day. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased. When initiating cariprazine in a patient who is stable on a strong CYP3A4 inhibitor, the patient should be administered 1.5 mg of cariprazine on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, then increased to a maximum dose of 3 mg daily. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased.
    Celecoxib: (Minor) Celecoxib is a substrate of the cytochrome P450 (CYP) 2C9 isoenzyme. In vitro, ketoconazole weakly inhibits CYP2C9; however, the in vivo inhibition potential is questionable. In a crossover study, ketoconazole 200 mg daily did not alter the pharmacokinetics of celecoxib; however, abnormally high celecoxib plasma concentrations were noted in 1 of about 45 subjects. An interaction between celecoxib and ketoconazole may be more pronounced in patients who are known or suspected to be poor CYP2C9 metabolizers based on data with other CYP2C9 substrates. Cautious use of celecoxib in poor CYP2C9 metabolizers is advised, especially if a concurrent CYP2C9 inhibitor is taken. Consider starting celecoxib at half the lowest recommended dose in CYP2C9 poor metabolizers. No clinically important effect of celecoxib on the pharmacokinetics or pharmacodynamics of ketoconazole was noted in vivo.
    Ceritinib: (Major) Avoid coadministration of ceritinib with ketoconazole due to increased exposure to ceritinib; Coadministration may also result in additive QT prolongation and increased ketoconazole exposure. If coadministration cannot be avoided, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of the 150 mg capsules; monitor for treatment-related adverse reactions. Periodically monitor electrolytes and ECGs; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. After ketoconazole is discontinued, resume the dose of ceritinib taken prior to initiating ketoconazole. Ceritinib is a CYP3A4 substrate and inhibitor that causes concentration-dependent prolongation of the QT interval. Ketoconazole is a CYP3A4 substrate as well as a strong CYP3A4 inhibitor, and is also associated with QT prolongation.
    Cerivastatin: (Major) Systemic ketoconazole use is not recommended during cerivastatin therapy. There are reports that ketoconazole and other azole antifungals increase the risk of myopathy and rhabdomyolysis when given with HMG-CoA reductase inhibitors, such as cerivastatin. If no alternative to a short course of ketoconazole is available, brief interruption of cerivastatin should be considered. Ketoconazole potently inhibits CYP3A4. Cerivastatin is metabolized by both CYP2C8 and CYP3A4. When cerivastatin was administered with a similar azole antifungal, the exposure of cerivastatin was increased by approximately 1.5-fold.
    Cevimeline: (Moderate) Cevimeline is metabolized by cytochrome P450 3A4 and CYP2D6. Concurrent administration of inhibitors of these enzymes, such as ketoconazole, may lead to increased cevimeline plasma concentrations.
    Chlordiazepoxide: (Moderate) CYP3A4 inhibitors, such as ketoconazole, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
    Chlordiazepoxide; Clidinium: (Moderate) CYP3A4 inhibitors, such as ketoconazole, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
    Chloroquine: (Major) Coadminister chloroquine with other drugs known to prolong the QT interval, such as ketoconazole, with caution. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses. Ketoconazole has also been associated with prolongation of the QT interval.
    Chlorpheniramine; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and ketoconazole are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpheniramine; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and ketoconazole are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and ketoconazole are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and ketoconazole are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Chlorpromazine: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include chlorpromazine.
    Chlorpropamide: (Moderate) Hypoglycemia, sometimes severe, has been reported when ketoconazole is coadministered with oral hypoglycemic agents. The most likely mechanism for this interaction is inhibition of the CYP450 metabolism of oral hypoglycemics by ketoconazole. Blood glucose concentrations should be monitored during concomitant treatment; patients should be aware of the symptoms of hypoglycemia. In some cases, dosage adjustment of the sulfonylurea may be necessary. There is no evidence that an interaction occurs between oral hypoglycemics and topical or vaginal azole antifungal preparations.
    Ciclesonide: (Minor) Potent inhibitors of CYP3A4 may increase serum concentrations of ciclesonide and its active metabolite des-ciclesonide. In a drug interaction study, orally inhaled ciclesonide coadministered with oral ketoconazole increased the AUC of des-ciclesonide by approximately 3.6-fold at steady state, while concentrations of ciclesonide remained unchanged.
    Cilostazol: (Major) Decrease cilostazol dose to one half of the recommended dosage when coadministered with ketoconazole. Coadministration may increase cilostazol serum concentrations and increase the risk for adverse reactions. Cilostazol is extensively metabolized by hepatic isoenzyme CYP3A4; ketoconazole is a strong inhibitor of CYP3A4. In a drug interaction study, coadministration of ketoconazole and cilostazol increased cilostazol Cmax by 94% and AUC by 117%.
    Cimetidine: (Major) Ketoconazole requires an acidic pH for absorption. Medications that increase gastric pH or decrease acid output can cause a notable decrease in the bioavailability of ketoconazole. Medications that have this effect are antacids, antimuscarinics, histamine H2-blockers, and proton pump inhibitors (PPIs). Except for antacids, these medications have a prolonged duration of action, and staggering their time of administration with ketoconazole by several hours may not prevent the drug interaction. An alternative imidazole antifungal should be chosen if any of these gastrointestinal medications are required. If these drugs must be coadministered, administer ketoconazole tablets with an acidic beverage and closely monitor for breakthrough infection.
    Cinacalcet: (Major) Cinacalcet is metabolized primarily by the CYP3A4 isoenzyme. Subjects being treated with 200 mg ketoconazole twice daily for 7 days received a single 90 mg cinacalcet dose on day 5 of therapy. The AUC and Cmax for cinacalcet increased 2.3 to 2.2 times, respectively, compared to 90 mg cinacalcet given alone. Therefore, caution is recommended when co-administering cinacalcet with other CYP3A4 enzyme inhibitors. If a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor during cinacalcet therapy, the manufacturer recommends that dosage adjustment may be needed with close monitoring of PTH and serum calcium concentrations.
    Ciprofloxacin: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include ciprofloxacin.
    Cisapride: (Severe) The combination of cisapride and ketoconazole is contraindicated. Ketoconazole inhibits the metabolism of cisapride, and may lead to cardiac toxicity. Ketoconazole causes a mean eight-fold increase in cisapride concentrations, which may result in QT prolongation and torsade de pointes.
    Citalopram: (Major) Avoid coadministration of citalopram and ketoconazole due to the potential for additive effects on the QT interval. If concurrent therapy is considered essential, ECG monitoring is recommended. Use of these drugs together may also increase the risk for breakthrough fungal infections. When ketoconazole was coadministered with citalopram, the Cmax and AUC of ketoconazole decreased by 21% and 10%, respectively, suggesting induction of ketoconazole metabolism by citalopram. Ketoconazole did not alter the pharmacokinetics of citalopram.
    Clarithromycin: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as clarithromycin. Both clarithromycin and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, both drugs are substrates and inhibitors of CYP3A4. Coadministration may result in increased plasma concentrations of both drugs, thereby further increasing the risk for adverse events. Azithromycin can be considered as an alternative macrolide antimicrobial if appropriate for the clinical circumstance, due to its lack of metabolism via CYP3A4.
    Clindamycin: (Moderate) Concomitant use of clindamycin and ketoconazole may decrease clindamycin clearance and increase the risk of adverse reactions. Clindamycin is a CYP3A4 substrate; ketoconazole is a strong inhibitor of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
    Clobazam: (Moderate) During co-administration of ketoconazole and clobazam, the AUC of clobazam was increased by 54%. However, there were no significant changes in AUC and Cmax of N-desmethylclobazam, the active metabolite of clobazam. No dosage adjustments are recommended by the manufacturer during concurrent use of these agents.
    Clomipramine: (Minor) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; ketoconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope have occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred. Close clinical monitoring is necessary if concurrent use is medically necessary.
    Clonazepam: (Moderate) Ketoconazole could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, such as clonazepam. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with ketoconazole, as these benzodiazepines are not oxidatively metabolized.
    Clopidogrel: (Major) Administer clopidogrel and systemic azole antifungals together with caution. Clopidogrel requires hepatic biotransformation via 2 cytochrome dependent oxidative steps. The CYP3A4 isoenzyme is involved in one of the metabolic steps, and the CYP2C19 isoenzyme is involved in both steps. Systemic azole antifungals are inhibitors of CYP3A4 and some also inhibit CYP2C19 (e.g., fluconazole, ketoconazole, miconazole, voriconazole) and may decrease the hepatic metabolism of clopidogrel to its active metabolite. In a randomized crossover study, healthy subjects received a clopidogrel loading dose of 300 mg followed by 5 daily doses of 75 mg with or without the ketoconazole (400 mg/day). Ketoconazole decreased the active metabolite of clopidogrel by 48% after the 300 mg dose and 61% after the last maintenance dose was given. Ketoconazole also decreased the area under the concentration-time curve of clopidogrel's active metabolite by 22% after the loading dose and 29% after the last maintenance dose. If coadministration is unavoidable, the therapeutic effectiveness of clopidogrel should be closely monitored.
    Clorazepate: (Moderate) Ketoconazole is a CYP3A4 inhibitor and may reduce the metabolism of clorazepate and increase the potential for benzodiazepine toxicity.
    Clozapine: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as clozapine. Both clozapine and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with clozapine (a CYP3A4 substrate) may result in elevated clozapine plasma concentrations and an increased risk for adverse events, including QT prolongation. Consider reducing the dose of clozapine if necessary.
    Cobicistat: (Major) Avoid concurrent use of ketoconazole with regimens containing cobicistat and atazanavir or darunavir. Use of these drugs together may result in increase plasma concentrations of ketoconazole, cobicistat, atazanavir, and darunavir. Specific dosage recommendations have not been determined.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concurrent use of ketoconazole with regimens containing cobicistat and atazanavir or darunavir. Use of these drugs together may result in increase plasma concentrations of ketoconazole, cobicistat, atazanavir, and darunavir. Specific dosage recommendations have not been determined. (Major) Coadministration of ketoconazole with elvitegravir may result in increased plasma concentrations of both drugs. During concurrent use, a maximum ketoconazole dose of 200 mg/day is recommended.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concurrent use of ketoconazole with regimens containing cobicistat and atazanavir or darunavir. Use of these drugs together may result in increase plasma concentrations of ketoconazole, cobicistat, atazanavir, and darunavir. Specific dosage recommendations have not been determined. (Major) Coadministration of ketoconazole with elvitegravir may result in increased plasma concentrations of both drugs. During concurrent use, a maximum ketoconazole dose of 200 mg/day is recommended. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ketoconazole. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with ketoconazole due to the risk of cobimetinib toxicity. Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; ketoconazole is a P-gp inhibitor in vitro, as well as a strong CYP3A inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
    Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Codeine; Guaifenesin: (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Codeine; Phenylephrine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include ketoconazole. (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Codeine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include ketoconazole. (Moderate) The activity of codeine is due to its conversion to morphine via the cytochrome P450 (CYP) 2D6 hepatic isoenzyme. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by CYP3A4 inhibitors, such as azole antifungals, may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Monitor patients for increased opiate-related side effects and adjust the dose of codeine as necessary.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and ketoconazole in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Ketoconazole can inhibit colchicine's metabolism via P-glycoprotein (P-gp) and CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken ketoconazole in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
    Conivaptan: (Severe) Coadministration of conivaptan (CYP3A4 substrate) with ketoconazole, a potent CYP3A4 inhibitor, is contraindicated according to the manufacturer. Coadministration of oral conivaptan 10 mg with ketoconazole 200 mg resulted in a 4-fold and 11-fold increase in the Cmax and AUC of conivaptan, respectively. The effect of coadministration of ketoconazole with intravenous conivaptan has not been studied. In addition, conivaptan inhibits both CYP3A4; ketoconazole is a substrate of CYP3A4. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Conjugated Estrogens: (Minor) In vitro and in vivo studies have shown that estrogens are metabolized partially by CYP3A4. Therefore, inhibitors of CYP3A4 may affect estrogen drug metabolism. Inhibitors of CYP3A4, such as ketoconazole, may increase the exposure of conjugated estrogens resulting in an increased risk of endometrial hyperplasia. Therefore, for chronically administered CYP3A4 inhibitors ( > 30 days) concurrently administered with conjugated estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
    Conjugated Estrogens; Bazedoxifene: (Minor) In vitro and in vivo studies have shown that estrogens are metabolized partially by CYP3A4. Therefore, inhibitors of CYP3A4 may affect estrogen drug metabolism. Inhibitors of CYP3A4, such as ketoconazole, may increase the exposure of conjugated estrogens resulting in an increased risk of endometrial hyperplasia. Therefore, for chronically administered CYP3A4 inhibitors ( > 30 days) concurrently administered with conjugated estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
    Conjugated Estrogens; Medroxyprogesterone: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with ketoconazole, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro. (Minor) In vitro and in vivo studies have shown that estrogens are metabolized partially by CYP3A4. Therefore, inhibitors of CYP3A4 may affect estrogen drug metabolism. Inhibitors of CYP3A4, such as ketoconazole, may increase the exposure of conjugated estrogens resulting in an increased risk of endometrial hyperplasia. Therefore, for chronically administered CYP3A4 inhibitors ( > 30 days) concurrently administered with conjugated estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
    Copanlisib: (Major) Avoid the concomitant use of copanlisib and ketoconazole if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; ketoconazole is a strong CYP3A inhibitor.
    Crizotinib: (Major) Avoid coadministration of crizotinib with ketoconazole due to increased crizotinib exposure; QT prolongation may also occur. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Ketoconazole is a strong CYP3A inhibitor that is also associated with QT prolongation. Coadministration of a single dose of crizotinib with ketoconazole increased the AUC of crizotinib by 3.2-fold; the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated.
    Cyclobenzaprine: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as cyclobenzaprine. Both cyclobenzaprine and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with cyclobenzaprine (a CYP3A4 substrate) may result in elevated cyclobenzaprine plasma concentrations and an increased risk for adverse events, including QT prolongation.
    Cyclosporine: (Major) The interactions between cyclosporine and systemic azole antifungals (e.g., ketoconazole) can be significant. Ketoconazole may inhibit cyclosporine CYP3A4-mediated metabolism, which may result in increased cyclosporine blood concentrations. Cyclosporine concentrations may increase within 1 to 3 days after starting azole antifungal therapy, and may persist for > 1 week after discontinuing antifungal treatment. Of the azoles, ketoconazole is the most potent CYP3A4 inhibitor; it also inhibits p-glycoprotein. Ketoconazole can increase cyclosporine concentrations up to 3-fold within days of addition of ketoconazole to cyclosporine therapy. It takes about 7 to 10 days for cyclosporine concentrations to normalize after stopping ketoconazole. Ketoconazole has been documented to lower the daily maintenance dosage of cyclosporine, thus reducing the overall cost of therapy; however, this approach is not routinely used. Ketoconazole may also potentiate renal dysfunction associated with cyclosporine. In all cases, renal function in these patients should be carefully monitored. Close monitoring of cyclosporine concentrations is required when given in combination with systemic azole antifungals; a 50% reduction in cyclosporine dosage may be required.
    Dabigatran: (Major) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with ketoconazole, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like ketoconazole in patients with CrCl less than 50 mL/minute. When used in patients with non-valvular atrial fibrillation, avoid the coadministration of dabigatran and systemic ketoconazole in patients with severe renal impairment (CrCl less than 30 mL/minute), and consider reducing the dabigatran dose to 75 mg twice daily when ketoconazole and dabigatran are coadministered in patients with moderate renal impairment (CrCl 30 to 50 ml/min). Coadministration of dabigatran and ketoconazole results in increased dabigatran serum concentrations and, therefore, an increased risk of bleeding. Coadministration of a single dose of 400 mg ketoconazole increased the dabigatran AUC and Cmax by 138% and 135%, respectively. Coadministration of multiple daily doses of 400 mg ketoconazole increased dabigatran AUC and Cmax by 153% and 149%, respectively. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Dabrafenib: (Major) Avoid the concomitant use of dabrafenib and ketoconazole; dabrafenib exposure increased by 71% when these drugs were administered together in a drug interaction study. Additionally, the concentrations of ketoconazole may be decreased resulting in loss of efficacy. Use of an alternate agent in place of ketoconazole is recommended. If concomitant use cannot be avoided, monitor patients for dabrafenib toxicity (e.g., skin toxicity, ocular toxicity, and cardiotoxicity) and for loss of ketoconazole efficacy. Dabrafenib is a CYP3A4 substrate and moderate CYP3A4 inducer; ketoconazole is a strong CYP3A4 inhibitor and a CYP3A4 substrate. The AUC values of dabrafenib and its active metabolites, hydroxy-dabrafenib and desmethyl-dabrafenib, were increased by 71%, 82%, and 68%, respectively, when dabrafenib 75 mg PO twice daily was administered with ketoconazole 400 mg PO once daily for 4 days in a drug interaction study.
    Daclatasvir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as ketoconazole. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects.
    Dapagliflozin; Saxagliptin: (Major) Saxagliptin is a p-glycoprotein substrate, and the metabolism of saxagliptin is primarily mediated by CYP3A4/5. Ketoconazole is a strong inhibitor of both p-glycoprotein and CYP3A4/5. Saxagliptin did not meaningfully alter the pharmacokinetics of ketoconazole, but coadministration increased the maximum serum saxagliptin concentration by 62% and the systemic exposure by 2.5-fold. As expected, the maximum serum concentration of the saxagliptin active metabolite was decreased by 95% and the systemic exposure was decreased by 91%. In another study, the maximum serum saxagliptin concentration increased by 2.4-fold and the systemic exposure increased by 3.4-fold. The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP 3A4/5 inhibitor such as ketoconazole.
    Darifenacin: (Moderate) Darifenacin may raise intragastric pH. This effect may decrease the oral bioavailability of ketoconazole. In addition, the daily dose of darifenacin should not exceed 7.5 mg when coadministered with ketoconazole, because ketoconazole may increase the Cmax, and AUC concentrations of darifenacin.
    Darunavir: (Moderate) Ketoconazole is a potent inhibitor and substrate of CYP3A. Concomitant systemic use of ketoconazole with darunavir may increase plasma concentrations of darunavir. Additionally, plasma concentrations of ketoconazole may be increased when coadministered with darunavir (in the FDA approved dosage regimen). When coadministration is required, high doses (i.e., > 200 mg) of ketoconazole should be avoided.
    Darunavir; Cobicistat: (Major) Avoid concurrent use of ketoconazole with regimens containing cobicistat and atazanavir or darunavir. Use of these drugs together may result in increase plasma concentrations of ketoconazole, cobicistat, atazanavir, and darunavir. Specific dosage recommendations have not been determined. (Moderate) Ketoconazole is a potent inhibitor and substrate of CYP3A. Concomitant systemic use of ketoconazole with darunavir may increase plasma concentrations of darunavir. Additionally, plasma concentrations of ketoconazole may be increased when coadministered with darunavir (in the FDA approved dosage regimen). When coadministration is required, high doses (i.e., > 200 mg) of ketoconazole should be avoided.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) When administering ketoconazole with ritonavir or ritonavir-containing drugs, do not exceed the maximum recommended ketoconazole dose of 200 mg per day. Concurrent administration of ritonavir (a potent CYP3A4 inhibitor) with ketoconazole (a CYP3A4 substrate) significantly increases ketoconazole systemic concentrations. In one drug interaction study, ketoconazole exposure was increased by 3.4-fold when given concurrently with ritonavir (500 mg twice daily). In addition, because both drugs are associated with prolongation of the QT interval, coadministration may increase the risk for developing QT prolongation. If these drugs are given together, closely monitor patients for ketoconazole-associated adverse effects, including QT prolongation.
    Dasatinib: (Major) Avoid concurrent administration of ketoconazole and dasatinib. An alternative to ketoconazole is recommended, if possible. If dasatinib must be administered with ketoconazole, reduce the dose of dasatinib to 20 mg PO daily (if original dose was 100 mg daily) or 40 mg PO daily (if original dose 140 mg daily). Once ketoconazole is discontinued, wait approximately 1 week before increasing back to the original dasatinib dose. Coadministration of ketoconazole (a potent CYP3A4 inhibitor) with dasatinib (a CYP3A4 substrate) results in elevated dasatinib plasma concentrations and may increase the risk for adverse events. In a study of 18 patients with solid tumors, concurrent administration of dasatinib 20 mg once daily and ketoconazole 200 mg twice daily increased dasatinib Cmax and AUC 4-fold and 5-fold, respectively. In addition, both dasatinib and ketoconazole are associated with QT prolongation; coadministration may increase this risk. Carefully monitor the patient for dasatinib-related toxicity.
    Daunorubicin: (Major) Ketoconazole has been associated with prolongation of the QT interval. Acute cardiotoxicity can occur during administration of daunorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with ketoconazole. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; ketoconazole is a strong inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
    Degarelix: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include degarelix.
    Delavirdine: (Minor) Ketoconazole is a known inhibitor of cytochrome P450 3A4. Trough plasma concentrations of delavirdine may be increased by about 50% in patients receiving ketoconazole concurrently with delavirdine.
    Desflurane: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include halogenated anesthetics.
    Desipramine: (Minor) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; ketoconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope have occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred. Close clinical monitoring is necessary if concurrent use is medically necessary.
    Deutetrabenazine: (Major) For patients taking a deutetrabenazine dosage more than 24 mg/day with ketoconazole, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. Ketoconazole has been associated with prolongation of the QT interval.
    Dexamethasone: (Moderate) Coadministration may result in increased exposure to dexamethasone and increased corticosteroid-related adverse effects. Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%. In addition, ketoconazole alone can inhibit adrenal corticosteroid synthesis and may cause adrenal insufficiency during corticosteroid withdrawal.
    Dextromethorphan; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include ketoconazole.
    Dextromethorphan; Quinidine: (Severe) Ketoconazole inhibits the hepatic CYP3A4 isoenzyme; quinidine is metabolized by this isoenzyme. Coadministration results in increased quinidine serum concentrations, with potential to result in proarrhythmias. A single case report has documented substantial elevations in serum quinidine concentrations after the addition of ketoconazole. The patient was receiving other drugs concomitantly and it is unclear if drug-induced arrhythmias occurred. Until more data are available, ketoconazole should be considered contraindicated in patients receiving quinidine.
    Diazepam: (Moderate) Ketoconazole could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines such as diazepam.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and ketoconazole together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including antifungals. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment. If hypokalemia occurs or persists, consider reducing the dichlorphenamide dose or discontinuing dichlorphenamide therapy.
    Diclofenac: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as ketoconazole; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Diclofenac; Misoprostol: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as ketoconazole; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Didanosine, ddI: (Major) Administer ketoconazole at least 2 hours before or several hours after didanosine chewable tablets and powder for oral solution. Didanosine chewable tablets and powder for oral solution contain acid buffers to enhance the bioavailability of didanosine. These buffers, however, may decrease the absorption of ketoconazole, which requires an acid environment for absorption. The delayed-release didanosine capsules do not contain a buffering agent and would not be expected to interact with ketoconazole.
    Dienogest; Estradiol valerate: (Minor) As ketoconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives. (Minor) Estradiol valerate and dienogest are both substrates of CYP3A4. Certain azole antifungals, including fluconazole, itraconazole, ketonconazole, miconazole (systemic formulation only), posaconazole, and voriconazole, are CYP3A4 inhibitors and therefore may inhibit the metabolism of dienogest; estradiol valerate, possibly leading to increased serum concentrations. In a pharmacokinetic study evaluating the effect of ketoconazole on dienogest and estradiol, co-administration with ketoconazole increased the AUC at steady-state for dienogest and estradiol by 2.86 and 1.57-fold, respectively. There was also a 1.94 and 1.65-fold increase of Cmax at steady-state for dienogest and estradiol when co-administered with ketoconazole.
    Digoxin: (Moderate) Concomitant use of digoxin with ketoconazole has resulted in increased digoxin serum concentrations. Ketoconazole inhibits p-glycoprotein, an enzyme which metabolizes digoxin. Plasma concentrations of digoxin should be monitored closely if ketoconazole is added.
    Dihydroergotamine: (Severe) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as ketoconazole, is contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, and/or other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
    Diltiazem: (Moderate) Ketoconazole may increase diltiazem serum concentrations via inhibition of CYP3A4 with the potential for diltiazem toxicity. Exercise caution when co-administering systemic azole antifungals and calcium-channel blockers.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and ketoconazole are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Disopyramide: (Severe) Concomitant use of ketoconazole with disopyramide is contraindicated due to the risk of serious adverse events, such as QT prolongation and torsade de pointes. If coadministered, ketoconazole may inhibit the CYP3A4 metabolism of disopyramide, resulting in elevated disopyramide plasma concentrations.
    Docetaxel: (Minor) Docetaxel is metabolized by CYP3A4 and CYP3A5 enzymes. Drugs that inhibit CYP3A enzymes, such as ketoconazole, can significantly decrease the metabolism of docetaxel. Use docetaxel cautiously when administered concurrently with inhibitors of CYP3A enzymes.
    Dofetilide: (Severe) Concurrent use of dofetilide with ketoconazole is contraindicated due to the risk of serious cardiovascular events. Ketoconazole co-administered with dofetilide for 7 days has been shown to increase dofetilide Cmax by 53% in males and 97% in females, and increase dofetilide AUC by 41% in males and 69% in females. This interaction is proposed to occur primarily by inhibition of cationic renal tubular secretion of dofetilide by ketoconazole, however, inhibition of CYP 3A4 metabolism may also contribute.
    Dolasetron: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as dolasetron. Both dolasetron and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with dolasetron (a CYP3A4 substrate) may result in elevated dolasetron plasma concentrations and an increased risk for adverse events, including QT prolongation.
    Donepezil: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as donepezil. Both donepezil and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, ketoconazole has been shown, in vitro, to inhibit the metabolism of donepezil by inhibiting CYP3A4. In a 7-day cross-over study in 18 subjects, ketoconazole (200 mg daily) increased mean donepezil (5 mg daily) concentrations (AUC and Cmax) by 36%. The clinical relevance of this interaction is not known, but elevated donepezil concentrations could result in greater incidence of dose-related toxicity.
    Donepezil; Memantine: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as donepezil. Both donepezil and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, ketoconazole has been shown, in vitro, to inhibit the metabolism of donepezil by inhibiting CYP3A4. In a 7-day cross-over study in 18 subjects, ketoconazole (200 mg daily) increased mean donepezil (5 mg daily) concentrations (AUC and Cmax) by 36%. The clinical relevance of this interaction is not known, but elevated donepezil concentrations could result in greater incidence of dose-related toxicity.
    Doxazosin: (Moderate) Monitor blood pressure and for signs of hypotension during coadministration. The plasma concentrations of doxazosin may be elevated when administered concurrently with ketoconazole. Ketoconazole is a strong CYP3A4 inhibitor; doxazosin is a CYP3A4 substrate. Coadministration of doxazosin with a moderate CYP3A4 inhibitor resulted in a 10% increase in mean AUC and an insignificant increase in mean Cmax and mean half-life of doxazosin. Although not studied in combination with doxazosin, strong CYP3A4 inhibitors may have a larger impact on doxazosin concentrations and therefore should be used with caution.
    Doxepin: (Minor) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; ketoconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope have occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred. Close clinical monitoring is necessary if concurrent use is medically necessary.
    Doxercalciferol: (Moderate) Cytochrome P450 enzyme inhibitors, such as ketoconazole, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy.
    Doxorubicin: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as doxorubicin. Ketoconazole is a potent inhibitor of CYP3A4. Coadministration of ketoconazole with doxorubicin may result in an elevated doxorubicin plasma concentrations and an increased risk for adverse events, including QT prolongation. Ketoconazole has been associated with QT prolongation. Acute cardiotoxicity can occur during the administration of doxorubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Dronabinol, THC: (Major) Use caution if coadministration of dronabinol with ketoconazole is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; ketoconazole is a strong inhibitor of CYP3A4 and a weak CYP2C9 inhibitor in vitro. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Dronedarone: (Severe) Concomitant use of dronedarone and ketoconazole is contraindicated. Dronedarone is metabolized by CYP3A and is a moderate inhibitor of CYP3A. Repeated doses of ketoconazole, a strong CYP3A4 inhibitor and also a CYP3A substrate, increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold. The effects of dronedarone on the pharmacokinetics of ketoconazole have not been described, although an increase in ketoconazole serum concentrations is possible.
    Droperidol: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as droperidol. Both droperidol and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with droperidol (a CYP3A4 substrate) may result in elevated droperidol plasma concentrations and an increased risk for adverse events, including QT prolongation.
    Drospirenone; Estradiol: (Moderate) Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Ketoconazole is a strong CYP3A4 inhibitor and may increase drospirenone serum concentrations. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. (Minor) As ketoconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Drospirenone; Ethinyl Estradiol: (Moderate) Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Ketoconazole is a strong CYP3A4 inhibitor and may increase drospirenone serum concentrations. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as ketoconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Ketoconazole is a strong CYP3A4 inhibitor and may increase drospirenone serum concentrations. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly. (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as ketoconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Dutasteride: (Moderate) Dutasteride is metabolized by CYP3A4 enzyme. CYP3A4 inhibitors, such as ketoconazole, may decrease the clearance of dutasteride.
    Dutasteride; Tamsulosin: (Major) Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes, and strong inhibitors of CYP3A4 are expected to significantly raise tamsulosin concentrations. Plasma concentrations of tamsulosin are increased with concomitant use of ketoconazole, a strong inhibitor of CYP3A4. Concomitant treatment with ketoconazole resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use with a strong CYP3A4 inhibitor, such as ketoconazole, itraconazole, posaconazole, or voriconazole should be avoided. (Moderate) Dutasteride is metabolized by CYP3A4 enzyme. CYP3A4 inhibitors, such as ketoconazole, may decrease the clearance of dutasteride.
    Edoxaban: (Major) Reduce the dose of edoxaban to 30 mg/day PO in patients being treated for deep venous thrombosis (DVT) or pulmonary embolism and receiving concomitant therapy with oral ketoconazole. No dosage adjustment is required in patients with atrial fibrillation. Edoxaban is a P-glycoprotein (P-gp) substrate and oral ketoconazole is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of ketoconazole; monitor for increased adverse effects of edoxaban.
    Efavirenz: (Major) Avoid concurrent administration of ketoconazole and efavirenz or efavirenz-containing medications. Administering ketoconazole with inducers of CYP3A4, such as efavirenz, may decrease the bioavailability of ketoconazole to such an extent that efficacy may be reduced. Efavirenz is also partially metabolized by CYP3A4; taking efavirenz with ketoconazole (a potent CYP3A4 inhibitor) may increase exposure to efavirenz. In addition, both drugs are associated with QT prolongation; coadministration may increase this risk. Use of an alternative antifungal medication should be considered. If these drugs must be used together, monitor for breakthrough fungal infections and adverse events.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid concurrent administration of ketoconazole and efavirenz or efavirenz-containing medications. Administering ketoconazole with inducers of CYP3A4, such as efavirenz, may decrease the bioavailability of ketoconazole to such an extent that efficacy may be reduced. Efavirenz is also partially metabolized by CYP3A4; taking efavirenz with ketoconazole (a potent CYP3A4 inhibitor) may increase exposure to efavirenz. In addition, both drugs are associated with QT prolongation; coadministration may increase this risk. Use of an alternative antifungal medication should be considered. If these drugs must be used together, monitor for breakthrough fungal infections and adverse events. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ketoconazole. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Elbasvir; Grazoprevir: (Major) Concurrent administration of elbasvir with systemic ketoconazole should be avoided if possible. Use of these drugs together significantly increases the plasma concentrations of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ketoconazole is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with systemic ketoconazole should be avoided if possible. Use of these drugs together significantly increases the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ketoconazole is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A.
    Eletriptan: (Severe) Do not administer eletriptan within at least 72 hours of using ketoconazole. Ketoconazole inhibits the CYP3A4 metabolism of eletriptan, causing increases in eletriptan serum concentrations. Concomitant use resulted in a 3-fold increase in the Cmax and about a 6-fold increase in the AUC of eletriptan.
    Eliglustat: (Severe) In intermediate or poor CYP2D6 metabolizers (IMs or PMs), coadministration of ketoconazole and eliglustat is contraindicated. In extensive CYP2D6 metabolizers (EMs), coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. The coadministration of eliglustat with both ketoconazole and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Both eliglustat and ketoconazole can independently prolong the QT interval, and coadministration increases this risk. Ketoconazole is a strong CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Coadministration of eliglustat with CYP3A inhibitors increases eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A. Although ketoconazole's product labeling states that coadministration of other drugs that prolong the QT interval and are metabolized by CYP3A4 is contraindicated, the specific interaction between ketoconazole and eliglustat was studied during clinical trials. The resultant data supports eliglustat dosage reduction in EMs instead of contraindication. During clinical trials in EMs (n = 31), Cmax and AUC increased 4-fold and 4.4-fold, respectively, after co-administration of eliglustat 84 mg PO twice daily with ketoconazole 400 mg once daily. Physiology-based pharmacokinetic (PBPK) models suggest that ketoconazole may increase the Cmax and AUC of eliglustat 4.4- and 5.4-fold, respectively, in IMs. PBPK suggests ketoconazole may increase the Cmax and AUC of eliglustat 4.3- and 6.2-fold, respectively, when administered with eliglustat 84 mg PO once daily in PMs. In addition, PBPK modeling suggests concomitant use of eliglustat (84 mg PO twice daily) with a strong 2D6 inhibitor and ketoconazole (strong 3A4 inhibitor) may increase the Cmax and AUC of eliglustat 16.7- and 24.2-fold, respectively, in EMs and 7.5- and 9.8-fold, respectively, in IMs.
    Elvitegravir: (Major) Coadministration of ketoconazole with elvitegravir may result in increased plasma concentrations of both drugs. During concurrent use, a maximum ketoconazole dose of 200 mg/day is recommended.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Caution is advised when administering ketoconazole with rilpivirine due to the potential for additive effects on the QT interval and increased exposure to rilpivirine. Both rilpivirine and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with rilpivirine (a CYP3A4 substrate) results in elevated rilpivirine plasma concentrations. Conversely, ketoconazole concentrations are decreased when administered with rilpivirine. If these drugs must be administered together, closely monitor for rilpivirine-related adverse events and the potential for breakthrough fungal infections. Rilpivirine dosage adjustments are not recommended.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Caution is advised when administering ketoconazole with rilpivirine due to the potential for additive effects on the QT interval and increased exposure to rilpivirine. Both rilpivirine and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with rilpivirine (a CYP3A4 substrate) results in elevated rilpivirine plasma concentrations. Conversely, ketoconazole concentrations are decreased when administered with rilpivirine. If these drugs must be administered together, closely monitor for rilpivirine-related adverse events and the potential for breakthrough fungal infections. Rilpivirine dosage adjustments are not recommended. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ketoconazole. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ketoconazole. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Enalapril; Felodipine: (Severe) Concomitant use of ketoconazole with felodipine is contraindicated due to the risk of serious adverse events, such as edema and congestive heart failure. Felodipine is metabolized by the hepatic isoenzyme CYP3A4; ketoconazole is a potent inhibitor of this isoenzyme. If coadministered, the plasma concentrations of felodipine may significantly increase.
    Enflurane: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include halogenated anesthetics.
    Entecavir: (Moderate) Both entecavir and ketoconazole are secreted by active tubular secretion. In theory, coadministration of entecavir with ketoconazole may increase the serum concentrations of either drug due to competition for the drug elimination pathway. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Enzalutamide: (Major) The use of enzalutamide within 2 weeks of systemic ketoconazole therapy is not recommended. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole; increase the dose of ketoconazole as necessary. Ketoconazole is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer.
    Epirubicin: (Major) Ketoconazole has been associated with prolongation of the QT interval. Acute cardiotoxicity can occur during administration of daunorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Eplerenone: (Severe) Concomitant use of ketoconazole and eplerenone is contraindicated. Ketoconazole, due to the inhibition of hepatic CYP3A4 isoenzymes, increases serum eplerenone concentrations by roughly 5-fold and, hence, increases the risk of developing hyperkalemia and hypotension.
    Ergoloid Mesylates: (Severe) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as ketoconazole, is contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, and/or other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
    Ergonovine: (Severe) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as ketoconazole, is contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, and/or other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
    Ergot alkaloids: (Severe) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as ketoconazole, is contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, and/or other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
    Ergotamine: (Severe) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as ketoconazole, is contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, and/or other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
    Eribulin: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include eribulin.
    Erlotinib: (Major) Avoid the coadministration of erlotinib with ketoconazole due to the risk of increased erlotinib-related adverse reactions; if concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Ketoconazole is a strong CYP3A4 inhibitor. Coadministration of erlotinib with ketoconazole increased the erlotinib AUC by 67%.
    Erythromycin: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as erythromycin. Both erythromycin and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, both ketoconazole and erythromycin are CYP3A4 inhibitors and substrates. Use of these drugs together may result in elevated plasma concentrations of both drugs, further increasing the risk for adverse effects. A retrospective cohort study evaluated the association of erythromycin with sudden death due to cardiac causes and whether strong CYP3A inhibitors (nitroimidazole antifungal agents, diltiazem, verapamil, and troleandomycin) increased the risk. The study population was a Tennessee Medicaid cohort that included 1,249,943 person-years of follow-up and 1,476 cases of confirmed sudden death from cardiac causes. Strong CYP3A inhibitors were identified by their ability to produce a doubling or more of the AUC for a recognized CYP3A substrate. While there were no deaths associated with nitroimidazoles, the authors recommended that erythromycin not be administered with strong inhibitors of CYP3A.
    Erythromycin; Sulfisoxazole: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as erythromycin. Both erythromycin and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, both ketoconazole and erythromycin are CYP3A4 inhibitors and substrates. Use of these drugs together may result in elevated plasma concentrations of both drugs, further increasing the risk for adverse effects. A retrospective cohort study evaluated the association of erythromycin with sudden death due to cardiac causes and whether strong CYP3A inhibitors (nitroimidazole antifungal agents, diltiazem, verapamil, and troleandomycin) increased the risk. The study population was a Tennessee Medicaid cohort that included 1,249,943 person-years of follow-up and 1,476 cases of confirmed sudden death from cardiac causes. Strong CYP3A inhibitors were identified by their ability to produce a doubling or more of the AUC for a recognized CYP3A substrate. While there were no deaths associated with nitroimidazoles, the authors recommended that erythromycin not be administered with strong inhibitors of CYP3A.
    Escitalopram: (Major) Caution is advised when administering ketoconazole with escitalopram. Both escitalopram and ketoconazole are possibly associated with QT prolongation; coadministration may increase this risk. In addition, use of these drugs together may increase the risk for breakthrough fungal infections. When ketoconazole was coadministered with racemic citalopram, the Cmax and AUC of ketoconazole decreased by 21% and 10%, respectively, suggesting induction of ketoconazole metabolism by citalopram. Ketoconazole did not alter the pharmacokinetics of citalopram.
    Estazolam: (Major) In theory, CYP3A4 inhibitors, such as ketoconazole, may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity. Although one study using single oral doses of estazolam suggests that itraconazole has no effect on the pharmacokinetics or pharmacodynamics of estazolam, the manufacturer for Prosom recommends that estazolam should be avoided in patients receiving itraconazole and ketoconazole.
    Esterified Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as systemic azole antifungals (fluconazole, itraconazole, ketoconazole, miconazole, posaconazole, and voriconazole) may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Esterified Estrogens; Methyltestosterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as systemic azole antifungals (fluconazole, itraconazole, ketoconazole, miconazole, posaconazole, and voriconazole) may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Estradiol Cypionate; Medroxyprogesterone: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with ketoconazole, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro. (Minor) As ketoconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol: (Minor) As ketoconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol; Levonorgestrel: (Minor) As ketoconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol; Norethindrone: (Minor) As ketoconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol; Norgestimate: (Minor) As ketoconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Eszopiclone: (Major) The adult dose of eszopiclone should not exceed 2 mg/day during co-administration of potent CYP3A4 inhibitors, such as ketoconazole or itraconazole. CYP3A4 is a primary metabolic pathway for eszopiclone, and increased systemic exposure to eszopiclone increases the risk of next-day psychomotor or memory impairment, which may decrease the ability to perform tasks requiring full mental alertness such as driving. A pharmacokinetic study of ketoconazole coadministered with eszopiclone resulted in an a 2.2-fold increase in eszopiclone AUC. Although other azole antifungals (e.g., fluconazole, voriconazole) inhibit CYP3A4 to a lesser extent than ketoconazole or itraconazole, a clinically relevant interaction is possible, and dose adjustments of eszopiclone may be necessary.
    Ethanol: (Severe) A disulfiram-like reaction has been reported when patients taking ketoconazole consume ethanol. Symptoms include facial flushing, difficult breathing, slight fever, and tightness of the chest. This reaction usually resolves spontaneously within 24 hours, with no lasting effects. Ethanol should be avoided during and for at least 48 hours following ketoconazole therapy.
    Ethinyl Estradiol: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as ketoconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Ethinyl Estradiol; Desogestrel: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as ketoconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as ketoconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Ethinyl Estradiol; Etonogestrel: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as ketoconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events. (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as ketoconazole may increase the serum concentration of etonogestrel.
    Ethinyl Estradiol; Levonorgestrel: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as ketoconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as ketoconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Ethinyl Estradiol; Norelgestromin: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as ketoconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as ketoconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as ketoconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Ethinyl Estradiol; Norethindrone: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as ketoconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as ketoconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Ethinyl Estradiol; Norgestimate: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as ketoconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Ethinyl Estradiol; Norgestrel: (Moderate) The estrogens in oral contraceptives are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as ketoconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Ethosuximide: (Moderate) Ketoconazole may inhibit the CYP3A4 metabolism of ethosuximide. This interaction may or may not be clinically significant, since ethosuximide serum concentrations are not well correlated to drug efficacy or side effects.
    Etonogestrel: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as ketoconazole may increase the serum concentration of etonogestrel.
    Etoposide, VP-16: (Major) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with ketoconazole. Ketoconazole is a strong inhibitor of CYP3A4 as well as an in vitro P-glycoprotein (P-gp) inhibitor; etoposide, VP-16 is a CYP3A4 and P-gp substrate. Coadministration may cause accumulation of etoposide and decreased metabolism, resulting in increased etoposide concentrations.
    Etravirine: (Moderate) Ketoconazole is a potent inhibitor and a substrate of CYP3A4. Etravirine is a substrate and an inducer of CYP3A4. Coadministration with ketoconazole may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of ketoconazole may be decreased by etravirine. Dose adjustments for ketoconazole may be necessary when coadministered with etravirine. Monitor patients closely for etravirine-related adverse effects and for efficacy of ketoconazole.
    Everolimus: (Major) Avoid coadministration of ketoconazole with everolimus (Afinitor; Afinitor Disperz) due to increased plasma concentrations of everolimus. Coadministration of ketoconazole with everolimus (Zortress) is not recommended without close monitoring of everolimus whole blood trough concentrations. Everolimus is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp); ketoconazole is a strong inhibitor of CYP3A4 and a P-gp inhibitor. Coadministration with ketoconazole increased everolimus exposure by 15-fold.
    Ezetimibe; Simvastatin: (Severe) Concurrent use of simvastatin and ketoconazole is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A4 inhibitors such as ketoconazole. If therapy with ketoconazole is unavoidable, simvastatin therapy must be suspended during the course of ketoconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
    Ezogabine: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include ezogabine.
    Famotidine: (Major) Ketoconazole requires an acidic pH for absorption. Medications that increase gastric pH or decrease acid output can cause a notable decrease in the bioavailability of ketoconazole. Medications that have this effect are antacids, antimuscarinics, histamine H2-blockers, and proton pump inhibitors (PPIs). Except for antacids, these medications have a prolonged duration of action, and staggering their time of administration with ketoconazole by several hours may not prevent the drug interaction. An alternative imidazole antifungal should be chosen if any of these gastrointestinal medications are required. If these drugs must be coadministered, administer ketoconazole tablets with an acidic beverage and closely monitor for breakthrough infection.
    Famotidine; Ibuprofen: (Major) Ketoconazole requires an acidic pH for absorption. Medications that increase gastric pH or decrease acid output can cause a notable decrease in the bioavailability of ketoconazole. Medications that have this effect are antacids, antimuscarinics, histamine H2-blockers, and proton pump inhibitors (PPIs). Except for antacids, these medications have a prolonged duration of action, and staggering their time of administration with ketoconazole by several hours may not prevent the drug interaction. An alternative imidazole antifungal should be chosen if any of these gastrointestinal medications are required. If these drugs must be coadministered, administer ketoconazole tablets with an acidic beverage and closely monitor for breakthrough infection.
    Felodipine: (Severe) Concomitant use of ketoconazole with felodipine is contraindicated due to the risk of serious adverse events, such as edema and congestive heart failure. Felodipine is metabolized by the hepatic isoenzyme CYP3A4; ketoconazole is a potent inhibitor of this isoenzyme. If coadministered, the plasma concentrations of felodipine may significantly increase.
    Fentanyl: (Moderate) Ketoconazole may decrease the systemic clearance of fentanyl. Prolonged duration of opiate action, increased sedation, respiratory depression or other opiate side effects may occur. Close monitoring of patients is warranted.
    Fesoterodine: (Moderate) Fesoterodine is rapidly hydrolyzed to its active metabolite, 5-hydroxymethyltolterodine, which is metabolized via hepatic CYP3A4. The potent CYP3A4 inhibitory effects of ketoconazole may result in an increase in Cmax and AUC of 5-hydroxymethyltolterodine. During one study, the Cmax and AUC of 5-hydroxymethyltolterodine increased 2- and 2.3-fold, respectively, during concurrent use of fesoterodine 8 mg/day and ketoconazole 200 mg twice daily in CYP2D6 extensive metabolizers. In the same study, CYP2D6 poor metabolizers of 5-hydroxymethyltolterodine experienced a 2.1- and 2.5-fold increase in Cmax and AUC, respectively. Adult doses of fesoterodine greater than 4 mg/day PO are not recommended during concurrent use of systemic ketoconazole.
    Fexofenadine: (Minor) Ketoconazole may inhibit the metabolism of fexofenadine via its effects on the CYP3A4 isozyme of the cytochrome P-450 microsomal enzyme system.
    Fexofenadine; Pseudoephedrine: (Minor) Ketoconazole may inhibit the metabolism of fexofenadine via its effects on the CYP3A4 isozyme of the cytochrome P-450 microsomal enzyme system.
    Fingolimod: (Moderate) Ketoconazole is a potent inhibitor of CYP3A and CYP4F. Coadministration of ketoconazole 200 mg twice daily at steady-state and a single dose of fingolimod 5 mg led to a 70% increase in the systemic exposure of fingolimod and fingolimod-phosphate. Closely monitor patients who use fingolimod and systemic ketoconazole concomitantly. The risk of adverse reactions from fingolimod is greater.
    Flecainide: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include flecainide.
    Flibanserin: (Severe) The concomitant use of flibanserin and strong CYP3A4 inhibitors, such as ketoconazole, is contraindicated. Strong CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a strong CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a strong CYP3A4 inhibitor following flibanserin use, start the strong CYP3A4 inhibitor at least 2 days after the last dose of flibanserin. In a pharmacokinetic drug interaction study of 50 mg flibanserin and 400 mg ketoconazole, syncope occurred in 4% of healthy subjects treated with concomitant flibanserin and ketoconazole, 4% of subjects receiving flibanserin alone, and no subjects receiving ketoconazole alone. In this study, the concomitant use of flibanserin and ketoconazole increased flibanserin exposure 4.5-fold.
    Fluoxetine: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include fluoxetine.
    Fluoxetine; Olanzapine: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include fluoxetine. (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include olanzapine.
    Fluphenazine: (Minor) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ketoconazole include fluphenazine.
    Flurazepam: (Moderate) Ketoconazole could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, such as flurazepam.
    Fluticasone: (Major) Coadministration of ketoconazole and fluticasone may result in increased systemic corticosteroid adverse effects. Per the manufacturer of fluticasone propionate, concurrent use of ketoconazole is not recommended; the manufacturer of fluticasone furoate recommends caution during concurrent use. Coadministration of ketoconazole increases the systemic exposure to fluticasone. Ketoconazole is a strong CYP3A4 inhibitor; fluticasone is a CYP3A4 substrate.
    Fluticasone; Salmeterol: (Major) Avoid use of salmeterol with strong CYP3A4 inhibitors. Salmeterol is a CYP3A4 substrate. The coadministration of with strong CYP3A4 inhibitors such as ketoconazole results in elevated salmeterol plasma concentrations and increased risk for adverse reactions such as nervousness, tremor, or cardiovascular effects. Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the beta-agonists. In a placebo-controlled, drug interaction study of 20 healthy subjects, coadministration of another LABA. salmeterol (50 mcg twice daily), and ketoconazole (400 mg PO once daily) for 7 days resulted in a 16-fold increase in salmeterol AUC. Three of the 20 subjects were withdrawn from the study due to cardiovascular adverse effects (2 with QT prolongation and 1 with palpitations and sinus tachycardia). (Major) Coadministration of ketoconazole and fluticasone may result in increased systemic corticosteroid adverse effects. Per the manufacturer of fluticasone propionate, concurrent use of ketoconazole is not recommended; the manufacturer of fluticasone furoate recommends caution during concurrent use. Coadministration of ketoconazole increases the systemic exposure to fluticasone. Ketoconazole is a strong CYP3A4 inhibitor; fluticasone is a CYP3A4 substrate.
    Fluticasone; Umeclidinium; Vilanterol: (Major) Coadministration of ketoconazole and fluticasone may result in increased systemic corticosteroid adverse effects. Per the manufacturer of fluticasone propionate, concurrent use of ketoconazole is not recommended; the manufacturer of fluticasone furoate recommends caution during concurrent use. Coadministration of ketoconazole increases the systemic exposure to fluticasone. Ketoconazole is a strong CYP3A4 inhibitor; fluticasone is a CYP3A4 substrate. (Major) Use extreme caution when coadministering vilanterol with strong CYP3A4 inhibitors. Vilanterol is a CYP3A4 substrate. The coadministration of vilanterol with strong CYP3A4 inhibitors such as ketoconazole may result in elevated vilanterol plasma concentrations and increased risk for adverse reactions such as nervousness, tremor, or cardiovascular effects. Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the beta-agonists. In a placebo-controlled, drug interaction study of 20 healthy subjects, coadministration of another LABA. salmeterol (50 mcg twice daily), and ketoconazole (400 mg PO once daily) for 7 days resulted in a 16-fold increase in salmeterol AUC. Three of the 20 subjects were withdrawn from the study due to cardiovascular adverse effects (2 with QT prolongation and 1 with palpitations and sinus tachycardia). Similar interactions may occur when ketoconazole is added to vilanterol.
    Fluticasone; Vilanterol: (Major) Coadministration of ketoconazole and fluticasone may result in increased systemic corticosteroid adverse effects. Per the manufacturer of fluticasone propionate, concurrent use of ketoconazole is not recommended; the manufacturer of fluticasone furoate recommends caution during concurrent use. Coadministration of ketoconazole increases the systemic exposure to fluticasone. Ketoconazole is a strong CYP3A4 inhibitor; fluticasone is a CYP3A4 substrate. (Major) Use extreme caution when coadministering vilanterol with strong CYP3A4 inhibitors. Vilanterol is a CYP3A4 substrate. The coadministration of vilanterol with strong CYP3A4 inhibitors such as ketoconazole may result in elevated vilanterol plasma concentrations and increased risk for adverse reactions such as nervousness, tremor, or cardiovascular effects. Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the beta-agonists. In a placebo-controlled, drug interaction study of 20 healthy subjects, coadministration of another LABA. salmeterol (50 mcg twice daily), and ketoconazole (400 mg PO once daily) for 7 days resulted in a 16-fold increase in salmeterol AUC. Three of the 20 subjects were withdrawn from the study due to cardiovascular adverse effects (2 with QT prolongation and 1 with palpitations and sinus tachycardia). Similar interactions may occur when ketoconazole is added to vilanterol.
    Fluvoxamine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and ketoconazole. Ketoconazole has been associated with prolongation of the QT interval. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
    Fomepizole: (Minor) Drugs that inhibit the cytochrome P450 enzyme system, such as ketoconazole, may decrease the rate of elimination of fomepizole.
    Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with ketoconazole. Ketoconazole is an inhibitor of CYP2C9 and CYP3A4, two isoenzymes responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with ketoconazole the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Formoterol: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the beta-agonists. In addition, the long-acting beta agonists (LABAs) indacaterol, vilanterol, salmeterol are CYP3A4 substrates. The coadministration of these LABAs with strong CYP3A4 inhibitors such as ketoconazole may result in elevated LABA plasma concentrations and increased risk for adverse reactions, particularly systemic side effects such as nervousness, tremor, or cardiovascular effects. In a placebo-controlled, drug interaction study of 20 healthy subjects, coadministration of salmeterol (50 mcg twice daily), and ketoconazole (400 mg PO once daily) for 7 days resulted in a 16-fold increase in salmeterol AUC. Three of the 20 subjects were withdrawn from the study due to cardiovascular adverse effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia). An increase in AUC also occurred when ketoconazole was coadministered with indacaterol. Similar interactions may occur when ketoconazole is added to vilanterol, such as umeclidinium; vilanterol.
    Formoterol; Mometasone: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the beta-agonists. In addition, the long-acting beta agonists (LABAs) indacaterol, vilanterol, salmeterol are CYP3A4 substrates. The coadministration of these LABAs with strong CYP3A4 inhibitors such as ketoconazole may result in elevated LABA plasma concentrations and increased risk for adverse reactions, particularly systemic side effects such as nervousness, tremor, or cardiovascular effects. In a placebo-controlled, drug interaction study of 20 healthy subjects, coadministration of salmeterol (50 mcg twice daily), and ketoconazole (400 mg PO once daily) for 7 days resulted in a 16-fold increase in salmeterol AUC. Three of the 20 subjects were withdrawn from the study due to cardiovascular adverse effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia). An increase in AUC also occurred when ketoconazole was coadministered with indacaterol. Similar interactions may occur when ketoconazole is added to vilanterol, such as umeclidinium; vilanterol.
    Fosamprenavir: (Major) Coadministration of fosamprenavir with ketoconazole results in clinically significant increases in ketoconazole plasma concentrations. The dose of ketoconazole should not exceed 200 mg/day if coadministered with fosamprenavir and ritonavir; 400 mg/day if coadministered with fosamprenavir alone. If these drugs are coadministered, patients should be monitored for adverse events due to ketoconazole.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as ketoconazole. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Ketoconazole has also been associated with prolongation of the QT interval. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Fosphenytoin: (Moderate) Phenytoin is a known hepatic enzyme inducer, while ketoconazole inhibits hepatic metabolism. Although data suggest no interaction occurs when these agents are administered concomitantly, metabolism of either or both medications may be altered. Serum concentrations of phenytoin can increase, and time to peak ketoconazole serum concentrations can be delayed. Serum phenytoin levels should be closely monitored if ketoconazole is added to phenytoin or fosphenytoin therapy.
    Galantamine: (Moderate) Galantamine is a primary substrate of CYP3A4 and the bioavailability of galantamine may be increased when coadministered with strong CYP3A4 inhibitors, such as ketoconazole. In one pharmacokinetic study, ketoconazole administered at a dose of 200 mg two times a day for 4 days increased the AUC of galantamine by 30%. Monitor patients for galantamine-related adverse effects such as nausea, vomiting, diarrhea, headache, loss of appetite, excess sweating, and confusion during use of this combination.
    Gefitinib: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and ketoconazole are used concomitantly. Gefitinib is metabolized significantly by CYP3A4 and ketoconazole is a strong CYP3A4 inhibitor; coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%.
    Gemifloxacin: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include gemifloxacin.
    Gemtuzumab Ozogamicin: (Major) Use gemtuzumab ozogamicin and ketoconazole together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Ketoconazole has been associated with prolongation of the QT interval.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and ketoconazole as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of P-glycoprotein (P-gp); ketoconazole is a P-gp inhibitor. (Moderate) Caution is advised with the coadministration of pibrentasvir and ketoconazole as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of P-glycoprotein (P-gp); ketoconazole is an inhibitor of P-gp.
    Glimepiride: (Moderate) Hypoglycemia, sometimes severe, has been reported when ketoconazole is coadministered with oral hypoglycemic agents. The most likely mechanism for this interaction is inhibition of the CYP450 metabolism of oral hypoglycemics by ketoconazole. Blood glucose concentrations should be monitored during concomitant treatment; patients should be aware of the symptoms of hypoglycemia. In some cases, dosage adjustment of the sulfonylurea may be necessary. There is no evidence that an interaction occurs between oral hypoglycemics and topical or vaginal azole antifungal preparations.
    Glimepiride; Pioglitazone: (Moderate) Hypoglycemia, sometimes severe, has been reported when ketoconazole is coadministered with oral hypoglycemic agents. The most likely mechanism for this interaction is inhibition of the CYP450 metabolism of oral hypoglycemics by ketoconazole. Blood glucose concentrations should be monitored during concomitant treatment; patients should be aware of the symptoms of hypoglycemia. In some cases, dosage adjustment of the sulfonylurea may be necessary. There is no evidence that an interaction occurs between oral hypoglycemics and topical or vaginal azole antifungal preparations. (Moderate) Ketoconazole appears to significantly inhibit the metabolism of pioglitazone. It is recommended that patients receiving both pioglitazone and ketoconazole be evaluated more frequently with respect to glycemic control.
    Glimepiride; Rosiglitazone: (Moderate) Hypoglycemia, sometimes severe, has been reported when ketoconazole is coadministered with oral hypoglycemic agents. The most likely mechanism for this interaction is inhibition of the CYP450 metabolism of oral hypoglycemics by ketoconazole. Blood glucose concentrations should be monitored during concomitant treatment; patients should be aware of the symptoms of hypoglycemia. In some cases, dosage adjustment of the sulfonylurea may be necessary. There is no evidence that an interaction occurs between oral hypoglycemics and topical or vaginal azole antifungal preparations. (Moderate) If ketoconazole and rosiglitazone are to be coadministered, patients should be closely monitored. A pharmacokinetic study found that the administration of rosiglitazone to subjects who had been receiving ketoconazole resulted in increased rosiglitazone AUC, peak plasma concentrations, and half-life, and decreased rosiglitazone clearance. The clinical significance (i.e., altered blood glucose concentrations) of this interaction is unknown.
    Glipizide: (Moderate) Hypoglycemia, sometimes severe, has been reported when ketoconazole is coadministered with oral hypoglycemic agents. The most likely mechanism for this interaction is inhibition of the CYP450 metabolism of oral hypoglycemics by ketoconazole. Blood glucose concentrations should be monitored during concomitant treatment; patients should be aware of the symptoms of hypoglycemia. In some cases, dosage adjustment of the sulfonylurea may be necessary. There is no evidence that an interaction occurs between oral hypoglycemics and topical or vaginal azole antifungal preparations.
    Glipizide; Metformin: (Moderate) Hypoglycemia, sometimes severe, has been reported when ketoconazole is coadministered with oral hypoglycemic agents. The most likely mechanism for this interaction is inhibition of the CYP450 metabolism of oral hypoglycemics by ketoconazole. Blood glucose concentrations should be monitored during concomitant treatment; patients should be aware of the symptoms of hypoglycemia. In some cases, dosage adjustment of the sulfonylurea may be necessary. There is no evidence that an interaction occurs between oral hypoglycemics and topical or vaginal azole antifungal preparations.
    Glyburide: (Moderate) Hypoglycemia, sometimes severe, has been reported when ketoconazole is coadministered with oral hypoglycemic agents. The most likely mechanism for this interaction is inhibition of the CYP450 metabolism of oral hypoglycemics by ketoconazole. Blood glucose concentrations should be monitored during concomitant treatment; patients should be aware of the symptoms of hypoglycemia. In some cases, dosage adjustment of the sulfonylurea may be necessary. There is no evidence that an interaction occurs between oral hypoglycemics and topical or vaginal azole antifungal preparations.
    Glyburide; Metformin: (Moderate) Hypoglycemia, sometimes severe, has been reported when ketoconazole is coadministered with oral hypoglycemic agents. The most likely mechanism for this interaction is inhibition of the CYP450 metabolism of oral hypoglycemics by ketoconazole. Blood glucose concentrations should be monitored during concomitant treatment; patients should be aware of the symptoms of hypoglycemia. In some cases, dosage adjustment of the sulfonylurea may be necessary. There is no evidence that an interaction occurs between oral hypoglycemics and topical or vaginal azole antifungal preparations.
    Glycopyrrolate; Formoterol: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the beta-agonists. In addition, the long-acting beta agonists (LABAs) indacaterol, vilanterol, salmeterol are CYP3A4 substrates. The coadministration of these LABAs with strong CYP3A4 inhibitors such as ketoconazole may result in elevated LABA plasma concentrations and increased risk for adverse reactions, particularly systemic side effects such as nervousness, tremor, or cardiovascular effects. In a placebo-controlled, drug interaction study of 20 healthy subjects, coadministration of salmeterol (50 mcg twice daily), and ketoconazole (400 mg PO once daily) for 7 days resulted in a 16-fold increase in salmeterol AUC. Three of the 20 subjects were withdrawn from the study due to cardiovascular adverse effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia). An increase in AUC also occurred when ketoconazole was coadministered with indacaterol. Similar interactions may occur when ketoconazole is added to vilanterol, such as umeclidinium; vilanterol.
    Goserelin: (Major) Ketoconazole should be used cautiously and with close monitoring with goserelin. Ketoconazole has been associated with prolongation of the QT interval. Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Granisetron: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as granisetron. Both granisetron and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with granisetron (a CYP3A4 substrate) may result in elevated granisetron plasma concentrations and an increased risk for adverse events, including QT prolongation.
    Green Tea: (Moderate) Ketoconazole decreases the metabolism of caffeine via CYP1A2 and exaggerated effects of caffeine may be expected. During concomitant therapy with ketoconazole, it may be prudent to limit or avoid caffeine containing products such as green tea an effort to minimize caffeine-related side effects.
    Guaifenesin; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and ketoconazole are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and ketoconazole are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Guanfacine: (Major) Ketoconazole may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon ketoconazole discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and ketoconazole is a strong CYP3A4 inhibitor.
    Guarana: (Moderate) Caffeine is an active component of guarana. Inhibitors of the hepatic CYP450 isoenzyme CYP1A2, may inhibit the hepatic oxidative metabolism of caffeine. Ketoconazole, a CYP1A2 inhibitor, has been shown to inhibit the clearance of caffeine by 11%. No specific management is recommended except in patients who complain of caffeine-related side effects like nausea, tremor, or palpitations. Such patients should reduce their intake of guarana.
    H2-blockers: (Major) Ketoconazole requires an acidic pH for absorption. Medications that increase gastric pH or decrease acid output can cause a notable decrease in the bioavailability of ketoconazole. Medications that have this effect are antacids, antimuscarinics, histamine H2-blockers, and proton pump inhibitors (PPIs). Except for antacids, these medications have a prolonged duration of action, and staggering their time of administration with ketoconazole by several hours may not prevent the drug interaction. An alternative imidazole antifungal should be chosen if any of these gastrointestinal medications are required. If these drugs must be coadministered, administer ketoconazole tablets with an acidic beverage and closely monitor for breakthrough infection.
    Halofantrine: (Moderate) Drugs which significantly inhibit cytochrome CYP3A4, such as ketoconazole, may lead to an inhibition of halofantrine metabolism, placing the patient at risk for halofantrine cardiac toxicity. If concurrent use of halofantrine and a CYP3A4 inhibitor is warranted, it would be prudent to use caution and monitor the ECG periodically.
    Halogenated Anesthetics: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include halogenated anesthetics.
    Haloperidol: (Major) It is best to avoid ketoconazole with haloperidol. Haloperidol is primarily metabolized by CYP2D6. However, in patients that are lacking in CYP2D6 enzyme activity (slow metabolizers), the CYP3A4 enzyme plays a larger role in haloperidol metabolism. Concurrent use of ketoconazole (a potent inhibitor of CYP3A4) with haloperidol is likely to result in increased serum haloperidol concentrations; inhibition of haloperidol CYP3A4 metabolism is the suspected mechanism of the interaction. Increases in QTc have been observed during concurrent use of haloperidol with ketoconazole. Both ketoconazole and haloperidol have been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. If use of these drugs is medically necessary, a reduced haloperidol dosage may be required.
    Halothane: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include halogenated anesthetics.
    Homatropine; Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and ketoconazole are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone: (Major) Monitor for respiratory depression and sedation if hydrocodone and ketoconazole are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Ibuprofen: (Major) Monitor for respiratory depression and sedation if hydrocodone and ketoconazole are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Phenylephrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and ketoconazole are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Monitor for respiratory depression and sedation if hydrocodone and ketoconazole are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and ketoconazole are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydrocodone; Pseudoephedrine: (Major) Monitor for respiratory depression and sedation if hydrocodone and ketoconazole are coadministered; consider dosage adjustments if necessary. Hydrocodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in hydrocodone plasma concentrations, which could increase or prolong adverse effects.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and ketoconazole. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes have been reported with the use of hydroxychloroquine. Ketoconazole has been associated with prolongation of the QT interval.
    Hydroxyprogesterone: (Minor) In vitro data indicate that the metabolism of hydroxyprogesterone is predominantly mediated by CYP3A4 and CYP3A5. The metabolism of progesterone is inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes. Theoretically, the metabolism of hydroxyprogesterone may also be inhibited by ketoconazole.
    Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include ketoconazole.
    Ibrutinib: (Major) Avoid the concomitant use of ibrutinib and ketoconazole; ibrutinib plasma concentrations are increased and severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection) may occur. If short-term use (i.e., 7 days or less) of ketoconazole is necessary, hold ibrutinib therapy until after ketoconazole is discontinued. Ibrutinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of ketoconazole, the Cmax and AUC values of ibrutinib increased by 29-fold and 24-fold, respectively.
    Ibuprofen; Oxycodone: (Major) Oxycodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in oxycodone plasma concentrations, which could increase or prolong adverse effects and may cause potentially fatal respiratory depression. If coadministration of these agents is necessary, patients should be monitored for an extended period of time and dosage adjustments made if warranted.
    Ibutilide: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include ibutilide.
    Idarubicin: (Major) Ketoconazole has been associated with prolongation of the QT interval. Acute cardiotoxicity can occur during administration of daunorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Idelalisib: (Severe) Concomitant use of idelalisib, a CYP3A4 substrate, and ketoconazole, a strong CYP3A4 inhibitor, may increase the exposure of idelalisib. In healthy subjects, ketoconazole 400 mg administered daily for 4 days increased the geometric mean AUC of idelalisib by 1.8-fold. No changes to the geometric mean Cmax were observed. Additionally, idelalisib is a strong CYP3A inhibitor while ketoconazole is a CYP3A substrate. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. Avoid concomitant use of idelalisib and ketoconazole.
    Ifosfamide: (Major) The concomitant use of ifosfamide, a CYP3A4 substrate, and ketoconazole, a strong CYP3A4 inhibitor and substrate, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced. A small pharmacokinetic trial (n=12) examined the effects of ketoconazole on the pharmacokinetics of ifosfamide. In a double-randomized, 2-way crossover study, patients received ifosfamide 3 grams/m2/day IV either alone or in combination with 200 mg ketoconazole twice daily (1 day prior and 3 days concurrently). Ketoconazole did not affect the fraction of metabolized or the exposure to the dechlorethylated metabolites; however, the metabolism and exposure to the active 4-hydroxyifosfamide metabolite were reduced.
    Iloperidone: (Major) Avoid concurrent administration of ketoconazole and iloperidone. If concurrent use is necessary, the iloperidone dose should be reduced by one-half. If ketoconazole is subsequently withdrawn, the iloperidone dose should be returned to the previous amount. Both iloperidone and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with iloperidone (a CYP3A4 substrate) results in elevated iloperidone plasma concentrations and may increase the risk for adverse events, including QT prolongation. In one study, concurrent use of ketoconazole (200 mg twice daily for 4 days) and iloperidone (3 mg single dose) resulted in an increase in AUC of iloperidone and its metabolites P88 and P95 by 57%, 55%, and 35%, respectively. In a separate study of combination therapy with iloperidone, paroxetine, and ketoconazole, the steady-state concentrations of iloperidone and its metabolite P88 increased by 1.4-fold and steady-state concentrations of the iloperidone metabolite P95 were decreased by 1.4-fold. Results of this study indicate that inhibiting both metabolic pathways of iloperidone does not add to the effect of giving each inhibitor alone.
    Imatinib: (Major) Agents that inhibit cytochrome P450 3A4, such as ketoconazole, decrease imatinib, STI-571 metabolism and increase concentrations leading to toxicity. There was a significant increase in imatinib Cmax and AUC (26% and 40%, respectively) in healthy subjects when imatinib was given with a single dose of ketoconazole.
    Imipramine: (Minor) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; ketoconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope have occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred. Close clinical monitoring is necessary if concurrent use is medically necessary.
    Indacaterol: (Major) Although no dosage adjustment of the 75 mcg/day indacaterol dose is needed, avoid use together if possible; consider alternative therapy. By inhibiting CYP3A4 and P-gp, ketoconazole inhibits indacaterol metabolism. In drug interaction studies, coadministration of indacaterol inhalation powder 300 mcg (single dose) with ketoconazole (200 mcg bid for 7 days) caused a 1.9-fold increase in indacaterol expisure (AUC), and a 1.3-fold increase in indacaterol maximal concentration (Cmax). This may result in indacaterol side effects like tremor, nervousness, or a fast, irregular heart rate. Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Indacaterol; Glycopyrrolate: (Major) Although no dosage adjustment of the 75 mcg/day indacaterol dose is needed, avoid use together if possible; consider alternative therapy. By inhibiting CYP3A4 and P-gp, ketoconazole inhibits indacaterol metabolism. In drug interaction studies, coadministration of indacaterol inhalation powder 300 mcg (single dose) with ketoconazole (200 mcg bid for 7 days) caused a 1.9-fold increase in indacaterol expisure (AUC), and a 1.3-fold increase in indacaterol maximal concentration (Cmax). This may result in indacaterol side effects like tremor, nervousness, or a fast, irregular heart rate. Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Indinavir: (Major) Due to effects on CYP3A4, the combination of indinavir and ketoconazole may result in changes in the concentrations of both drugs. During coadministration, the indinavir dose should be decreased to 600 mg every 8 hours.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with ketoconazole due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Both inotuzumab and ketoconazole have been associated with QT prolongation.
    Irinotecan Liposomal: (Major) If possible, avoid concomitant use of irinotecan liposomal with ketoconazole, a strong CYP3A4 and UGT1A1 inhibitor, due to increased risk of irinotecan-related toxicity. Discontinue ketoconazole at least 1 week prior to initiation of liposomal irinotecan therapy. The metabolism of liposomal irinotecan has not been evaluated; however, coadministration of ketoconazole with non-liposomal irinotecan HCl resulted in increased exposure to both irinotecan and its active metabolite, SN-38.
    Irinotecan: (Major) Ketoconazole is a strong CYP3A4 inhibitor and an inhibitor of UGT1A1; irinotecan is a CYP3A4 and UGT1A1 substrate. Exposure to irinotecan and to the active metabolite, SN-38, is increased when the drugs are used together. Discontinue ketoconazole at least 1 week before starting irinotecan. Do not administer ketoconazole concurrently with irinotecan unless there are no therapeutic alternatives. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Isavuconazonium: (Severe) Concomitant use of isavuconazonium with ketoconazole is contraindicated due to the risk for increased isavuconazole serum concentrations and serious adverse reactions, such as hepatic toxicity. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of hepatic isoenzyme CYP3A4; ketoconazole is a strong inhibitor of this enzyme. According to the manufacturer, coadministration of isavuconazole with strong CYP3A4 inhibitors is contraindicated. Isavuconazole serum concentrations were increased 5-fold when codadministered with ketoconazole. Elevated ketoconazole concentrations would also be expected with coadministration, as ketoconazole is a CYP3A4 substrate and isavuconazole is a moderate CYP3A4 inhibitor.
    Isoflurane: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include halogenated anesthetics.
    Isoniazid, INH: (Major) Avoid the concomitant use of isonazid for 2 weeks before and during treatment with ketoconazole. Isoniazid may decrease the biovailability of ketoconazole resulting in antifungal treatment failure. If coadministration is necessary, monitor the antifungal activity of ketoconazole and increase the dose as necessary.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the concomitant use of isonazid for 2 weeks before and during treatment with ketoconazole. Isoniazid may decrease the biovailability of ketoconazole resulting in antifungal treatment failure. If coadministration is necessary, monitor the antifungal activity of ketoconazole and increase the dose as necessary. (Major) Ketoconazole and rifampin each affect the pharmacokinetics of the other. Ketoconazole has been shown to reduce serum concentrations of rifampin but the clinical significance of this effect on rifampin concentrations is not known. More significant are the effects of rifampin on ketoconazole pharmacokinetics. Rifampin is a potent inducer of hepatic microsomal enzymes. When rifampin is used in combination with isoniazid, INH, isoniazid appears to intensify the effect of rifampin on the pharmacokinetics of other drugs, despite the fact that isoniazid is generally considered an inhibitor of drug metabolism. The effects of isoniazid with rifampin on ketoconazole have been significant enough to result in antifungal treatment failure. Ketoconazole doses may need to be increased if rifampin, or the combination of rifampin with isoniazid, is used concomitantly. However, it is generally not recommended that ketoconazole be used with INH or rifampin.
    Isoniazid, INH; Rifampin: (Major) Avoid the concomitant use of isonazid for 2 weeks before and during treatment with ketoconazole. Isoniazid may decrease the biovailability of ketoconazole resulting in antifungal treatment failure. If coadministration is necessary, monitor the antifungal activity of ketoconazole and increase the dose as necessary. (Major) Ketoconazole and rifampin each affect the pharmacokinetics of the other. Ketoconazole has been shown to reduce serum concentrations of rifampin but the clinical significance of this effect on rifampin concentrations is not known. More significant are the effects of rifampin on ketoconazole pharmacokinetics. Rifampin is a potent inducer of hepatic microsomal enzymes. When rifampin is used in combination with isoniazid, INH, isoniazid appears to intensify the effect of rifampin on the pharmacokinetics of other drugs, despite the fact that isoniazid is generally considered an inhibitor of drug metabolism. The effects of isoniazid with rifampin on ketoconazole have been significant enough to result in antifungal treatment failure. Ketoconazole doses may need to be increased if rifampin, or the combination of rifampin with isoniazid, is used concomitantly. However, it is generally not recommended that ketoconazole be used with INH or rifampin.
    Isradipine: (Moderate) Ketoconazole may decrease the clearance of calcium-channel blockers, such as isradipine, via inhibition of CYP3A4 metabolism.
    Itraconazole: (Major) Typically voriconazole would not be used in combination with other systemic azole antifungal agents due to similar mechanisms of action and indications for use (duplicate therapies). Itraconazole has the potential to exhibit multiple hepatic cytochrome P450 interactions with voriconazole. Serum concentrations of voriconazole or itraconazole may increase or decrease. Furthermore, all systemic azole antifungal agents (fluconazole, itraconazole, ketoconazole, posaconazole, and voriconazole) have been associated with prolongation of the QT interval. Coadministration would increase the risk of QT prolongation.
    Ivabradine: (Severe) Coadministration of ivabradine and ketoconazole is contraindicated. Ivabradine is primarily metabolized by CYP3A4; ketoconazole is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ivacaftor: (Major) If ketoconazole and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg twice weekly). Ivacaftor is a CYP3A substrate. Coadministration with ketoconazole, a strong CYP3A inhibitor, increased ivacaftor exposure by 8.5-fold. Ivacaftor is also an inhibitor of CYP3A; ketoconazole is metabolized by CYP3A4. Coadministration may increase ketoconazole exposure leading to increased or prolonged therapeutic effects and adverse events.
    Ixabepilone: (Major) Ixabepilone is a CYP3A4 substrate, and concomitant use of ixabepilone with strong CYP3A4 inhibitors such as ketoconazole should be avoided. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. If concurrent treatment with a strong CYP3A4 inhibitor is necessary, strongly consider an ixabepilone dose reduction. Closely monitor patients for ixabepilone-related toxicities. If a strong CYP3A4 inhibitor is discontinued, allow 7 days to elapse before increasing the ixabepilone dose
    Lacosamide: (Moderate) Use caution during concurrent use of lacosamide and ketoconazole, particularly in patients with renal or hepatic impairment. Lacosamide is a CYP3A4 substrate; ketoconazole is a potent inhibitor of CYP3A4. Patients with renal or hepatic impairment may have significantly increased exposure to lacosamide if coadminsitered with a strong CYP3A4 inhibitor. Dosage reduction of lacosamide may be necessary in this population.
    Lapatinib: (Major) Avoid concurrent administration of ketoconazole and lapatinib. If concurrent treatment is necessary, strongly consider a lapatinib dose reduction. If ketoconazole is discontinued, allow 7 days to elapse before increasing the lapatinib dose. Both lapatinib and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with lapatinib (a CYP3A4 substrate) results in elevated lapatinib plasma concentrations and may increase the risk for adverse events, including QT prolongation. When given concomitantly with ketoconazole 200 mg twice daily for 7 days, lapatinib AUC was increased by approximately 3.6-fold and the half-life was increased by 1.7-fold.
    Leflunomide: (Moderate) A pharmacodynamic interaction may occur when leflunomide is given concomitantly with other hepatotoxic drugs, such as ketoconazole, The potential for hepatotoxicity should also be considered when ketoconazole would be prescribed after leflunomide administration has ceased, if the patient has not received the leflunomide elimination procedure.
    Lenvatinib: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include lenvatinib. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects.
    Lesinurad: (Moderate) Use lesinurad and ketoconazole together with caution; ketoconazole may increase the systemic exposure of lesinurad. Ketoconazole is a mild inhibitor of CYP2C9 in vitro and lesinurad is a CYP2C9 substrate.
    Lesinurad; Allopurinol: (Moderate) Use lesinurad and ketoconazole together with caution; ketoconazole may increase the systemic exposure of lesinurad. Ketoconazole is a mild inhibitor of CYP2C9 in vitro and lesinurad is a CYP2C9 substrate.
    Leuprolide: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include ketoconazole.
    Leuprolide; Norethindrone: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include ketoconazole.
    Levalbuterol: (Minor) Coadministration may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists such as albuterol.
    Levofloxacin: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include levofloxacin.
    Levomethadyl: (Major) Ketoconazole inhibits hepatic cytochrome P450 CYP3A4 and may decrease the metabolism of levomethadyl, increase levomethadyl levels, and may precipitate severe arrhythmias including torsade de pointes.
    Levomilnacipran: (Major) The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors such as ketoconazole. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention. A clinically significant increase in levomilnacipran exposure occurred during co-administration with ketoconazole.
    Lidocaine: (Moderate) Concomitant use of systemic lidocaine and ketoconazole may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; ketoconazole inhibits CYP3A4.
    Lithium: (Major) Lithium should be used cautiously and with close monitoring with ketoconazole. Both ketoconazole and lithium have been associated with prolongation of the QT interval.
    Lomitapide: (Severe) Concomitant use of ketoconazole and lomitapide is contraindicated. If treatment with ketoconazole is unavoidable, lomitapide should be stopped during the course of treatment. The exposure to lomitapide was increased 27-fold in the presence of ketoconazole, a strong CYP3A4 inhibitor.
    Loperamide: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as loperamide. Ketoconazole has been associated with QT prolongation; at high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest. Use of these drugs together may increase this risk. In addition, coadministration of ketoconazole (a CYP3A4 inhibitor) with loperamide (a CYP3A4 substrate) may result in elevated loperamide plasma concentrations and could increase the risk for adverse events, including QT prolongation. If these drugs are given together, closely monitor for prolongation of the QT interval.
    Loperamide; Simethicone: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as loperamide. Ketoconazole has been associated with QT prolongation; at high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest. Use of these drugs together may increase this risk. In addition, coadministration of ketoconazole (a CYP3A4 inhibitor) with loperamide (a CYP3A4 substrate) may result in elevated loperamide plasma concentrations and could increase the risk for adverse events, including QT prolongation. If these drugs are given together, closely monitor for prolongation of the QT interval.
    Lopinavir; Ritonavir: (Major) When administering ketoconazole with lopinavir; ritonavir, do not exceed the maximum recommended ketoconazole dose of 200 mg per day. Concurrent administration of lopinavir; ritonavir (a potent CYP3A4 inhibitor) with ketoconazole (a CYP3A4 substrate) significantly increases ketoconazole systemic concentrations. In one drug interaction study, ketoconazole exposure was increased by 4-fold when given concurrently with lopinavir; ritonavir. In addition, because both drugs are associated with prolongation of the QT interval, coadministration may increase the risk for developing QT prolongation. If these drugs are given together, closely monitor patients for ketoconazole-associated adverse effects, including QT prolongation. (Major) When administering ketoconazole with ritonavir or ritonavir-containing drugs, do not exceed the maximum recommended ketoconazole dose of 200 mg per day. Concurrent administration of ritonavir (a potent CYP3A4 inhibitor) with ketoconazole (a CYP3A4 substrate) significantly increases ketoconazole systemic concentrations. In one drug interaction study, ketoconazole exposure was increased by 3.4-fold when given concurrently with ritonavir (500 mg twice daily). In addition, because both drugs are associated with prolongation of the QT interval, coadministration may increase the risk for developing QT prolongation. If these drugs are given together, closely monitor patients for ketoconazole-associated adverse effects, including QT prolongation.
    Loratadine: (Minor) Ketoconazole has been shown to interfere with the metabolism of loratadine, probably through inhibition of the CYP3A4 isozyme, resulting in increased serum concentrations of loratadine and its metabolite.
    Loratadine; Pseudoephedrine: (Minor) Ketoconazole has been shown to interfere with the metabolism of loratadine, probably through inhibition of the CYP3A4 isozyme, resulting in increased serum concentrations of loratadine and its metabolite.
    Lovastatin: (Severe) Concurrent use of lovastatin and ketoconazole is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is substantially increased if lovastatin is administered concomitantly with strong CYP3A4 inhibitors including ketoconazole. If no alternative to a short course of treatment with ketoconazole is available, a brief suspension of lovastatin therapy during such treatment can be considered as there are no known adverse consequences to brief interruptions of long-term cholesterol-lowering therapy.
    Lovastatin; Niacin: (Severe) Concurrent use of lovastatin and ketoconazole is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is substantially increased if lovastatin is administered concomitantly with strong CYP3A4 inhibitors including ketoconazole. If no alternative to a short course of treatment with ketoconazole is available, a brief suspension of lovastatin therapy during such treatment can be considered as there are no known adverse consequences to brief interruptions of long-term cholesterol-lowering therapy.
    Lumacaftor; Ivacaftor: (Major) If ketoconazole and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg twice weekly). Ivacaftor is a CYP3A substrate. Coadministration with ketoconazole, a strong CYP3A inhibitor, increased ivacaftor exposure by 8.5-fold. Ivacaftor is also an inhibitor of CYP3A; ketoconazole is metabolized by CYP3A4. Coadministration may increase ketoconazole exposure leading to increased or prolonged therapeutic effects and adverse events.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of ketoconazole; avoid concomitant use if possible. Consider alternative antifungals such as fluconazole. If concomitant use of ketoconazole is necessary, monitor for antifungal efficacy and adjust the dosage as appropriate. Lumacaftor; ivacaftor dosage adjustment is not required when ketoconazole is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking ketoconazole, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking ketoconazole. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Ketoconazole is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of ketoconazole and decrease its therapeutic efficacy. Although ketoconazole is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with itraconazole, another strong CYP3A4 inhibitor, increased ivacaftor exposure by 4.3-fold.
    Lurasidone: (Severe) Concurrent use of lurasidone with strong CYP3A4 inhibitors, such as ketoconazole, is contraindicated. Lurasidone is primarily metabolized by CYP3A4. Increased lurasidone plasma concentrations are expected when the drug is co-administered with inhibitors of CYP3A4. When a single dose of lurasidone 10 mg was co-administered with ketoconazole 400 mg/day for 5 days, the lurasidone Cmax and AUC increased by 6.9-times and 9-times, respectively.
    Macitentan: (Major) Avoid concurrent use of macitentan and ketoconazole. Ketoconazole is a strong inhibitor of CYP3A4. Coadminsitration with macitentan approximately doubles macitentan exposure. Consider alternative treatment options for pulmonary hypertension if treatment with ketoconazole is necessary.
    Maprotiline: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as maprotiline. Both maprotiline and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with maprotiline (a CYP3A4 substrate) may result in elevated maprotiline plasma concentrations and an increased risk for adverse events, including QT prolongation.
    Maraviroc: (Major) Coadministration of maraviroc, a CYP3A/P-gp substrate, with ketoconazole, a strong CYP3A4 inhibitor and P-gp inhibitor, may result in increased maraviroc concentrations. Reduce the dose of maraviroc when coadministered with strong CYP3A inhibitors; coadministration of maraviroc with strong CYP3A inhibitors is contraindicated in patients with CrCl less than 30 mL/min. Adjust the maraviroc dosage as follows when administered with ketoconazole (with or without a concomitant CYP3A inducer): adults and children weighing 40 kg or more: 150 mg PO twice daily; children weighing 30 to 39 kg: 100 mg PO twice daily; children weighing 20 to 29 kg: 75 mg PO twice daily (or 80 mg PO twice daily for solution); children weighing 10 to 19 kg: 50 mg PO twice daily.
    Medroxyprogesterone: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with ketoconazole, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro.
    Mefloquine: (Severe) Ketoconazole should not be administered with mefloquine or within 15 weeks of the last dose of mefloquine due to the risk of fatal QT prolongation. Mefloquine and ketoconazole are both associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with mefloquine (a CYP3A4 substrate) may result in elevated mefloquine plasma concentrations and an increased risk for adverse events, including QT prolongation. In healthy volunteers receiving both drugs, ketoconazole increased mefloquine AUC by 79%, half-life by 39%, and Cmax by 64%.
    Meglitinides: (Moderate) Hypoglycemia, sometimes severe, has been reported when ketoconazole is coadministered with oral hypoglycemic agents (i.e., repaglinide, nateglinide). The most likely mechanism of this interaction is ketoconazole-mediated inhibition of the metabolism of these agents. When coadministered, ketoconazole increases the AUC and Cmax of repaglinide by 15% and 26%, respectively. Patients should be monitored for signs and symptoms of hypoglycemia if ketoconazole is added to oral hypoglycemic therapy. There is no evidence that an interaction occurs between oral hypoglycemics and topical azole antifungal preparations.
    Mepenzolate: (Moderate) Antimuscarinic drugs can raise intragastric pH. Since ketoconazole requires an acidic environment for absorption, the bioavailability of ketoconazole may be reduced when combined with mepenzolate.
    Meperidine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include ketoconazole.
    Metaproterenol: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the beta-agonists. In addition, the long-acting beta agonists (LABAs) indacaterol, vilanterol, salmeterol are CYP3A4 substrates. The coadministration of these LABAs with strong CYP3A4 inhibitors such as ketoconazole may result in elevated LABA plasma concentrations and increased risk for adverse reactions, particularly systemic side effects such as nervousness, tremor, or cardiovascular effects. In a placebo-controlled, drug interaction study of 20 healthy subjects, coadministration of salmeterol (50 mcg twice daily), and ketoconazole (400 mg PO once daily) for 7 days resulted in a 16-fold increase in salmeterol AUC. Three of the 20 subjects were withdrawn from the study due to cardiovascular adverse effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia). An increase in AUC also occurred when ketoconazole was coadministered with indacaterol. Similar interactions may occur when ketoconazole is added to vilanterol, such as umeclidinium; vilanterol.
    Metformin; Pioglitazone: (Moderate) Ketoconazole appears to significantly inhibit the metabolism of pioglitazone. It is recommended that patients receiving both pioglitazone and ketoconazole be evaluated more frequently with respect to glycemic control.
    Metformin; Repaglinide: (Moderate) Hypoglycemia, sometimes severe, has been reported when ketoconazole is coadministered with oral hypoglycemic agents (i.e., repaglinide, nateglinide). The most likely mechanism of this interaction is ketoconazole-mediated inhibition of the metabolism of these agents. When coadministered, ketoconazole increases the AUC and Cmax of repaglinide by 15% and 26%, respectively. Patients should be monitored for signs and symptoms of hypoglycemia if ketoconazole is added to oral hypoglycemic therapy. There is no evidence that an interaction occurs between oral hypoglycemics and topical azole antifungal preparations.
    Metformin; Rosiglitazone: (Moderate) If ketoconazole and rosiglitazone are to be coadministered, patients should be closely monitored. A pharmacokinetic study found that the administration of rosiglitazone to subjects who had been receiving ketoconazole resulted in increased rosiglitazone AUC, peak plasma concentrations, and half-life, and decreased rosiglitazone clearance. The clinical significance (i.e., altered blood glucose concentrations) of this interaction is unknown.
    Metformin; Saxagliptin: (Major) Saxagliptin is a p-glycoprotein substrate, and the metabolism of saxagliptin is primarily mediated by CYP3A4/5. Ketoconazole is a strong inhibitor of both p-glycoprotein and CYP3A4/5. Saxagliptin did not meaningfully alter the pharmacokinetics of ketoconazole, but coadministration increased the maximum serum saxagliptin concentration by 62% and the systemic exposure by 2.5-fold. As expected, the maximum serum concentration of the saxagliptin active metabolite was decreased by 95% and the systemic exposure was decreased by 91%. In another study, the maximum serum saxagliptin concentration increased by 2.4-fold and the systemic exposure increased by 3.4-fold. The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP 3A4/5 inhibitor such as ketoconazole.
    Methadone: (Severe) Concomitant use of ketoconazole with methadone is contraindicated due to the risk of serious adverse events, such as QT prolongation, torsade de pointes, and respiratory and/or CNS depression. If coadministered, ketoconazole may inhibit the CYP3A4 metabolism of methadone, resulting in elevated methadone plasma concentrations. Furthermore, ketoconazole in itself can prolong the QT interval. Coadministration with methadone can increase the risk for QT prolongation.
    Methylergonovine: (Severe) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as ketoconazole, is contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, and/or other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
    Methylprednisolone: (Moderate) Ketoconazole can decrease the hepatic clearance of methylprednisolone, resulting in increased plasma concentrations. The interaction may be due to the inhibition of CYP3A4 by ketoconazole, and subsequent decreases in corticosteroid metabolism by the same isoenzyme. Prednisolone and prednisone pharmacokinetics appear less susceptible than methylprednisolone to CYP3A4 inhibitory interactions. Ketoconazole also can enhance the adrenal suppressive effects of corticosteroids.
    Methysergide: (Severe) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as ketoconazole, is contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, and/or other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
    Metronidazole: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include metronidazole. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Midazolam: (Severe) Concomitant use of ketoconazole with oral midazolam and triazolam is contraindicated due to the risk of serious adverse events, such as prolonged hypnotic and/or sedative effects. Ketoconazole has been shown to dramatically inhibit the hepatic metabolism of midazolam and triazolam in healthy volunteers. Because the interaction with midazolam occurred with oral midazolam, the significance of an interaction between ketoconazole and IV midazolam is uncertain but may be less significant due to absence of an effect on pre-systemic midazolam clearance. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with ketoconazole, as these benzodiazepines are not oxidatively metabolized.
    Midostaurin: (Major) Avoid the concomitant use of midostaurin and ketoconazole as significantly increased exposure of midostaurin and its active metabolites may occur resulting in increased toxicity. Coadministration may also increase the risk of QT prolongation. Consider an alternative agent to replace ketoconazole. If coadministration cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Consider interval assessments of QT by EKG. Midostaurin is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin (50 mg on day 6) was administered in combination with ketoconazole (400 mg/day on days 1 to 10) in a placebo-controlled, drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
    Mifepristone, RU-486: (Major) Avoid coadministration of ketoconazole with mifepristone (RU-486) because it can result in increased serum concentrations of either drug and an increased risk of QT prolongation. Both mifepristone and ketoconazole have been associated with QT prolongation. Coadministration may result in increased serum concentrations further increasing this risk. The CYP3A4 metabolism of mifepristone could be theoretically inhibited by the ketoconazole, a strong CYP3A4 inhibitor. In addition, mifepristone inhibits CYP3A4 in vitro and may lead to an increase in serum concentrations of CYP3A4 substrates, such as ketoconazole. When mifepristone is used in the treatment of Cushing's syndrome, coadministration with strong CYP3A inhibitors should be done only when necessary, and in such cases the dose of mifepristone should be limited to 600 mg per day. In a patient already receiving ketoconazole, initiate mifepristone at a dose of 300 mg and titrate to a maximum of 600 mg if clinically indicated. If therapy with ketoconazole is initiated in a patient already receiving mifepristone 300 mg, dosage adjustments are not required. If therapy with ketoconazole is initiated in a patient already receiving mifepristone 600 mg, reduce dose of mifepristone to 300 mg and titrate to a maximum of 600 mg if clinically indicated. If therapy with ketoconazole is initiated in a patient already receiving mifepristone 900 mg or 1200 mg, reduce the mifepristone dose to 600 mg.
    Mirabegron: (Moderate) As a potent CYP3A4 inhibitor, ketoconazole increased mirabegron Cmax by 45% and mirabegron AUC by 80% after multiple dose administration of 400 mg of ketoconazole for 9 days prior to the administration of a single dose of 100 mg mirabegron. Although, no dosage adjustments are recommended for mirabegron, it is prudent to monitor patients for increased adverse effects such as increases in blood pressure. Periodic blood pressure determinations are recommended.
    Mirtazapine: (Severe) The concurrent use of ketoconazole and mirtazapine is contraindicated. Ketoconazole has been associated with QT prolongation and mirtazapine has a risk of QT prolongation and torsade de pointes (TdP). In addition, ketoconazole is a potent CYP3A4 inhibitor and mirtazapine is a CYP3A4 substrate. Coadministration may result in elevated plasma concentrations of mirtazapine and an increased risk for adverse events, including QT prolongation and TdP. In a study of 24 healthy patients, ketoconazole 200 mg PO twice daily increased the peak plasma concentrations and AUC of a single dose of mirtazapine 30 mg by about 40% and 50%, respectively.
    Mitotane: (Major) The use of mitotane within 2 weeks of ketoconazole therapy is not recommended; if coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole. Mitotane is a strong CYP3A4 inducer and ketoconazole is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of ketoconazole.
    Modafinil: (Moderate) Modafinil is significantly metabolized by the CYP3A4 hepatic microsomal enzyme system. Azole antifungals are significant inhibitors of this isoenzyme and may reduce the clearance of modafinil.
    Moxifloxacin: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include moxifloxacin.
    Nadolol: (Moderate) Careful monitoring is recommended when ketoconazole is coadministered with nadolol. If these drugs are administered together, monitor patient for signs or symptoms of increased or prolonged nadolol-related side effects.
    Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with ketoconazole. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; ketoconazole is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
    Naloxegol: (Severe) Concomitant use of naloxegol with strong CYP3A4 inhibitors is contraindicated. Naloxegol is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inhibitors, such as ketoconazole, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
    Nateglinide: (Moderate) Hypoglycemia, sometimes severe, has been reported when ketoconazole is coadministered with oral hypoglycemic agents (i.e., repaglinide, nateglinide). The most likely mechanism of this interaction is ketoconazole-mediated inhibition of the metabolism of these agents. When coadministered, ketoconazole increases the AUC and Cmax of repaglinide by 15% and 26%, respectively. Patients should be monitored for signs and symptoms of hypoglycemia if ketoconazole is added to oral hypoglycemic therapy. There is no evidence that an interaction occurs between oral hypoglycemics and topical azole antifungal preparations.
    Neratinib: (Major) Avoid concomitant use of ketoconazole with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 481%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
    Netupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 since the plasma concentrations of the primary substrate can increase; the inhibitory effect on CYP3A4 can last for multiple days. Ketoconazole is partially metabolized by CYP3A4. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor, such as ketoconazole, can significantly increase the systemic exposure to netupitant. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
    Nevirapine: (Major) Concomitant use of nevirapine and ketoconazole is not recommended. Unless the benefits outweigh the risk, these drugs should not be administered within 2 weeks of each other. If administered concurrently, monitor for breakthrough fungal infections. Ketoconazole is a substrate/inhibitor of the hepatic isoenzyme CYP3A4, nevirapine is a substrate/inducer. Coadministration results in a 15% to 30% increase in nevirapine plasma concentrations and a 63% and 40% reduction in ketoconazole AUC and Cmax, respectively.
    Niacin; Simvastatin: (Severe) Concurrent use of simvastatin and ketoconazole is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A4 inhibitors such as ketoconazole. If therapy with ketoconazole is unavoidable, simvastatin therapy must be suspended during the course of ketoconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
    Nicardipine: (Moderate) Ketoconazole may decrease the clearance of calcium-channel blockers, such as nicardipine, via inhibition of CYP3A4 metabolism.
    Nifedipine: (Moderate) Ketoconazole may decrease the clearance of calcium-channel blockers, such as nifedipine, via inhibition of CYP3A4 metabolism.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib and ketoconazole due to the potential for additive effects on the QT interval and increased exposure to nilotinib; ketoconazole concentrations may also be increased. Nilotinib is a substrate and moderate inhibitor of CYP3A4. Ketoconazole is a substrate and strong inhibitor of CYP3A4. If the use of a strong CYP3A4 inhibitor like ketoconazole is necessary, hold nilotinib therapy. If the use of nilotinib and ketoconazole cannot be avoided, consider a nilotinib dose reduction (to nilotinib 200 mg PO once daily in adult patients with newly diagnosed Ph+ CML or to nilotinib 300 mg PO once daily in adult patients with resistant or intolerant Ph+ CML); close monitoring of the QT interval is recommended. If ketoconazole is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period. Concurrent use of nilotinib and ketoconazole 400 mg once daily for 6 days led to an approximate 3-fold increase in the nilotinib AUC.
    Nimodipine: (Moderate) Ketoconazole may decrease the clearance of calcium-channel blockers, such as nimodipine, via inhibition of CYP3A4 metabolism.
    Nintedanib: (Moderate) Ketoconazole is a potent inhibitor of CYP3A4 and, in vitro, a moderate P-glycoprotein (P-gp) inhibitor; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration with ketoconazole increased nintedanib concentrations by 60%; the nintedanib AUC was increased by 1.61-fold and the Cmax by 1.83-fold. If concomitant use of ketoconazole and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    Nisoldipine: (Severe) Concurrent administration of ketoconazole and nisoldipine is contraindicated due to the potential for adverse events. Nisoldipine is a substrate of CYP3A4, and ketoconazole is a potent inhibitor of CYP3A4; taking these drugs together is likely to result in increased exposure to nisoldipine. In a randomized, crossover study, ketoconazole increased the AUC of nisoldipine by 24-fold and the Cmax by 11-fold in 7 healthy male volunteers. Subjects received ketoconazole 200 mg/day PO for 5 days before receiving a single PO dose of immediate-release nisoldipine 5 mg. As compared to nisoldipine alone, ketoconazole pretreatment resulted in an increase in heart rate and decrease in blood pressure.
    Nizatidine: (Major) Ketoconazole requires an acidic pH for absorption. Medications that increase gastric pH or decrease acid output can cause a notable decrease in the bioavailability of ketoconazole. Medications that have this effect are antacids, antimuscarinics, histamine H2-blockers, and proton pump inhibitors (PPIs). Except for antacids, these medications have a prolonged duration of action, and staggering their time of administration with ketoconazole by several hours may not prevent the drug interaction. An alternative imidazole antifungal should be chosen if any of these gastrointestinal medications are required. If these drugs must be coadministered, administer ketoconazole tablets with an acidic beverage and closely monitor for breakthrough infection.
    Norfloxacin: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include norfloxacin.
    Nortriptyline: (Minor) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; ketoconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope have occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred. Close clinical monitoring is necessary if concurrent use is medically necessary.
    Nystatin: (Moderate) The combination of ketoconazole and nystatin represents duplication of therapy whenever the drugs are used by similar routes and are usually avoided.
    Octreotide: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include octreotide.
    Ofloxacin: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include ofloxacin.
    Olanzapine: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include olanzapine.
    Olaparib: (Major) Avoid coadministration of olaparib with ketoconazole and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 100 mg twice daily; reduce the dose of olaparib capsules to 150 mg twice daily. Olaparib is a CYP3A4/5 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    Olodaterol: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the beta-agonists. In a drug interaction study of olodaterol with ketoconazole, a strong dual CYP and P-gp inhibitor, coadministration of 400 mg ketoconazole once a day for 14 days increased olodaterol Cmax by 66% and AUC by 68%. Olodaterol was evaluated in clinical trials for up to one year at doses up to twice the recommended therapeutic dose. No dose adjustment is necessary. However, since coadministration may result in elevated LABA plasma concentrations there may be possibility for increased risk for adverse reactions, particularly systemic side effects such as nervousness, tremor, or cardiovascular effects.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) When administering ketoconazole with ritonavir or ritonavir-containing drugs, do not exceed the maximum recommended ketoconazole dose of 200 mg per day. Concurrent administration of ritonavir (a potent CYP3A4 inhibitor) with ketoconazole (a CYP3A4 substrate) significantly increases ketoconazole systemic concentrations. In one drug interaction study, ketoconazole exposure was increased by 3.4-fold when given concurrently with ritonavir (500 mg twice daily). In addition, because both drugs are associated with prolongation of the QT interval, coadministration may increase the risk for developing QT prolongation. If these drugs are given together, closely monitor patients for ketoconazole-associated adverse effects, including QT prolongation.
    Omeprazole; Sodium Bicarbonate: (Major) Ketoconazole requires an acidic pH for absorption. Medications that increase gastric pH or decrease acid output can cause a notable decrease in the bioavailability of ketoconazole. Medications that have this effect are antacids, antimuscarinics, histamine H2-blockers, and proton pump inhibitors (PPIs). Except for antacids, these medications have a prolonged duration of action, and staggering their time of administration with ketoconazole by several hours may not prevent the drug interaction; ketoconazole should be administered at least 2 hours before or 1 hour after antacids. An alternative imidazole antifungal should be chosen if any of these gastrointestinal medications are required. If these drugs must be coadministered, administer ketoconazole tablets with an acidic beverage and closely monitor for breakthrough infection.
    Ondansetron: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as ondansetron. Both ondansetron and ketoconazole are associated with QT prolongation; coadministration may increase this risk. If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with ondansetron (a CYP3A4 substrate) may result in elevated ondansetron plasma concentrations and an increased risk for adverse events, including QT prolongation.
    Oritavancin: (Moderate) Ketoconazole is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of ketoconazole may be reduced if these drugs are administered concurrently.
    Osimertinib: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of ketoconazole with osimertinib is necessary; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Ketoconazole has also been associated with prolongation of the QT interval.
    Ospemifene: (Moderate) Ketoconazole, a strong CYP3A4 inhibitor, increased the systemic exposure of ospemifene by 1.4-fold. Administration of systemic ketoconazole chronically with ospemifene may increase the risk of ospemifene-related adverse reactions. Consider an alternative antifungal agent, if appropriate.
    Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of ketoconazole with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Ketoconazole has been associated with prolongation of the QT interval. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
    Oxybutynin: (Moderate) Systemic azole antifungals, such as ketoconazole, are CYP3A4 inhibitors and can reduce the metabolism of drugs metabolized by CYP3A4, including oxybutynin. Serum concentrations of oxybutynin were approximately 2-fold higher when administered with ketoconazole or itraconazole. Oxybutynin should be used cautiously in patients receiving these drugs. In addition, antimuscarinic drugs can raise intragastric pH. This effect may decrease the oral bioavailability of ketoconazole.
    Oxycodone: (Major) Oxycodone is metabolized by CYP3A4. Concomitant administration of a CYP3A4 inhibitor, such as ketoconazole, may cause an increase in oxycodone plasma concentrations, which could increase or prolong adverse effects and may cause potentially fatal respiratory depression. If coadministration of these agents is necessary, patients should be monitored for an extended period of time and dosage adjustments made if warranted.
    Paclitaxel: (Minor) Paclitaxel is metabolized by hepatic cytochrome P450 isoenzymes 2C8 and 3A4. The metabolism of paclitaxel is inhibited by inhibitors of CYP3A4, such as ketoconazole. Closely monitor patients for toxicity when administering paclitaxel with ketoconazole.
    Palbociclib: (Major) Avoid coadministration of ketoconazole with palbociclib; significantly increased plasma exposure of palbociclib may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If ketoconazole is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of ketoconazole) to the dose used before initiation of ketoconazole. Palbociclib is primarily metabolized by CYP3A4 and ketoconazole is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
    Paliperidone: (Major) Avoid coadministration of paliperidone and ketoconazole due to the potential for additive effects on the QT interval. Both paliperidone and ketoconazole are associated with QT prolongation; coadministration may increase this risk. If coadministration is considered necessary by the practitioner, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential.
    Panobinostat: (Major) Avoid coadministration of ketoconazole and panobinostat due to the potential for QT prolongation; increased exposure to panobinostat may also occur. If these drugs are administered together, reduce the starting dose of panobinostat to 10 mg. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to 480 milliseconds or higher during therapy; permanently discontinue if QT prolongation does not resolve. Both panobinostat and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with panobinostat (a CYP3A4 substrate) results in elevated panobinostat plasma concentrations and may increase the risk for adverse events, including QT prolongation. The Cmax and AUC (0-48hr) of panobinostat were increased by 62% and 73%, respectively, in 14 patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking ketoconazole 200 mg PO twice daily for 14 days.
    Paricalcitol: (Moderate) Paricalcitol is partially metabolized by CYP3A4. Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as ketoconazole. Dose adjustments of paricalcitol may be required. Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with this combination.
    Pasireotide: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include pasireotide.
    Pazopanib: (Major) Avoid concurrent administration of ketoconazole and pazopanib. If coadministration is unavoidable, reduce the pazopanib dose to 400 mg PO once daily; further dose adjustments may be necessary if adverse effects occur. Both pazopanib and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with pazopanib (a CYP3A4 substrate) results in elevated pazopanib plasma concentrations and may increase the risk for adverse events, including QT prolongation. Following multiple doses of pazopanib 400 mg PO with multiple doses of ketoconazole 400 mg PO, the pazopanib AUC and Cmax values were increased by 1.7-fold and 1.5-fold, respectively, compared with pazopanib administered alone. Additionally, the administration of pazopanib eye drops with ketoconazole resulted in a 2-fold and 1.5-fold increase in pazopanib mean AUC and Cmax values, respectively, in healthy volunteers.
    Pentamidine: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include pentamidine.
    Perampanel: (Moderate) Ketoconazole, a potent CYP3A4 inhibitor, can prolong the half-life of perampanel and decrease perampanel metabolism. Administration of a single dose of perampanel 1 mg with ketoconazole 400 mg once daily for 8 days in healthy subjects increased perampanel half-life from 58.4 to 67.8 hours, and increased perampanel AUC by 20%. Patients taking ketoconazole and perampanel should be closely monitored for adverse effects; a perampanel dose adjustment may be necessary.
    Pergolide: (Severe) Coadministration of ergot alkaloids with inhibitors of CYP3A4, such as ketoconazole, is contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia, and/or other serious effects). Cabergoline may be minimally eliminated by the CYP isoenzyme system; therefore, interactions may be less than that of other ergot alkaloids.
    Perindopril; Amlodipine: (Moderate) Ketoconazole may decrease the clearance of calcium-channel blockers, including amlodipine, via inhibition of CYP3A4 metabolism.
    Perphenazine: (Minor) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include perphenazine.
    Perphenazine; Amitriptyline: (Minor) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include perphenazine. (Minor) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; ketoconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope have occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred. Close clinical monitoring is necessary if concurrent use is medically necessary.
    Phenylephrine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include ketoconazole.
    Phenytoin: (Moderate) Conflicting data exist about the combination of ketoconazole and phenytoin. Phenytoin is a known hepatic enzyme inducer, while ketoconazole inhibits hepatic metabolism. Although data suggest no interaction occurs when these agents are administered concomitantly, metabolism of either or both medications may be altered. Serum concentrations of phenytoin can increase, and time to peak ketoconazole serum concentrations can be delayed. Serum phenytoin levels should be closely monitored if ketoconazole is added to phenytoin therapy.
    Pimavanserin: (Major) Avoid concurrent administration of ketoconazole and pimavanserin due to the potential for additive effects on the QT interval and increased exposure to pimavanserin. If an alternative to ketoconazole is not available and coadministration is unavoidable, the manufacturer recommends reducing the pimavanserin dose to 17 mg once daily. Both drugs have been associated with prolongation of the QT interval; coadministration increases this risk. In addition, coadministration of ketoconazole (a CYP3A4 inhibitor) with pimavanserin (a CYP3A4 substrate) may result in elevated pimavanserin plasma concentrations and an increased risk for adverse events, including QT prolongation. If these drugs are given together, closely monitor for prolongation of the QT interval.
    Pimozide: (Severe) Coadministration of ketoconazole with pimozide is contraindicated. Ketoconazole inhibits the CYP3A4 metabolism of pimozide. Elevated pimozide concentrations resulting from inhibition of CYP3A4 may lead to QT prolongation, ventricular arrhythmias, and sudden death. Rare cases of QT prolongation, ventricular arrhythmia, and sudden death have occurred when a CYP3A4 inhibitor was added to pimozide.
    Pioglitazone: (Moderate) Ketoconazole appears to significantly inhibit the metabolism of pioglitazone. It is recommended that patients receiving both pioglitazone and ketoconazole be evaluated more frequently with respect to glycemic control.
    Pirbuterol: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the beta-agonists. In addition, the long-acting beta agonists (LABAs) indacaterol, vilanterol, salmeterol are CYP3A4 substrates. The coadministration of these LABAs with strong CYP3A4 inhibitors such as ketoconazole may result in elevated LABA plasma concentrations and increased risk for adverse reactions, particularly systemic side effects such as nervousness, tremor, or cardiovascular effects. In a placebo-controlled, drug interaction study of 20 healthy subjects, coadministration of salmeterol (50 mcg twice daily), and ketoconazole (400 mg PO once daily) for 7 days resulted in a 16-fold increase in salmeterol AUC. Three of the 20 subjects were withdrawn from the study due to cardiovascular adverse effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia). An increase in AUC also occurred when ketoconazole was coadministered with indacaterol. Similar interactions may occur when ketoconazole is added to vilanterol, such as umeclidinium; vilanterol.
    Pomalidomide: (Minor) A clinically insignificant increase in pomalidomide exposure occurred when pomalidomide and ketoconazole were administered together in a drug interaction study. Pomalidomide is a CYP3A4 and P-glycoprotein (P-gp) substrate and ketoconazole is a strong CYP3A4 and P-gp inhibitor. In 16 healthy male volunteers, the pomalidomide AUC value was increased by 19% when pomalidomide was co-administered with ketoconazole.
    Ponatinib: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and ketoconazole, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. Coadministration of a single oral dose of ponatinib 15 mg with ketoconazole 400 mg daily increased AUC and Cmax values by 78% and 47%, respectively, compared with ponatinib alone in a drug interaction study in 22 healthy volunteers. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day.
    Praziquantel: (Moderate) Ketoconazole inhibits CYP3A4 and may reduce metabolism of praziquantel. This interaction may be beneficial. The combination may prolong the exposure of the parasites to praziquantel and may not result in an increased risk of side effects.
    Prednisolone: (Moderate) Ketoconazole can decrease the hepatic clearance of prednisolone, resulting in increased plasma concentrations. The interaction may be due to the inhibition of CYP3A4 isoenzyme by ketoconazole, and subsequent decreases in corticosteroid metabolism by the same isoenzyme. Prednisolone and prednisone pharmacokinetics appear less susceptible than methylprednisolone to CYP3A4 inhibitory interactions. Ketoconazole also can enhance the adrenal suppressive effects of corticosteroids.
    Prednisone: (Moderate) Ketoconazole can decrease the hepatic clearance of prednisone, resulting in increased plasma concentrations. The interaction may be due to the inhibition of cytochrome P-450 3A4 isoenzyme by ketoconazole, and subsequent decreases in corticosteroid metabolism by the same isoenzyme. The dose of corticosteroid should be titrated to avoid steroid toxicity. Prednisolone and prednisone pharmacokinetics appear less susceptible than methylprednisolone to CYP3A4 inhibitory interactions. Ketoconazole also can enhance the adrenal suppressive effects of corticosteroids.
    Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include ketoconazole.
    Procainamide: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include procainamide.
    Prochlorperazine: (Minor) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include prochlorperazine.
    Progesterone: (Minor) The metabolism of progesterone is inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes.
    Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include ketoconazole.
    Propafenone: (Major) Use caution during coadministration of propafenone and ketoconazole due to the potential for additive effects on the QT interval and increased exposure to propafenone. Both propafenone and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with propafenone (a CYP3A4 substrate) may result in elevated propafenone plasma concentrations and an increased risk for adverse events, including QT prolongation.
    Propoxyphene: (Moderate) Propoxyphene is a substrate and an inhibitor of CYP3A4. Increased serum concentrations of propoxyphene would be expected from concurrent use of a CYP3A4 inhibitor, such as ketoconazole. A reduced dosage of propoxyphene may be needed. Monitor patients for central nervous system (CNS) and respiratory depression.
    Proton pump inhibitors: (Major) Because ketoconazole requires an acidic pH for absorption, coadministration of a proton pump inhibitor (PPI) with ketoconazole can cause a notable decrease in the bioavailability of ketoconazole. PPIs have a prolonged duration of action, and staggering their time of administration with ketoconazole by several hours may not prevent the drug interaction. An alternative imidazole antifungal should be chosen if any of these gastrointestinal medications are required. If these drugs must be coadministered, administer ketoconazole tablets with an acidic beverage and closely monitor for breakthrough infection.
    Protriptyline: (Minor) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; ketoconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope have occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred. Close clinical monitoring is necessary if concurrent use is medically necessary.
    Quazepam: (Moderate) CYP3A4 inhibitors, such as ketoconazole, may reduce the metabolism of quazepam and increase the potential for benzodiazepine toxicity.
    Quetiapine: (Major) Avoid coadministration of quetiapine and ketoconazole due to the potential for additive effects on the QT interval; increased exposure to quetiapine may also occur. If coadministration cannot be avoided, the dose of quetiapine should be reduced to one-sixth the original dose. Both quetiapine and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with quetiapine (a CYP3A4 substrate) results in elevated quetiapine plasma concentrations and an increased risk for adverse events, including QT prolongation. Ketoconazole reduced the oral clearance of quetiapine by 84% resulting in a 335% increase in quetiapine maximum plasma concentrations.
    Quinidine: (Severe) Ketoconazole inhibits the hepatic CYP3A4 isoenzyme; quinidine is metabolized by this isoenzyme. Coadministration results in increased quinidine serum concentrations, with potential to result in proarrhythmias. A single case report has documented substantial elevations in serum quinidine concentrations after the addition of ketoconazole. The patient was receiving other drugs concomitantly and it is unclear if drug-induced arrhythmias occurred. Until more data are available, ketoconazole should be considered contraindicated in patients receiving quinidine.
    Quinine: (Major) Ketoconazole, a potent CYP3A4 inhibitor, may inhibit the metabolism of quinine, a CYP3A4 substrate. Co-administration with ketoconazole decreases the oral clearance of quinine by 31 percent and reduces the AUC of 3-hydroxyquinine.
    Ramelteon: (Moderate) Ramelteon should be used cautiously in combination with systemic ketoconazole, which is a strong CYP3A4 inhibitor. When ketoconazole 200 mg twice daily was administered for 3 days prior to single-dose coadministration of ramelteon 16 mg, the AUC and Cmax of ramelteon increased by approximately 84% and 36%, respectively. Similar increases were seen in regard to the active metabolite of ramelteon, M-II. The patient should be monitored closely for toxicity from ramelteon if coadministration cannot be avoided.Topical ketoconazole products are not expected to interact.
    Ranitidine: (Major) Ketoconazole requires an acidic pH for absorption. Medications that increase gastric pH or decrease acid output can cause a notable decrease in the bioavailability of ketoconazole. Medications that have this effect are antacids, antimuscarinics, histamine H2-blockers, and proton pump inhibitors (PPIs). Except for antacids, these medications have a prolonged duration of action, and staggering their time of administration with ketoconazole by several hours may not prevent the drug interaction. An alternative imidazole antifungal should be chosen if any of these gastrointestinal medications are required. If these drugs must be coadministered, administer ketoconazole tablets with an acidic beverage and closely monitor for breakthrough infection.
    Ranolazine: (Severe) Ranolazine is contraindicated in patients receiving drugs known to be moderate or potent CYP3A inhibitors including systemic azole antifungal agents. Ketoconazole (200 mg PO twice daily) increases the average steady-state plasma concentrations of ranolazine by 3.2-fold. Avoid coadministering ranolazine with ketoconazole. Inhibition of ranolazine CYP3A metabolism could lead to increased ranolazine plasma concentrations, prolonged QTc prolongation, and possibly torsade de pointes.
    Red Yeast Rice: (Severe) The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if lovastatin is administered concomitantly with CYP3A4 inhibitors, such as ketoconazole. Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity and certain products (i.e., pre-2005 Cholestin formulations) contain lovastatin, red yeast rice should not be used in combination with ketoconazole. If no alternative to a short course of treatment with a systemic azole antifungal is available, a brief suspension of red yeast rice therapy during such treatment can be considered. Topical ketoconazole formulations are not expected to alter red yeast rice concentrations.
    Regadenoson: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include regadenoson.
    Regorafenib: (Major) Avoid concomitant use of regorafenib, a CYP3A4 substrate, and ketoconazole, a strong CYP3A4 inhibitor, as the exposure of regorafenib may increase and the exposure of the active metabolites, M-2 and M-5, may decrease. In 18 healthy volunteers who received a single oral dose of regorafenib 160 mg once and then again after 5 days of oral ketoconazole 400 mg/day, the mean AUC of regorafenib increased by 33% and the mean AUC of M-2 and M-5 both decreased by 93%.
    Repaglinide: (Moderate) Hypoglycemia, sometimes severe, has been reported when ketoconazole is coadministered with oral hypoglycemic agents (i.e., repaglinide, nateglinide). The most likely mechanism of this interaction is ketoconazole-mediated inhibition of the metabolism of these agents. When coadministered, ketoconazole increases the AUC and Cmax of repaglinide by 15% and 26%, respectively. Patients should be monitored for signs and symptoms of hypoglycemia if ketoconazole is added to oral hypoglycemic therapy. There is no evidence that an interaction occurs between oral hypoglycemics and topical azole antifungal preparations.
    Ribociclib: (Major) Avoid coadministration of ribociclib with ketoconazole due to the potential for additive effects on the QT interval and significantly increased exposure to ribociclib; exposure to ketoconazole may also increase. If coadministration cannot be avoided, reduce the ribociclib dose to 400 mg once daily. If ketoconazole is discontinued, resume the previous ribociclib dose after at least 5 half-lives of ketoconazole. Both ketoconazole and ribociclib have been reported to prolong the QT interval. Concomitant use may increase the risk for QT prolongation. Ribociclib is extensively metabolized by CYP3A4 and ketoconazole is a strong CYP3A4 inhibitor. Additionally, ribociclib is a moderate CYP3A4 inhibitor and ketoconazole is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with ketoconazole due to the potential for additive effects on the QT interval and significantly increased exposure to ribociclib; exposure to ketoconazole may also increase. If coadministration cannot be avoided, reduce the ribociclib dose to 400 mg once daily. If ketoconazole is discontinued, resume the previous ribociclib dose after at least 5 half-lives of ketoconazole. Both ketoconazole and ribociclib have been reported to prolong the QT interval. Concomitant use may increase the risk for QT prolongation. Ribociclib is extensively metabolized by CYP3A4 and ketoconazole is a strong CYP3A4 inhibitor. Additionally, ribociclib is a moderate CYP3A4 inhibitor and ketoconazole is a CYP3A4 substrate.
    Rifabutin: (Major) Concurrent use of ketoconzole with rifabutin is not recommended. Taking these drug together may result in increased exposure to rifabutin and decreased exposure to ketoconazole. Both drugs are substrates for CYP3A4, while rifabutin is also a CYP3A4 inducer and ketoconazole is a potent inhibitor of CYP3A4.
    Rifampin: (Major) Ketoconazole and rifampin each affect the pharmacokinetics of the other. Ketoconazole has been shown to reduce serum concentrations of rifampin but the clinical significance of this effect on rifampin concentrations is not known. More significant are the effects of rifampin on ketoconazole pharmacokinetics. Rifampin is a potent inducer of hepatic microsomal enzymes. When rifampin is used in combination with isoniazid, INH, isoniazid appears to intensify the effect of rifampin on the pharmacokinetics of other drugs, despite the fact that isoniazid is generally considered an inhibitor of drug metabolism. The effects of isoniazid with rifampin on ketoconazole have been significant enough to result in antifungal treatment failure. Ketoconazole doses may need to be increased if rifampin, or the combination of rifampin with isoniazid, is used concomitantly. However, it is generally not recommended that ketoconazole be used with INH or rifampin.
    Rifapentine: (Major) Rifapentine induces hepatic isoenzymes CYP3A4 and CYP2C8/9; rifapentine does not induce its own metabolism. Drugs metabolized by CYP3A4 and CYP2C8/9 may require dosage adjustments when administered concurrently with rifapentine. Although no formal studies are available regarding itraconazole and rifapentine, induction of itraconazole metabolism and decreased serum concentrations of itraconazole may be expected. Therefore, the efficacy of itraconazole could be substantially reduced if given concomitantly with rifapentine; concurrent administration is not recommended. Although specific data are not available, similar interactions might occur between rifapentine and fluconazole, ketoconazole or voriconazole; monitor patients on these agents for signs of decreased antifungal efficacy when rifapentine is given concurrently.
    Rifaximin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and ketoconazole, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Rilpivirine: (Major) Caution is advised when administering ketoconazole with rilpivirine due to the potential for additive effects on the QT interval and increased exposure to rilpivirine. Both rilpivirine and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with rilpivirine (a CYP3A4 substrate) results in elevated rilpivirine plasma concentrations. Conversely, ketoconazole concentrations are decreased when administered with rilpivirine. If these drugs must be administered together, closely monitor for rilpivirine-related adverse events and the potential for breakthrough fungal infections. Rilpivirine dosage adjustments are not recommended.
    Riociguat: (Major) Concomitant use of riociguat with strong cytochrome CYP inhibitors and P-gp/BCRP inhibitors such as azole antimycotics (e.g., ketoconazole, itraconazole) or anti-retroviral protease inhibitors (such as ritonavir) increase riociguat exposure and may result in hypotension. Consider a starting dose of 0.5 mg 3 times a day when initiating riociguat in patients receiving strong CYP and P-gp/BCRP inhibitors. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat.
    Risperidone: (Major) Caution is advised when administering ketoconazole with risperidone due to the potential for additive effects on the QT interval. Both risperidone and ketoconazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP); coadministration may increase this risk.
    Ritonavir: (Major) When administering ketoconazole with ritonavir or ritonavir-containing drugs, do not exceed the maximum recommended ketoconazole dose of 200 mg per day. Concurrent administration of ritonavir (a potent CYP3A4 inhibitor) with ketoconazole (a CYP3A4 substrate) significantly increases ketoconazole systemic concentrations. In one drug interaction study, ketoconazole exposure was increased by 3.4-fold when given concurrently with ritonavir (500 mg twice daily). In addition, because both drugs are associated with prolongation of the QT interval, coadministration may increase the risk for developing QT prolongation. If these drugs are given together, closely monitor patients for ketoconazole-associated adverse effects, including QT prolongation.
    Rivaroxaban: (Major) Avoid concomitant administration of rivaroxaban and ketoconazole; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein transporter. Concurrent use of rivaroxaban and ketoconazole, a combined P-glycoprotein and strong CYP3A4 inhibitor, led to an increase in the steady-state rivaroxaban AUC by 160% and Cmax by 70%. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
    Roflumilast: (Moderate) Coadminister ketoconazole and roflumilast cautiously as increased systemic exposure to roflumilast has been demonstrated in pharmacokinetic study. Increased roflumilast-induced adverse reactions may result. Ketoconazole is a strong CYP3A4 inhibitor; roflumilast is a CYP3A4 substrate. In an open-label crossover study in 16 healthy volunteers, the coadministration of ketoconazole (200 mg twice daily for 13 days) with a single oral dose of roflumilast 500 mcg resulted in 23% and 99% increase in Cmax and AUC for roflumilast, respectively, and a 38% reduction in Cmax and 3% increase in AUC for the active metabolite roflumilast N-oxide.
    Romidepsin: (Major) The concomitant use of romidepsin, a CYP3A4 substrate, and ketoconazole, a strong CYP3A4 inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram (ECG) changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops. Additionally, ketoconazole has been associated with QT prolongation and rare cases of torsade de pointes and changes in ECGs (including T-wave and ST-segment changes) have been reported with romidepsin use. If romidepsin is administered with agents that may cause significant QT prolongation, such as ketoconazole, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and electrocardiograms at baseline and periodically during treatment. Following a 4-hour infusion of romidepsin 8 mg/m2 IV administered with multiple oral doses of ketoconazole, the AUC and Cmax values of romidepsin were increased by 25% and 10%, respectively, compared with romidepsin alone; the increase was statistically significant for AUC.
    Ropivacaine: (Moderate) Concurrent administration of ketoconazole and ropivacaine may result in elevated ropivacaine serum concentration; thereby increasing the risk for drug toxicity. The metabolism of ropivacaine to 3-hydroxyropivacaine is dependent on CYP1A2, and the metabolism of ropivacaine to (S)-2',6'-pipecoloxylidide is dependent on CYP3A4. Ropivacaine is metabolized to a lesser extent by cytochrome CYP3A4. Without the presence of an enzyme inducer or inhibitor, the fraction of a ropivacaine dose that is converted to (S)-2',6'-pipecoloxylidide is 0.01 +/- 0.02 whereas 0.39 +/- 0.05 is converted to 3-hydroxyropivacaine. In the presence of the CYP3A4 inhibitor, ketoconazole, the disposition of ketoconazole was all 3-hydroxyropivacaine (0.47 +/- 0.07). Concurrent administration of ketoconazole (100 mg twice daily for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 15% reduction in in vivo ropivacaine plasma clearance. Plasma ropivacaine concentrations increased slightly.
    Rosiglitazone: (Moderate) If ketoconazole and rosiglitazone are to be coadministered, patients should be closely monitored. A pharmacokinetic study found that the administration of rosiglitazone to subjects who had been receiving ketoconazole resulted in increased rosiglitazone AUC, peak plasma concentrations, and half-life, and decreased rosiglitazone clearance. The clinical significance (i.e., altered blood glucose concentrations) of this interaction is unknown.
    Ruxolitinib: (Major) Modify the ruxolitinib dosage when coadministered with ketoconazole. Subsequent ruxolitinib dose modifications should be made with frequent monitoring of safety and efficacy. Increased ruxolitinib exposure is possible if coadministered with ketoconazole. Ruxolitinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ruxolitinib dosage adjustments when coadministered with a strong CYP3A4 inhibitor are as follows: In patients with myelofibrosis (MF) and platelet counts greater than or equal to 100 x 10^9/L, initiate ruxolitinib at 10 mg PO twice daily; if platelet counts are greater than 50 x 10^9/L and less than 100 x 10^9/L, initiate ruxolitinib at 5 mg PO once daily. In patients with polycythemia vera (PV), stabilized on ruxolitinib doses greater than or equal to 10 mg PO twice daily, decrease the ruxolitinib dose by 50% rounded to the nearest available tablet strength; for PV patients stabilized on ruxolitinib 5 mg PO twice daily, decrease ruxolitinib to 5 mg PO once daily; avoid coadministration in PV patients stabilized on ruxolitinib 5 mg PO once daily or interrupt ruxolitinib therapy for the duration of ketoconazole use.
    Saccharomyces boulardii: (Major) Because Saccharomyces boulardii is an active yeast, it would be expected to be inactivated by any antifungals. The manufacturer does not recommend taking in conjunction with any antifungal agents. Patients should avoid use of this probiotic yeast until the patient's fungal or yeast infection is completely treated.
    Salmeterol: (Major) Avoid use of salmeterol with strong CYP3A4 inhibitors. Salmeterol is a CYP3A4 substrate. The coadministration of with strong CYP3A4 inhibitors such as ketoconazole results in elevated salmeterol plasma concentrations and increased risk for adverse reactions such as nervousness, tremor, or cardiovascular effects. Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the beta-agonists. In a placebo-controlled, drug interaction study of 20 healthy subjects, coadministration of another LABA. salmeterol (50 mcg twice daily), and ketoconazole (400 mg PO once daily) for 7 days resulted in a 16-fold increase in salmeterol AUC. Three of the 20 subjects were withdrawn from the study due to cardiovascular adverse effects (2 with QT prolongation and 1 with palpitations and sinus tachycardia).
    Saquinavir: (Major) Plasma concentrations of saquinavir are significantly increased if coadministered with ketoconazole; steady state saquinavir AUC and Cmax values may be three times those of saquinavir alone. However, no saquinavir dosage adjustments are recommended when saquinavir and ketoconazole are coadministered for a short period of time. When saquinavir boosted with ritonavir is coadministered with ketoconazole, ketoconazole plasma concentrations increase; therefore, doses of more than 200 mg/day of ketoconazole are not recommended. Although the manufacturer of saquinavir recommends a dosage maximum when coadministered with ketoconazole, saquinavir is contraindicated for use with drugs that prolong the QT interval and can increase the plasma concentration of saquinavir. Ketoconazole has been associated with QT prolongation and is a potent inhibitor of CYP3A4.
    Saxagliptin: (Major) Saxagliptin is a p-glycoprotein substrate, and the metabolism of saxagliptin is primarily mediated by CYP3A4/5. Ketoconazole is a strong inhibitor of both p-glycoprotein and CYP3A4/5. Saxagliptin did not meaningfully alter the pharmacokinetics of ketoconazole, but coadministration increased the maximum serum saxagliptin concentration by 62% and the systemic exposure by 2.5-fold. As expected, the maximum serum concentration of the saxagliptin active metabolite was decreased by 95% and the systemic exposure was decreased by 91%. In another study, the maximum serum saxagliptin concentration increased by 2.4-fold and the systemic exposure increased by 3.4-fold. The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP 3A4/5 inhibitor such as ketoconazole.
    Sertraline: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as sertraline. Both sertraline and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with sertraline (a CYP3A4 substrate) may result in an elevated sertraline plasma concentrations and an increased risk for adverse events, including QT prolongation.
    Sevoflurane: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include halogenated anesthetics.
    Sibutramine: (Major) The hepatic CYP450 3A4-mediated metabolism of sibutramine may be inhibited by ketoconazole, a CYP3A4 inhibitor.
    Sildenafil: (Major) A dosage reduction of sildenafil to 25 mg PO, approximately 1 hour prior to sexual activity, up to once daily is recommended during coadministration with ketoconazole. Sildenafil is metabolized principally by the hepatic isoenzyme CYP3A4; ketoconazole is a strong inhibitor of CYP3A4. Ketoconazole may increase the systemic exposure to sildenafil resulting in an increase in sildenafil-induced adverse effects. Population data from patients in clinical trials did indicate a reduction in sildenafil clearance when it was coadministered with CYP3A4 inhibitors.
    Silodosin: (Severe) Concurrent use of silodosin and ketoconazole is contraindicated. Silodosin is extensively metabolized by CYP3A4 and is a P-glycoprotein (P-gp) substrate; ketoconazole inhibits CYP3A4 and P-gp. Coadministration may cause significant increases in silodosin plasma concentrations. In one study, coadministration resulted in a 3.8-fold increase in maximum plasma silodosin concentrations and a 3.2-fold increase in silodosin AUC.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and ketoconazole. Inhibition of CYP3A4 by ketoconazole may significantly increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Simvastatin: (Severe) Concurrent use of simvastatin and ketoconazole is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A4 inhibitors such as ketoconazole. If therapy with ketoconazole is unavoidable, simvastatin therapy must be suspended during the course of ketoconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
    Simvastatin; Sitagliptin: (Severe) Concurrent use of simvastatin and ketoconazole is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A4 inhibitors such as ketoconazole. If therapy with ketoconazole is unavoidable, simvastatin therapy must be suspended during the course of ketoconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
    Sirolimus: (Severe) Avoid coadministration of ketoconazole with sirolimus. Ketoconazole may inhibit the CYP3A4 metabolism of sirolimus, leading to potential toxicity. Multiple-dose ketoconazole significantly increased sirolimus Cmax by 4.3-fold, Tmax by 38%, and AUC 10.9-fold. The terminal half-life of sirolimus is not affected. Single doses of sirolimus did not affect steady-state 12-hour ketoconazole serum concentrations.
    Sodium Bicarbonate: (Major) Ketoconazole requires an acidic pH for absorption. Medications that increase gastric pH or decrease acid output can cause a notable decrease in the bioavailability of ketoconazole. Medications that have this effect are antacids, antimuscarinics, histamine H2-blockers, and proton pump inhibitors (PPIs). Except for antacids, these medications have a prolonged duration of action, and staggering their time of administration with ketoconazole by several hours may not prevent the drug interaction; ketoconazole should be administered at least 2 hours before or 1 hour after antacids. An alternative imidazole antifungal should be chosen if any of these gastrointestinal medications are required. If these drugs must be coadministered, administer ketoconazole tablets with an acidic beverage and closely monitor for breakthrough infection.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with ketoconazole. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); ketoconazole is an inhibitor of P-gp. Ketoconazole is also a potent inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with ketoconazole. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); ketoconazole is an inhibitor of P-gp. Ketoconazole is also a potent inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
    Solifenacin: (Major) Caution is advised when administering ketoconazole with solifenacin due to the potential for additive effects on the QT interval and increased exposure to solifenacin. If these drugs must be administered together, do not exceed 5 mg per day of solifenacin. Conversely, ketoconazole requires an acidic pH for oral absorption. Medications that increase gastric pH or decrease acid output can cause a notable decrease in the bioavailability of ketoconazole. Medications that have this effect include antimuscarinics. Both solifenacin and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with solifenacin (a CYP3A4 substrate) may result in elevated solifenacin plasma concentrations and an increased risk for adverse events, including QT prolongation. Following the administration of solifenacin 10 mg and ketoconazole 400 mg PO, the peak concentration and AUC of solifenacin increased 150% and 270%, respectively.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and ketoconazole; sonidegib exposure was significantly increased in healthy subjects who received ketoconazole and sonidegib compared with sonidegib only. This interaction may result in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and ketoconazole is a strong CYP3A4 inhibitor. The sonidegib geometric mean Cmax and AUC (0-10 days) values were increased 2.2-fold and 1.5-fold, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of ketoconazole 200 mg twice daily (n = 15) compared with healthy subjects who received a single dose of sonidegib only (n = 16). Physiologic-based pharmacokinetics simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would be increased to a similar extent in cancer patients who received 14 days of sonidegib 200 mg/day with a strong CYP3A4 inhibitor.
    Sorafenib: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include sorafenib.
    Sotalol: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include sotalol.
    St. John's Wort, Hypericum perforatum: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system. Co-administration of St. John's wort could decrease the efficacy of some medications metabolized by these enzymes including ketoconazole.
    Sucralfate: (Major) Concomitant administration of oral ketoconazole with sucralfate may interfere with the absorption of ketoconazole. Separation of administration is advised.
    Sufentanil: (Moderate) Ketoconazole may decrease the systemic clearance of sufentanil. Prolonged duration of opiate action, increased sedation, respiratory depression or other opiate side effects may occur. Close monitoring of patients is warranted.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include sulfamethoxazole; trimethoprim, SMX-TMP.
    Sulfonylureas: (Moderate) Hypoglycemia, sometimes severe, has been reported when ketoconazole is coadministered with oral hypoglycemic agents. The most likely mechanism for this interaction is inhibition of the CYP450 metabolism of oral hypoglycemics by ketoconazole. Blood glucose concentrations should be monitored during concomitant treatment; patients should be aware of the symptoms of hypoglycemia. In some cases, dosage adjustment of the sulfonylurea may be necessary. There is no evidence that an interaction occurs between oral hypoglycemics and topical or vaginal azole antifungal preparations.
    Sunitinib: (Major) Avoid concurrent administration of ketoconazole and sunitinib due to the potential for additive effects on the QT interval and increased exposure to sunitinib. If coadministration is unavoidable, a reduction in the dose of sunitinib is recommended. Both sunitinib and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, concurrent administration of sunitinib (a CYP3A4 substrate) and ketoconazole (a potent CYP3A4 inhibitor) resulted in increases of 49% and 51% in the combined (sunitinib and primary active metabolite) Cmax and AUC values, respectively, after a single dose of sunitinib in healthy volunteers.
    Suvorexant: (Major) Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as ketoconazole. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
    Tacrolimus: (Major) Caution is advised when administering ketoconazole with tacrolimus due to the potential for additive effects on the QT interval and increased exposure to tacrolimus. Both tacrolimus and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, ketoconazole (a potent CYP3A4 inhibitor) may inhibit the metabolism of tacrolimus (a CYP3A4 substrate): concurrent use may result in elevated tacrolimus plasma concentrations and an increased risk for adverse events, including QT prolongation. In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14 +/- 5% vs. 30 +/- 8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone. Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole coadministration, although it was highly variable between patients. Close monitoring of tacrolimus blood levels is warranted. This interaction has been used clinically to reduce the nephrotoxicity and high cost of tacrolimus therapy.
    Tadalafil: (Major) Avoid coadministration of ketoconazole and tadalafil for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ketoconazole for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by the hepatic cytochrome P450 3A4 isoenzyme. Inhibitors of CYP3A4, such as ketoconazole, may reduce tadalafil clearance. Ketoconazole 400 mg daily increased tadalafil (20 mg single dose) AUC by 312% and Cmax by 22%, relative to the values for tadalafil (20 mg single dose) alone. Ketoconazole 200 mg daily increased tadalafil (10 mg single dose) AUC by 107% and Cmax by 15%, relative to the values for tadalafil 10 mg alone. Increased systemic exposure to tadalafil may result in an increase in tadalafil-induced adverse effects, including hypotension, syncope, visual changes, and prolonged erection.
    Tamoxifen: (Major) Concomitant use of tamoxifen and ketoconazole may cause an increased risk of QT prolongation; reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. If coadministration is unavoidable, monitor for altered tamoxifen efficacy, increased tamoxifen-related adverse effects, and evidence of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Ketoconazole has also been associated with prolongation of the QT interval. Ketoconazole may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4.
    Tamsulosin: (Major) Tamsulosin is extensively metabolized by CYP3A4 hepatic enzymes, and strong inhibitors of CYP3A4 are expected to significantly raise tamsulosin concentrations. Plasma concentrations of tamsulosin are increased with concomitant use of ketoconazole, a strong inhibitor of CYP3A4. Concomitant treatment with ketoconazole resulted in an increase in the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use with a strong CYP3A4 inhibitor, such as ketoconazole, itraconazole, posaconazole, or voriconazole should be avoided.
    Tasimelteon: (Major) Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as ketoconazole, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of ketoconazole 40 mg/day for 5 days, tasimelteon exposure increased by about 50%.
    Telaprevir: (Major) Close clinical monitoring is advised when administering ketoconazole with telaprevir due to an increased potential for serious ketoconazole and telaprevir-related adverse events. When concurrent administration is required, high doses of ketoconazole (> 200 mg/day) are not recommended. If ketoconazole dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Predictions about the interaction can be made based on the metabolic pathways of ketaconazole and telaprevir. Both ketoconazole and telaprevir are substrates and inhibitors of the hepatic isoenzyme CYP3A4. Additionally, ketoconazole is an inhibitor of P-glycoprotein (P-gp), a drug efflux transporter partially responsible for the metabolism of telaprevir. When used in combination, the plasma concentrations of both medications may be elevated.
    Telavancin: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include telavancin.
    Telbivudine: (Moderate) The risk of myopathy may be increased if ketoconazole is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Telithromycin: (Major) Avoid concurrent administration of ketoconazole and telithromycin. Coadministration results in elevated plasma concentrations of telithromycin and an increased risk for adverse events. A multi-dose interaction study found coadministration resulted in an increase of the Cmax and AUC of telithromycin by 51% and 95%, respectively. In addition, use of these drugs together may increase the risk for QT prolongation. Telithromycin is associated with QT prolongation and torsade de pointes (TdP); ketoconazole can also prolong the QT interval.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and ketoconazole is necessary, as the systemic exposure of ketoconazole may be decreased resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of ketoconazole as well as an increase in adverse reactions related to telotristat ethyl. Consider increasing the dose of ketoconazole if necessary. Ketoconazole is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and ketoconazole is a P-gp inhibitor in vitro. Exposure to telotristat ethyl may increase.
    Temsirolimus: (Major) Avoid concomitant use of temsirolimus with ketoconazole due to the risk of an increase in temsirolimus-related adverse events. If concomitant use cannot be avoided, consider a temsirolimus dose reduction to 12.5 mg per week. If ketoconazole is discontinued, allow a washout period of approximately 1 week before the temsirolimus dose is increased to the dose used before initiation of ketoconazole. Temsirolimus is a CYP3A4 and P-glycoprotein (P-gp; in vitro) substrate; ketoconazole is a strong inhibitor of CYP3A4 as well as a P-gp inhibitor. Coadministration of temsirolimus with ketoconazole had no significant effect on the AUC or Cmax of temsirolimus, but increased the sirolimus AUC and Cmax by 3.1-fold and 2.2-fold, respectively.
    Tenofovir Alafenamide: (Minor) According to the manufacturer, interactions are not expected during coadministration of ketoconazole and tenofovir alafenamide; however based on the metabolic pathways of these medications, monitoring for tenofovir-associated adverse reactions should be considered if these drugs are given together. Ketoconazole is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tenofovir, PMPA: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ketoconazole. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering ketoconazole. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may substantially increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C9, CYP2C19, and CYP3A4; ketoconazole is an inhibitor of these enzymes. Monitor patients for adverse reactions if these drugs are coadministered.
    Terbutaline: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the beta-agonists. In addition, the long-acting beta agonists (LABAs) indacaterol, vilanterol, salmeterol are CYP3A4 substrates. The coadministration of these LABAs with strong CYP3A4 inhibitors such as ketoconazole may result in elevated LABA plasma concentrations and increased risk for adverse reactions, particularly systemic side effects such as nervousness, tremor, or cardiovascular effects. In a placebo-controlled, drug interaction study of 20 healthy subjects, coadministration of salmeterol (50 mcg twice daily), and ketoconazole (400 mg PO once daily) for 7 days resulted in a 16-fold increase in salmeterol AUC. Three of the 20 subjects were withdrawn from the study due to cardiovascular adverse effects (2 with QTc prolongation and 1 with palpitations and sinus tachycardia). An increase in AUC also occurred when ketoconazole was coadministered with indacaterol. Similar interactions may occur when ketoconazole is added to vilanterol, such as umeclidinium; vilanterol.
    Tetrabenazine: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include tetrabenazine.
    Theophylline, Aminophylline: (Minor) Ketoconazole has been reported to decrease theophylline serum concentrations when theophylline was administered orally as sustained-release tablets, however, no interaction was noted when theophylline was administered IV. Since ketoconazole is well-known to inhibit the hepatic metabolism of many drugs and theophylline concentrations would be expected to increase, it is suspected that ketoconazole may have interfered with oral bioavailability of theophylline. As these results are based on a single case report, additional clinical data are necessary.
    Thioridazine: (Severe) Thioridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Thioridazine is contraindicated for use along with agents that, when combined with a phenothiazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension. Ketoconazole has been associated with prolongation of the QT interval. Because of the potential for TdP, use of systemic ketoconazole with thioridazine is considered contraindicated.
    Ticagrelor: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inhibitors, such as ketoconazole. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp) and concomitant use with ketoconazole substantially increases ticagrelor exposure which may increase the bleeding risk.
    Tinidazole: (Major) Ketoconazole is an enzyme inhibitor that can decrease the hepatic metabolism of tinidazole. As a result, elimination can be delayed and serum tinidazole concentrations can increase.
    Tiotropium; Olodaterol: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the beta-agonists. In a drug interaction study of olodaterol with ketoconazole, a strong dual CYP and P-gp inhibitor, coadministration of 400 mg ketoconazole once a day for 14 days increased olodaterol Cmax by 66% and AUC by 68%. Olodaterol was evaluated in clinical trials for up to one year at doses up to twice the recommended therapeutic dose. No dose adjustment is necessary. However, since coadministration may result in elevated LABA plasma concentrations there may be possibility for increased risk for adverse reactions, particularly systemic side effects such as nervousness, tremor, or cardiovascular effects.
    Tipranavir: (Major) Both tipranavir boosted with ritonavir and ketoconazole are inhibitors of CYP3A4. Additionally, both drugs are CYP3A4 substrates. Based on expected CYP drug interactions, tipranavir (in the FDA approved dosage regimen) should be used cautiously with ketoconazole; high doses (i.e., > 200 mg) of ketoconazole should be avoided.
    Tizanidine: (Major) Ketoconazole should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Both drugs have been associated with prolongation of the QT interval. Coadministration increases the risk for QT prolongation and torsade de pointes.
    Tofacitinib: (Major) Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as ketoconazole. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
    Tolazamide: (Moderate) Hypoglycemia, sometimes severe, has been reported when ketoconazole is coadministered with oral hypoglycemic agents. The most likely mechanism for this interaction is inhibition of the CYP450 metabolism of oral hypoglycemics by ketoconazole. Blood glucose concentrations should be monitored during concomitant treatment; patients should be aware of the symptoms of hypoglycemia. In some cases, dosage adjustment of the sulfonylurea may be necessary. There is no evidence that an interaction occurs between oral hypoglycemics and topical or vaginal azole antifungal preparations.
    Tolbutamide: (Moderate) Hypoglycemia, sometimes severe, has been reported when ketoconazole is coadministered with oral hypoglycemic agents. The most likely mechanism for this interaction is inhibition of the CYP450 metabolism of oral hypoglycemics by ketoconazole. Blood glucose concentrations should be monitored during concomitant treatment; patients should be aware of the symptoms of hypoglycemia. In some cases, dosage adjustment of the sulfonylurea may be necessary. There is no evidence that an interaction occurs between oral hypoglycemics and topical or vaginal azole antifungal preparations.
    Tolterodine: (Major) Caution is advised when administering ketoconazole with tolterodine due to the potential for additive effects on the QT interval, increased exposure to tolterodine, and a potential for decreased absorption of ketoconazole. Both tolterodine and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, the mean maximum plasma concentrations and exposure to tolterodine were increased by 2- and 2.5-fold, respectively, when administered with ketoconazole (a potent CYP3A4 inhibitor). In a small portion of patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, the maximum daily dose of tolterodine should be reduced to 2 mg in patients receiving strong CYP3A4 inhibitors, such as ketoconazole. Finally, because ketoconazole requires an acidic pH for oral absorption, medications that increase gastric pH or decrease acid output can cause a notable decrease in the bioavailability of ketoconazole. Medications that have this effect include antimuscarinics.
    Tolvaptan: (Severe) Concomitant use of tolvaptan and ketoconazole is contraindicated. Tolvaptan is metabolized by CYP3A4. Ketoconazole 200 mg, a strong CYP3A4 inhibitor, increased tolvaptan exposure 5-fold; larger ketoconazole doses are expected to produce larger increases in tolvaptan exposure. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Topotecan: (Major) Avoid the concomitant use of ketoconazole, an in vitro P-glycoprotein (P-gp) inhibitor, with oral topotecan, a P-gp substrate; P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. If coadministration of ketoconazole and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea. In a pharmacokinetic cohort study, coadministration of oral topotecan with a potent P-gp inhibitor (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant).
    Toremifene: (Major) Avoid concurrent administration of ketoconazole and toremifene due to the potential for additive effects on the QT interval and increased exposure to toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Ketoconazole can also prolong the QT interval. Use of these drugs together may increase the risk for QT prolongation. In addition, ketoconazole (a potent inhibitor of CYP3A4) may inhibit the metabolism of toremifene (a CYP3A4 substrate); concurrent use could result in increased toremifene systemic concentrations. If use of ketoconazole is required, temporarily interrupt toremifene therapy. If toremifene therapy cannot be interrupted, and use of these drugs together is unavoidable, closely monitor patient for prolongation of the QT interval. In one study involving 18 healthy subjects, coadministration of ketoconazole (200 mg twice daily) with toremifene (80 mg daily) resulted in a 1.4-fold and 2.9-fold increase in toremifene Cmax and AUC.
    Trabectedin: (Major) Avoid the concomitant use of trabectedin with ketoconazole due to significantly increased trabectedin exposure. If short-term ketoconazole (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days) increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Tramadol: (Moderate) Administration of CYP3A4 inhibitors such as ketoconazole with tramadol may affect the metabolism of tramadol leading to altered tramadol exposure. Increased serum tramadol concentrations may occur.
    Trandolapril; Verapamil: (Moderate) Ketoconazole may decrease the clearance of calcium-channel blockers, such as verapamil, via inhibition of CYP3A4 metabolism.
    Trazodone: (Major) Avoid coadministration of trazodone and ketoconazole due to the potential for additive effects on the QT interval; increased exposure to trazodone may also occur. Both trazodone and ketoconazole are associated with QT prolongation; there are also postmarketing reports of torsade de pointes (TdP) with trazodone. In addition, concurrent use may lead to substantial increases in trazodone plasma concentrations, further increasing the risk for adverse effects. If trazodone must be used with a potent CYP3A4 inhibitor, such as ketoconazole, a lower dose of trazodone should be considered.
    Tretinoin, ATRA: (Major) Concurrent oral tretinoin therapy with drugs that inhibit the hepatic cytochrome (CYP) P450 enzyme system can result in significant increases in serum tretinoin levels. In 13 patients who had received oral tretinoin daily for 4 consecutive weeks, a 72% increase in mean tretinoin plasma AUC was observed when ketoconazole (400 mg to 1200 mg PO) was given 1 hour before the tretinoin dose. This interaction may be due to inhibition of tretinoin metabolism by the azole antifungal; the precise CYP enzymes involved have not been identified, but CYP3A, 2C8 and 2E have been implicated in preliminary data. Similar interactions may occur with other systemic azole antifungals, such as voriconazole. No specific studies have been done with oral tretinoin and other inhibitors of CYP450 isoenzymes (such as cimetidine, cyclosporine, diltiazem, erythromycin, and verapamil), however, patients should be closely monitored for tretinoin toxicity while receiving concomitant therapy.
    Triamcinolone: (Moderate) Ketoconazole can decrease the hepatic clearance of triamcinolone, resulting in increased plasma concentrations. The interaction may be due to the inhibition of cytochrome P-450 3A4 isoenzyme by ketoconazole, and subsequent decreases in corticosteroid metabolism by the same isoenzyme. Ketoconazole also can enhance the adrenal suppressive effects of corticosteroids.
    Triazolam: (Severe) Concomitant use of ketoconazole with triazolam is contraindicated due to the risk of serious adverse events, such as prolonged hypnotic and/or sedative effects. Triazolam is metabolized by CYP3A4 and is susceptible to drug interactions with systemic azole antifungals that inhibit this enzyme. Ketoconazole has been shown to dramatically inhibit the CYP3A-mediated hepatic metabolism of triazolam in healthy volunteers. Consider safer alternatives if a benzodiazepine must be administered in combination with ketoconazole. Benzodiazepines not metabolized by the CYP3A4 enzyme (e.g., lorazepam, oxazepam) are less likely to be affected by the azole antifungals.
    Tricyclic antidepressants: (Minor) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; ketoconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope have occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred. Close clinical monitoring is necessary if concurrent use is medically necessary.
    Trifluoperazine: (Minor) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include trifluoperazine.
    Trimetrexate: (Moderate) Trimetrexate is extensively metabolized by CYP450 3A4. In vitro studies have shown that ketoconazole potently inhibits the metabolism of trimetrexate.
    Trimipramine: (Minor) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the tricyclic antidepressants (TCAs). TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). CYP2C19 and CYP3A4 may be partially involved in the metabolism of TCAs; ketoconazole may increase TCA concentrations via inhibition of CYP3A4. In at least one case, an increased incidence of TCA-related side effects, such as dizziness and syncope have occurred in combination with an azole antifungal. In another case, QT-prolongation and torsades de pointes occurred. Close clinical monitoring is necessary if concurrent use is medically necessary.
    Triptorelin: (Major) Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with triptorelin include ketoconazole.
    Trospium: (Moderate) Antimuscarinic drugs, including trospium, can raise intragastric pH. This effect may decrease the oral bioavailability of ketoconazole. In addition, because both trospium and ketoconazole are eliminated by active tubular secretion, concurrent use may result in increased effects of either drug; however, studies have not been conducted,
    Ulipristal: (Minor) Ulipristal is a substrate of CYP3A4 and ketoconazole is a CYP3A4 inhibitor. Concomitant use may increase the plasma concentration of ulipristal resulting in an increased risk for adverse events.
    Umeclidinium; Vilanterol: (Major) Use extreme caution when coadministering vilanterol with strong CYP3A4 inhibitors. Vilanterol is a CYP3A4 substrate. The coadministration of vilanterol with strong CYP3A4 inhibitors such as ketoconazole may result in elevated vilanterol plasma concentrations and increased risk for adverse reactions such as nervousness, tremor, or cardiovascular effects. Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include the beta-agonists. In a placebo-controlled, drug interaction study of 20 healthy subjects, coadministration of another LABA. salmeterol (50 mcg twice daily), and ketoconazole (400 mg PO once daily) for 7 days resulted in a 16-fold increase in salmeterol AUC. Three of the 20 subjects were withdrawn from the study due to cardiovascular adverse effects (2 with QT prolongation and 1 with palpitations and sinus tachycardia). Similar interactions may occur when ketoconazole is added to vilanterol.
    Valbenazine: (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as ketoconazole. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
    Valdecoxib: (Moderate) Concomitant single dose administration of valdecoxib 20 mg with multiple doses of ketoconazole produced a significant increase in exposure of valdecoxib. Monitor for NSAID-related side effects, such as GI irritation, fluid retention or increased blood pressure, GI bleeding, or renal dysfunction and adjust the dose of the NSAID if needed.
    Vandetanib: (Major) The manufacturer of vandetanib advises against coadministration with ketoconazole due to a risk of QT prolongation and torsade de pointes (TdP). Vandetanib can prolong the QT interval in a concentration-dependent manner. TdP and sudden death have been reported in patients receiving vandetanib. If a drug that can prolong the QT interval, such as ketoconazole, is given to a patient already taking vandetanib and no alternative therapy exists, perform more frequent monitoring of the QT interval. Monitor an ECG before and during use. If QTcF is greater than 500 msec, interrupt vandetanib dosing until the QTcF is less than 450 msec; then, vandetanib may be resumed at a reduced dose.
    Vardenafil: (Major) Caution is advised when administering ketoconazole with vardenafil due to the potential for additive effects on the QT interval and increased exposure to vardenafil. Both ketoconazole and vardenafil have been associated with QT prolongation; coadministration may increase this risk. If these drugs must be administered together, a lower dose of vardenafil is required. The vardenafil orally disintegrating tablets (ODTs) provide increased exposure as compared to the regular tablets; therefore, use of the vardenafil ODTs with potent CYP3A4 inhibitors should be avoided. For patients receiving ketoconazole 200 mg daily, the maximum single vardenafil dose is 5 mg every 24 hours. For patients receiving ketoconazole 400 mg daily, the maximum single vardenafil dose is 2.5 mg every 24 hours. In one study, health subjects receiving ketoconazole 200 mg PO daily with a single 5 mg vardenafil dose experienced a 10-fold increase in the AUC and a 4-fold increase in the Cmax of vardenafil.
    Vemurafenib: (Major) Avoid concurrent administration of ketoconazole and vemurafenib due to the potential for additive effects on the QT interval, increased exposure to vemurafenib, and altered ketoconazole concentrations; an alternate drug therapy should be used when possible. Both vemurafenib and ketoconazole are associated with QT prolongation; coadministration may increase this risk. ECG monitoring is recommended if coadminsitration cannot be avoided. In addition, ketoconazole is a strong CYP3A4 inhibitor and substrate as well as a P-glycoprotein (P-gp) inhibitor and substrate, while vemurafenib is a CYP3A4 substrate and inducer and a P-gp substrate and inhibitor. Concomitant administration may increase vemurafenib concentrations and alter ketoconazole concentrations, and result in an increased risk for adverse events.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and ketoconazole; the venetoclax Cmax and AUC values were significantly increased when ketoconazole was co-administered in a drug interaction study. The concomitant use of these agents together is contraindicated during the initial and dose titration phase of venetoclax. If concomitant use of these drugs is required when the patient is on a steady venetoclax dose (after the titration phase), reduce the venetoclax dosage by at least 75% (maximum dose of 100 mg/day). If ketoconazole is discontinued, wait 2 to 3 days and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. Venetoclax is a substrate of CYP3A4, P-glycoprotein (P-gp), and Breast Cancer Resistance Protein (BCRP); ketoconazole is an inhibitor of CYP3A4 (strong), P-gp, and BCRP. In a drug interaction study (n = 11), the venetoclax Cmax increased 2.3-fold and the venetoclax AUC value increased 6.4-fold following the co-administration of ketoconazole 400 mg/day PO for 7 days in previously treated NHL patients.
    Venlafaxine: (Major) Caution is advised when administering ketoconazole with venlafaxine due to the potential for additive effects on the QT interval and increased exposure to venlafaxine. Both venlafaxine and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, venlafaxine is a substrate of CYP2D6 (major) and CYP3A4 (minor). In patients who are poor CYP2D6 metabolizers, the CYP3A4 pathway for venlafaxine may become more important. Administration of venlafaxine and ketoconazole (a potent CYP3A4 inhibitor) to patients identified as CYP2D6 poor metabolizers resulted in a significant increase in venlafaxine mean AUC; there was no effect on venlafaxine half-life.
    Verapamil: (Moderate) Ketoconazole may decrease the clearance of calcium-channel blockers, such as verapamil, via inhibition of CYP3A4 metabolism.
    Vilazodone: (Major) Because CYP3A4 is the primary isoenzyme involved in the metabolism of vilazodone, the manufacturer of vilazodone recommends that the daily dose not exceed 20 mg/day during concurrent use of a strong CYP3A4 inhibitor, such as ketoconazole. The original vilazodone dose can be resumed when the CYP3A4 inhibitor is discontinued.
    Vinblastine: (Moderate) Ketoconazole is an inhibitor of cytochrome P450 (CYP) isoenzyme 3A4. Vinblastine is a CYP3A4 substrate. Increased concentrations of vinblastine are likely if it is coadministered with ketoconazole; exercise caution.
    Vincristine Liposomal: (Major) Ketoconazole inhibits CYP3A4 and P-glycoprotein (P-gp); vincristine is both a CYP3A and P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Vincristine: (Major) Ketoconazole inhibits CYP3A4 and P-glycoprotein (P-gp); vincristine is both a CYP3A and P-gp substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Vinorelbine: (Major) Use caution with concurrent use of ketoconazole, a CYP3A4 inhibitor, and vinorelbine, a CYP3A4 substrate, as the metabolism of vinorelbine may be decreased. Monitor patients for an earlier onset and/or an increased severity of adverse effects including neurotoxicity and myelosuppression.
    Vorapaxar: (Major) Avoid coadministration of vorapaxar and ketoconazole. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with ketoconazole, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Vorinostat: (Major) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include vorinostat.
    Warfarin: (Moderate) Ketoconazole may potentiate the anticoagulant effects of warfarin and should be used cautiously in patients receiving warfarin.
    Ziprasidone: (Severe) Ziprasidone has been associated with a possible risk for QT prolongation and/or torsades de pointes. Ziprasidone is contraindicated with any drug that lists QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs. Ketoconazole has been associated with prolongation of the QT interval. Also, ziprasidone is partially metabolized via CYP3A4. The concurrent use of ziprasidone with ketoconazole, a potent CYP3A4 inhibitor, causes a 35 to 40% increase in the AUC and Cmax of ziprasidone. While the inhibition of ziprasidone metabolism did not further increase the QTc interval above the administration of ziprasidone alone in this study, some patients might experience such side effects.
    Zolpidem: (Major) Pharmacokinetic studies have shown that the systemic azole antifungals inhibit the metabolism and clearance of zolpidem. Ketoconazole has been shown to increase the Cmax and AUC of zolpidem by 30% and 70%, respectively, and prolong the half-life by 30%. It is prudent to monitor the response to zolpidem during concurrent systemic azole antifungal use and adjust dosage as needed to minimize the potential for adverse CNS effects.

    PREGNANCY AND LACTATION

    Pregnancy

    Ketoconazole is classified as FDA pregnancy risk category C. Teratogenic effects have been demonstrated in animals using oral ketoconazole doses 10 times the maximum recommended human dose. Animal data are not always predictive of effects in humans. Birth defects have been reported in women who have taken fluconazole, another azole antifungal, for extended periods during pregnancy. The Guidelines for the Prevention of Opportunistic Infections in Patients with HIV recommend that oral azole antifungals, including ketoconazole, not be started during pregnancy and that these agents should be discontinued in HIV-positive women who become pregnant. There are no adequate and well-controlled studies of topical ketoconazole use in pregnant women; however, ketoconazole is not detected in human plasma after chronic shampooing on the scalp. Ketoconazole should be used in pregnant women only when the potential benefits to the mother outweigh the potential risks to the fetus. Women of childbearing potential should use effective contraception during ketoconazole therapy.

    Systemic ketoconazole is excreted in breast milk. In a case report of one mother prescribed 200 mg PO daily for 10 days, ketoconazole milk concentrations of 0.22 micrograms/ml (peak) were observed 3.25 hours post-dose and were undetectable at 24 hours post-dose. Assuming a milk intake of 150 ml/kg/day, the author calculated the daily ketoconazole dose of an exclusively breast-fed infant at 0.01 mg/kg/day or 0.4% of the mother's weight-adjusted dose. The manufacturer recommends mothers refrain from nursing their infants during oral therapy; however, the American Academy of Pediatrics (AAP) considers ketoconazole compatible with breast-feeding. There are no adequate and well-controlled studies of topical use in nursing women; however, ketoconazole is not detected in plasma after chronic shampooing on the scalp. If the topical gel is used during breast-feeding and is applied to the chest, care should be taken to avoid accidental ingestion by the infant. Fluconazole may be a potential alternative to consider during breast-feeding. However, site of infection, patient factors, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative agent. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested or administered drug, health care providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Like other azole antifungals, ketoconazole exerts its effect by altering the fungal cell membrane. Ketoconazole inhibits ergosterol synthesis by interacting with 14-alpha demethylase, a cytochrome P-450 enzyme that is necessary for the conversion of lanosterol to ergosterol, an essential component of the membrane. In contrast, amphotericin B binds to ergosterol after it is synthesized. Inhibition of ergosterol synthesis results in increased cellular permeability, which causes leakage of cellular contents. Ketoconazole does not appear to have the same effects on human cholesterol synthesis. Other antifungal effects of azole compounds have been proposed and include: inhibition of endogenous respiration, interaction with membrane phospholipids, and inhibition of yeast transformation to mycelial forms. Other mechanisms may involve inhibition of purine uptake and impairment of triglyceride and/or phospholipid biosynthesis. At higher concentrations, ketoconazole may have a direct physiochemical effect on the fungal cell membrane, which leads to a fungicidal action.
     
    Ketoconazole possesses actions that may make it useful in conditions other than fungal infections. Ketoconazole can inhibit sterol synthesis in humans including the synthesis of aldosterone, cortisol, and testosterone. Ketoconazole's effects on testosterone synthesis occur at lower doses than do the effects on cortisol synthesis; doses of of 200—400 mg/day can inhibit testosterone secretion and doses of 400—600 mg/day have been shown to inhibit cortisol synthesis. Ketoconazole acts at many of same steps as metyrapone and, in some sites, has been shown to be a more potent inhibitor. Both ketoconazole and metyrapone affect multiple steps in the steroid-synthesis pathway, while finasteride appears to work at a single site. Ketoconazole has been used successfully for treating advanced prostate cancer. Finally, ketoconazole is a known potent inhibitor of thromboxane synthesis and has been used clinically to prevent ARDS in patients at high risk of this syndrome.

    PHARMACOKINETICS

    Ketoconazole is administered orally and via topical administration. It is widely distributed into most body fluids, although CNS penetration is unpredictable and usually minimal. In animal studies, it crosses the placenta and is distributed into milk. Protein binding is 84—99%, mainly to albumin.
     
    Ketoconazole plasma concentrations decline in a biphasic manner. Initial phase half-life is approximately 2 hours, and the terminal phase half-life is approximately 8 hours. It is partially metabolized through oxidation, dealkylation, and aromatic hydroxylation. Most of the ketoconazole and its metabolites are excreted into the bile and then the feces. The rest is excreted in the urine. In a study involving fasting adults with normal renal function, about 57% of a 200 mg oral dose was excreted in the feces within 4 days. Between 20—65% of the ketoconazole excreted in the feces was unchanged drug. Within 4 days, approximately 13% of the dose was excreted in the urine; approximately 2—4% of this portion was as unchanged ketoconazole.
     
    Affected cytochrome P450 isoenzymes and drug transporters:  CYP3A4, CYP2C9, CYP2C19, P-gp, UGT1A1, UGT2B7
    Ketoconazole is a substrate and potent inhibitor of the CYP3A4 isoenzyme. In vitro, ketoconazole weakly inhibits CYP2C9 and CYP2C19; however, the in vivo inhibition potential is questionable. Ketoconazole has the ability to inhibit P-glycoprotein (P-gp) in vitro, but the potency of this inhibition may vary depending on the in vitro model or P-gp substrate used in the assay. Studies have also found ketoconazole to be an inhibitor of uridine diphosphoglucuronosyltransferase UGT1A1 and UGT2B7.

    Oral Route

    Ketoconazole is dissolved in gastric secretions and converted to the hydrochloride salt prior to rapid absorption from the stomach. Bioavailability of oral ketoconazole is a function of intragastric pH; an acidic environment is necessary for ketoconazole absorption. The concurrent administration of food with oral ketoconazole can lead to increased absorption either by increasing bile secretions, which increase the rate/extent of ketoconazole dissolution, or by delaying gastric emptying. The peak plasma concentration (Cmax) occurs between 1—4 hours after the oral dose is taken. After a 200 mg dose, the Cmax range is from 4.2—6.2 mcg/mL in healthy fasting adults to 1.5—4.5 mcg/mL in healthy non-fasting adults. Bioavailability of ketoconazole in an oral suspension form is greater than with the tablet. There is significant interindividual variation in peak plasma concentrations and AUCs from oral doses of ketoconazole. Ketoconazole may undergo saturable first-pass metabolism since bioavailability of lower doses is relatively poor compared with that of higher doses.

    Topical Route

    Topical ketoconazole does not have significant systemic absorption. Repeated topical application of ketoconazole 2% shampoo, however, will lead to absorption of the drug into hair keratin. Small amounts of intravaginal ketoconazole are absorbed systemically. Peak plasma concentrations in women receiving ketoconazole as a 400 mg vaginal suppository ranged from 0—20.7 ng/mL.