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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.

    Apheresis, AV block, bradycardia, cardiomyopathy, celiac disease, females, fever, heart failure, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, hypothyroidism, ketoconazole coadministration with other drugs, long QT syndrome, myocardial infarction, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE), 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 certain 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 conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus infection (HIV), fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) 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 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), only use oral ketoconazole to treat serious fungal infections when no other antifungal therapies are available.[55448] [60788]
    Oral dosage
    Adults

    200 to 400 mg PO once daily. For coccidioidomycosis, 400 mg PO once daily is recommended.

    Children and Adolescents 2 to 17 years

    3.3 to 6.6 mg/kg/dose PO once daily (Max: 400 mg/day).

    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 blastomycosis 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), only use oral ketoconazole to treat serious fungal infections when no other antifungal therapies are available.[55448] [60788]
    Oral dosage
    Adults

    400 to 800 mg PO once daily for 6 to 12 months for mild to moderate pulmonary disease in patients unable to take itraconazole. The FDA-approved dose is 200 to 400 mg PO once daily.

    Children and Adolescents 2 to 17 years

    3.3 to 6.6 mg/kg/dose PO once daily (Max: 400 mg/day).[27982] [63245]

    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.

    For the treatment of cutaneous leishmaniasis†.
    Oral dosage
    Adults

    600 mg PO once daily for 28 days.

    †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)
    - Store upright
    Ketodan:
    - Avoid direct heat and sunlight
    - Do not refrigerate
    - Do Not Store at Temperatures Above 120 degrees F (49 degrees C)
    - Flammable, keep away from heat and flame
    - 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, 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).

    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.

    Apheresis, AV block, bradycardia, cardiomyopathy, celiac disease, females, fever, heart failure, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, hypothyroidism, ketoconazole coadministration with other drugs, long QT syndrome, myocardial infarction, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE), 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 certain 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 conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus infection (HIV), fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) 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

    There are no adequate and well-controlled studies of ketoconazole use during human pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Use ketoconazole in pregnant women only if the potential benefit justifies the potential risk to the fetus.[27982] [38105] [40031] Guidelines recommend against starting oral azole antifungals, including ketoconazole, during pregnancy and to discontinue these agents in HIV-positive women who become pregnant.[24842] Embryotoxic and teratogenic effects (syndactylia and oligodactylia) have been demonstrated in animals receiving oral ketoconazole doses at 10-times the maximum recommended human dose. In addition, dystocia was observed in animals administered oral ketoconazole during the third trimester of gestation at doses approximately one-fourth the maximum human dose, based on body surface area comparisons. Ketoconazole is not detected in human plasma after chronic shampooing of the scalp.[27982] [40031]

    Breast-feeding

    Systemic ketoconazole is excreted in breast milk. In a case report of a mother prescribed 200 mg PO daily for 10 days, ketoconazole milk concentrations of 0.22 mcg/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 daily ketoconazole dose of an exclusively breast-fed infant was calculated as 0.01 mg/kg/day or 0.4% of the mother's weight-adjusted dose. There are no data on the effects of ketoconazole on the breast-fed infant or its effects on milk production. While the manufacturer recommends mothers refrain from breast-feeding while receiving oral therapy, previous American Academy of Pediatrics (AAP) recommendations considered ketoconazole compatible with breast-feeding. After topical application, ketoconazole concentrations in plasma are low; therefore, concentrations in human breast milk are likely to be low. Advise breast-feeding women not to apply topical ketoconazole directly to the nipple and areola to avoid direct infant exposure. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for topical ketoconazole and any potential adverse effects on the breast-fed infant from ketoconazole or the underlying maternal condition. Fluconazole may be a potential alternative to consider during breast-feeding.

    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.

    Human immunodeficiency virus (HIV) infection

    Use oral ketoconazole with caution in patients who have human immunodeficiency virus (HIV) infection. First, HIV infection may increase the risk of prolonging the QT interval when using oral ketoconazole. Second, hypochlorhydria has been reported in patients with HIV infection. Oral ketoconazole requires an acidic environment for dissolution and absorption, and patients with hypochlorhydria may achieve low plasma ketoconazole concentrations. To increase bioavailability, these patients should take ketoconazole with an acidic beverage (i.e., cola).

    ADVERSE REACTIONS

    Severe

    keratoconjunctivitis / Early / 0-1.0
    hemolytic anemia / Delayed / 0-1.0
    hepatotoxicity / Delayed / Incidence not known
    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
    vitamin D deficiency / Delayed / Incidence not known

    Mild

    nausea / Early / 3.0-3.0
    vomiting / 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
    rash / Early / 0-1.0
    skin irritation / Early / 0-1.0
    xerosis / Delayed / 0-1.0
    nail discoloration / Delayed / 0-1.0
    acne vulgaris / Delayed / 0-1.0
    cheilitis / Delayed / Incidence not known
    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; Codeine: (Moderate) Concomitant use of codeine with ketoconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of ketoconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ketoconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ketoconazole is a strong inhibitor of CYP3A4. (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: (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; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with ketoconazole may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of ketoconazole could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ketoconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Ketoconazole is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of 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) Concomitant use of codeine with ketoconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of ketoconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ketoconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ketoconazole is a strong inhibitor of CYP3A4.
    Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ketoconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. If ketoconazole is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like ketoconazole can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ketoconazole is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    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.
    Aclidinium; 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.
    Ado-Trastuzumab emtansine: (Major) Avoid coadministration of ketoconazole with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until ketoconazole has cleared from the circulation (approximately 3 half-lives of ketoconazole) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; ketoconazole is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
    Afatinib: (Moderate) If the concomitant use of ketoconazole and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of ketoconazole. 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. Afatinib is a P-glycoprotein (P-gp) substrate and ketoconazole is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor 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 the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
    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.
    Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. If ketoconazole is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If ketoconazole is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
    Alfuzosin: (Contraindicated) Alfuzosin is contraindicated for use with ketoconazole due to the potential for serious/life-threatening reactions, including hypotension. Additive effects on the QT interval may also occur. Alfuzosin is a CYP3A4 substrate that may prolong the QT interval in a dose-dependent manner. Ketoconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Coadministration of ketoconazole increased the alfuzosin AUC by 2.5-fold to 3.2-fold.
    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: (Moderate) 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: (Contraindicated) Coadministration of ketoconazole and alprazolam is contraindicated. Ketoconazole is a potent CYP3A4 inhibitor and significantly impairs the CYP3A4 metabolism of alprazolam, resulting in significantly 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.
    Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with ketoconazole. Amisulpride causes dose- and concentration- dependent QT prolongation. Ketoconazole has been associated with prolongation of the QT interval.
    Amitriptyline: (Minor) Use ketoconazole with caution in combination with tricyclic antidepressants (TCAs) as concurrent use may increase the risk of QT prolongation and increased TCA-related adverse effects. 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) Use ketoconazole with caution in combination with tricyclic antidepressants (TCAs) as concurrent use may increase the risk of QT prolongation and increased TCA-related adverse effects. 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) Use caution and the lowest atorvastatin dose necessary if coadministration with ketoconazole is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Ketoconazole inhibits the CYP3A4-mediated metabolism of atorvastatin. In addition, HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis and should be used with caution when given 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; Celecoxib: (Moderate) Ketoconazole may decrease the clearance of calcium-channel blockers, including amlodipine, via inhibition of CYP3A4 metabolism. (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.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (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.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (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.
    Apalutamide: (Major) The use of apalutamide within 2 weeks of systemic ketoconazole therapy is not recommended due to the potential for decreased exposure to ketoconazole; apalutamide exposure may also increase. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole and an increase in apalutamide-related adverse reactions. Increase the dose of ketoconazole as necessary; consider reducing the dose of apalutamide if necessary based on tolerability in patients experiencing grade 3 or higher adverse reactions or intolerable toxicities. Ketoconazole is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer.
    Apixaban: (Major) Reduce the apixaban dose by 50% when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as ketoconazole. If patients are already receiving the reduced dose of 2.5 mg twice daily, avoid concomitant administration of apixaban and ketoconazole. Concomitant administration of ketoconazole and apixaban results in increased exposure to apixaban and an increase in the risk of bleeding.
    Apomorphine: (Moderate) Exercise caution when administering apomorphine concomitantly with ketoconazole since concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
    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. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.
    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) Concomitant use of codeine with ketoconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of ketoconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ketoconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ketoconazole is a strong inhibitor of CYP3A4. (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; 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; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with ketoconazole may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of ketoconazole could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ketoconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Ketoconazole is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of 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; Caffeine; Orphenadrine: (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) Concomitant use of codeine with ketoconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of ketoconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ketoconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ketoconazole is a strong inhibitor of CYP3A4.
    Aspirin, ASA; Citric Acid; 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.
    Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. If ketoconazole is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like ketoconazole can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ketoconazole is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    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: (Moderate) Use ketoconazole with caution in combination with atomoxetine as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose.
    Atorvastatin: (Major) Use caution and the lowest atorvastatin dose necessary if coadministration with ketoconazole is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Ketoconazole inhibits the CYP3A4-mediated metabolism of atorvastatin. In addition, HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis and should be used with caution when given 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) Use caution and the lowest atorvastatin dose necessary if coadministration with ketoconazole is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Ketoconazole inhibits the CYP3A4-mediated metabolism of atorvastatin. In addition, HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis and should be used with caution when given 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.
    Avapritinib: (Major) Avoid coadministration of avapritinib with ketoconazole due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
    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 half; 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 a CYP3A4/5 substrate and ketoconazole is a strong CYP3A4 inhibitor. 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 inhaled fluticasone propionate and ketoconazole is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with ketoconazole increased plasma fluticasone exposure by 1.9-fold with a 45% decrease in plasma cortisol AUC, but had no effect on urinary excretion of cortisol. Ketoconazole increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Minor) Theoretically, systemic exposure of nasally administered azelastine may be increased by coadministration with ketoconazole, although an interaction has not been documented.
    Azithromycin: (Major) Avoid coadministration of azithromycin with ketoconazole due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Ketoconazole has been associated with prolongation of the QT interval.
    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: (Contraindicated) 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.
    Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with ketoconazole may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of ketoconazole in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If ketoconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Ketoconazole is a strong inhibitor of CYP3A4.
    Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking ketoconazole. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Berotralstat is a P-gp substrate and ketoconazole is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased berotralstat exposure by 69%.
    Betamethasone: (Moderate) Monitor for corticosteroid-related adverse effects if coadministration is necessary. Ketoconazole is a strong CYP3A4 inhibitor and betamethasone is a CYP3A4 substrate. Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid 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.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and ketoconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and ketoconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    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. 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 CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
    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: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ketoconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ketoconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    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.
    Budesonide; 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. (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.
    Bupivacaine; Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with ketoconazole is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and ketoconazole is a weak CYP2C9 inhibitor. (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.
    Butalbital; Acetaminophen; 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.
    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%.
    Cabotegravir; 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.
    Cabozantinib: (Major) Avoid coadministration of cabozantinib with ketoconazole due to the risk of increased cabozantinib exposure. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 40 mg/day; 40 mg/day to 20 mg/day); for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 100 mg/day or 100 mg/day to 60 mg/day). Resume the cabozantinib dose that was used prior to initiating treatment with ketoconazole 2 to 3 days after discontinuation of ketoconazole. Cabozantinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased single-dose cabozantinib 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: (Contraindicated) 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.
    Caffeine; Sodium Benzoate: (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; Famotidine; 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. (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.
    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 Carbonate; Simethicone: (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.
    Capmatinib: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with ketoconazole is necessary. Capmatinib is a CYP3A substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
    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: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ketoconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ketoconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    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; additive QT prolongation and increased ketoconazole exposure may also occur. If concomitant use is unavoidable, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg; 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. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with ketoconazole increased ceritinib exposure by 2.9-fold in healthy subjects. Concentration-dependent QT prolongation has been reported with ceritinib therapy. Ketoconazole 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.
    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) Avoid coadministration of chloroquine with systemic ketoconazole due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Ketoconazole has been associated with prolongation of the QT interval.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with ketoconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of ketoconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ketoconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ketoconazole is a strong inhibitor of CYP3A4.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with ketoconazole may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of ketoconazole could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ketoconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Ketoconazole is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with ketoconazole may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of ketoconazole could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ketoconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Ketoconazole is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ketoconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ketoconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ketoconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ketoconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    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: (Moderate) Use ketoconazole with caution in combination with ciprofloxacin as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Rare cases of QT prolongation and torsade de pointes (TdP) have been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Contraindicated) 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) Monitor for an increase in clindamycin-related adverse reactions with coadministration of ketoconazole as concurrent use may increase clindamycin exposure. Clindamycin is a CYP3A4 substrate; ketoconazole is a strong inhibitor of CYP3A4.
    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.
    Clofazimine: (Major) Monitor ECGs for QT prolongation when clofazimine is administered with ketoconazole. QT prolongation and torsade de pointes have been reported in patients receiving clofazimine in combination with QT prolonging medications. Ketoconazole has been associated with prolongation of the QT interval.
    Clomipramine: (Minor) Use ketoconazole with caution in combination with tricyclic antidepressants (TCAs) as concurrent use may increase the risk of QT prolongation and increased TCA-related adverse effects. 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) Use ketoconazole cautiously and carefully monitor patients receiving concurrent clonazepam due to impaired metabolism of clonazepam leading to exaggerated concentrations and adverse effects, such as CNS and/or respiratory depression. Clonazepam is a CYP3A4 substrate. Ketoconazole is a strong CYP3A4 inhibitor.
    Clopidogrel: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of ketoconazole. In a drug interaction study, ketoconazole decreased the active metabolite of clopidogrel.
    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.
    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) Concomitant use of codeine with ketoconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of ketoconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ketoconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ketoconazole is a strong inhibitor of CYP3A4.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with ketoconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of ketoconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ketoconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ketoconazole is a strong inhibitor of CYP3A4.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with ketoconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of ketoconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ketoconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ketoconazole is a strong inhibitor of CYP3A4. (Moderate) Use ketoconazole with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with ketoconazole may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of ketoconazole could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ketoconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ketoconazole is a strong inhibitor of CYP3A4. (Moderate) Use ketoconazole with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    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.
    Colchicine; Probenecid: (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: (Contraindicated) Coadministration of conivaptan with ketoconazole is contraindicated. Administration 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. Conivaptan is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor.
    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 concomitant use of ketoconazole and crizotinib due to increased plasma concentrations of crizotinib, which may increase the incidence and severity of adverse reactions; QT prolongation may also occur. If concomitant use is necessary for patients with non-small cell lung cancer, reduce the dose of crizotinib to 250 mg PO once daily. If concomitant use is necessary for patients with anaplastic large cell lymphoma, reduce the dose of crizotinib to 250 mg PO twice daily for BSA of 1.7 m2 or more; 200 mg PO twice daily for BSA of 1.17 to 1.69 m2; and 250 mg PO once daily for BSA of 0.81 to 1.16 m2; do not use this combination in patients with a BSA of 0.6 to 0.8 m2. Monitor ECGs for QT prolongation and electrolytes; an interruption of therapy, dose reduction, or discontinuation of crizotinib therapy may be necessary if QT prolongation occurs. Resume the original crizotinib dose after discontinuation of ketoconazole. Crizotinib is a CYP3A substrate that has been associated with concentration-dependent QT prolongation. Ketoconazole is a strong CYP3A4 inhibitor that is also associated with QT prolongation. Concomitant use with ketoconazole increased the AUC of single-dose crizotinib by 216%.
    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.
    Darolutamide: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with ketoconazole is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Ketoconazole is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
    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.
    Darunavir; Cobicistat; 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. (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).
    Dasatinib: (Major) Avoid coadministration of dasatinib and ketoconazole due to the potential for increased dasatinib exposure and subsequent toxicity including QT prolongation and torsade de pointes (TdP). An alternative to ketoconazole with no or minimal enzyme inhibition potential is recommended if possible. If coadministration cannot be avoided, consider a dasatinib dose reduction to 40 mg PO daily if original dose was 140 mg daily, 20 mg PO daily if original dose was 100 mg daily, or 20 mg PO daily if original dose was 70 mg daily. Stop dasatinib during use of ketoconazole in patients receiving dasatinib 60 mg or 40 mg PO daily. If dasatinib is not tolerated after dose reduction, either discontinue ketoconazole or stop dasatinib until ketoconazole is discontinued. Allow a washout of approximately 1 week after ketoconazole is stopped before increasing the dasatinib dose or reinitiating dasatinib. Dasatinib is a CYP3A4 substrate that has the potential to prolong the QT interval; ketoconazole is a strong CYP3A4 inhibitor that is associated with QT prolongation. Coadministration of ketoconazole increased the mean Cmax and AUC of dasatinib by 4-fold and 5-fold, respectively.
    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: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving ketoconazole as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Ketoconazole has also been associated with prolongation of the QT interval.
    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) Use ketoconazole with caution in combination with tricyclic antidepressants (TCAs) as concurrent use may increase the risk of QT prolongation and increased TCA-related adverse effects. 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.
    Desogestrel; 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.
    Deutetrabenazine: (Moderate) Use ketoconazole with caution in combination with deutetrabenazine. Ketoconazole has been associated with prolongation of the QT interval. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
    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; Quinidine: (Contraindicated) 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.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with ketoconazole may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of ketoconazole could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ketoconazole is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Ketoconazole is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Dihydroergotamine: (Contraindicated) 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: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ketoconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Disopyramide: (Contraindicated) 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: (Major) Avoid coadministration of docetaxel with ketoconazole if possible due to increased plasma concentrations of docetaxel. If concomitant use is unavoidable, closely monitor for docetaxel-related adverse reactions and consider a 50% dose reduction of docetaxel. Docetaxel is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Concomitant use with ketoconazole increased docetaxel exposure by 2.2-fold.
    Dofetilide: (Contraindicated) 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: (Moderate) Administer dolasetron with caution in combination with ketoconazole as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir; 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.
    Donepezil: (Moderate) Use donepezil with caution in combination with ketoconazole as concurrent use may increase the risk of QT prolongation. Clinical monitoring for donepezil-related adverse effects, such as GI or cholinergic effects, is also recommended. The plasma concentrations of donepezil may be elevated when administered concurrently with ketoconazole. Ketoconazole is a strong inhibitor of CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes. Donepezil is a CYP3A4 substrate; case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Coadministration with ketoconazole increased mean donepezil concentrations by 36%. The clinical significance of this increase is unknown.
    Donepezil; Memantine: (Moderate) Use donepezil with caution in combination with ketoconazole as concurrent use may increase the risk of QT prolongation. Clinical monitoring for donepezil-related adverse effects, such as GI or cholinergic effects, is also recommended. The plasma concentrations of donepezil may be elevated when administered concurrently with ketoconazole. Ketoconazole is a strong inhibitor of CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes. Donepezil is a CYP3A4 substrate; case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Coadministration with ketoconazole increased mean donepezil concentrations by 36%. The clinical significance of this increase is unknown.
    Doravirine: (Minor) Coadministration of doravirine and ketoconazole may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; ketoconazole is a strong inhibitor. In a drug interaction study, concurrent use of ketoconazole increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
    Doravirine; Lamivudine; 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. (Minor) Coadministration of doravirine and ketoconazole may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; ketoconazole is a strong inhibitor. In a drug interaction study, concurrent use of ketoconazole increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
    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) Use ketoconazole with caution in combination with tricyclic antidepressants (TCAs) as concurrent use may increase the risk of QT prolongation and increased TCA-related adverse effects. 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) Avoid coadministration of ketoconazole with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Ketoconazole is a potent CYP3A4 inhibitor, and a P-glycoprotein (P-gp) inhibitor; doxorubicin is a major substrate of CYP3A4 and P-gp. Concurrent use of CYP3A4 or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
    Dronabinol: (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: (Contraindicated) 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: (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.
    Drospirenone; Estetrol: (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.
    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) Avoid use of tamsulosin with strong CYP3A4 inhibitors such as systemic ketoconazole.Tamsulosin is extensively metabolized by CYP3A4 and potent CYP3A4 inhibitors are expected to significantly raise tamsulosin concentrations. Ketoconaozole increased plasma concentrations of tamsulosin; resulting in an increase in the Cmax and AUC of tamsulosin by a 2.2- and 2.8-fold, respectively. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. (Moderate) Dutasteride is metabolized by CYP3A4 enzyme. CYP3A4 inhibitors, such as ketoconazole, may decrease the clearance of dutasteride.
    Duvelisib: (Major) Reduce duvelisib dose to 15 mg PO twice daily and monitor for increased toxicity when coadministered with ketoconazole. Coadministration may increase the exposure of duvelisib. Duvelisib is a CYP3A substrate; ketoconazole is a strong CYP3A inhibitor. The increase in exposure to duvelisib is estimated to be approximately 2-fold when used concomitantly with strong CYP3A inhibitors such as ketoconazole.
    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.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (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.
    Elagolix: (Major) Concomitant use of elagolix 200 mg twice daily and ketoconazole for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and ketoconazole to 6 months. Elagolix is a CYP3A substrate and a weak to moderate CYP3A4 inducer; ketoconazole is a strong inhibitor of CYP3A and a CYP3A4 substrate. Coadministration may increase elagolix plasma concentrations and decrease ketoconazole concentrations. In drug interaction studies, coadministration of elagolix with ketoconazole increased the Cmax and AUC of elagolix by 77% and 120%, respectively.
    Elagolix; Estradiol; Norethindrone acetate: (Major) Concomitant use of elagolix 200 mg twice daily and ketoconazole for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and ketoconazole to 6 months. Elagolix is a CYP3A substrate and a weak to moderate CYP3A4 inducer; ketoconazole is a strong inhibitor of CYP3A and a CYP3A4 substrate. Coadministration may increase elagolix plasma concentrations and decrease ketoconazole concentrations. In drug interaction studies, coadministration of elagolix with ketoconazole increased the Cmax and AUC of elagolix by 77% and 120%, respectively. (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.
    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: (Contraindicated) Eletriptan is contraindicated with recent use (i.e., within 72 hours) of ketoconazole due to the potential for increased eletriptan exposure. Eletriptan is a sensitive substrate of CYP3A4; ketoconazole is a strong CYP3A4 inhibitor. Coadministration of ketoconazole increased the Cmax and AUC of eletriptan by 3-fold and 6-fold, respectively.
    Elexacaftor; tezacaftor; ivacaftor: (Major) If ketoconazole and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Ivacaftor is a CYP3A substrate. Coadministration with ketoconazole, a strong CYP3A inhibitor, increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor when coadministered with ketoconazole; coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 2 elexacaftor/tezacaftor/ivacaftor combination tablets twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Elexacaftor, tezacaftor, and ivacaftor are CYP3A4 substrates (ivacaftor is a sensitive substrate); ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased ivacaftor exposure by 8.5-fold; coadministration with a strong CYP3A4 inhibitor increased elexacaftor exposure by 2.8- fold and tezacaftor exposure by 4.5-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with ketoconazole; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); ketoconazole is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
    Eliglustat: (Contraindicated) 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.
    Elvitegravir; Cobicistat; 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.
    Elvitegravir; Cobicistat; 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.
    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: (Contraindicated) 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.
    Encorafenib: (Major) Avoid coadministration of encorafenib and ketoconazole due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ketoconazole. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If ketoconazole is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ketoconazole. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation; ketoconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively.
    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.
    Enfortumab vedotin: (Moderate) Monitor for signs of enfortumab vedotin-related adverse reactions if coadministration with ketoconazole is necessary. Concomitant use may increase free monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Clinical drug interaction studies have not been conducted for enfortumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with ketoconazole increased the Cmax and AUC of MMAE by 25% and 34%, respectively, with no change in the total exposure of the antibody-drug conjugate.
    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.
    Entrectinib: (Major) Avoid coadministration of entrectinib with ketoconazole due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If ketoconazole is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of ketoconazole. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; ketoconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    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.
    Eplerenone: (Contraindicated) 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.
    Erdafitinib: (Major) Avoid coadministration of erdafitinib and ketoconazole due to the risk of increased plasma concentrations of erdafitinib. If concomitant use is unavoidable, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. If ketoconazole is discontinued, the dose of erdafitinib may be increased in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. The mean ratios for the Cmax and AUC of erdafitinib were 105% and 134%, respectively, when coadministered with another strong CYP3A4 inhibitor.
    Ergoloid Mesylates: (Contraindicated) 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: (Contraindicated) 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: (Contraindicated) 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: (Contraindicated) 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 coadministration of erlotinib with ketoconazole if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased erlotinib exposure by 67%.
    Erythromycin: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval, such as erythromycin. Both erythromycin and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, ketoconazole is a substrate of CYP3A4 and erythromycin is an inhibitor of CYP3A4. Coadministration may result in increased plasma concentrations of ketoconazole, thereby further increasing the risk for adverse events.
    Erythromycin; Sulfisoxazole: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval, such as erythromycin. Both erythromycin and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, ketoconazole is a substrate of CYP3A4 and erythromycin is an inhibitor of CYP3A4. Coadministration may result in increased plasma concentrations of ketoconazole, thereby further increasing the risk for adverse events.
    Escitalopram: (Moderate) Caution is advised when administering ketoconazole with escitalopram as concurrent use may increase the risk of QT prolongation and decrease ketoconazole efficacy. 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.
    Estradiol; Progesterone: (Moderate) Use caution if coadministration of ketoconazole with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Ketoconazole is a strong CYP3A4 inhibitor. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (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: (Major) A disulfiram-like reaction has been reported when patients taking ketoconazole consume alcohol. 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. Due to the risk of hepatotoxicity, alcohol 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; 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; 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.
    Ethynodiol Diacetate; 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.
    Etonogestrel: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as ketoconazole may increase the serum concentration of etonogestrel.
    Etonogestrel; 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. (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as ketoconazole may increase the serum concentration of etonogestrel.
    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 everolimus with ketoconazole due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Ketoconazole is a strong CYP3A4 and P-gp inhibitor. Coadministration with ketoconazole increased the Cmax, AUC, and half-life of everolimus by 3.9-fold, 15-fold, and 89%, respectively.
    Ezetimibe; Simvastatin: (Contraindicated) 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: (Moderate) Use ketoconazole with caution in combination with ezogabine as concurrent use may increase the risk of QT prolongation. Ketoconazole and ezogabine are associated with prolongation of the QT interval.
    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.
    Fedratinib: (Major) Avoid coadministration of fedratinib with ketoconazole as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If ketoconazole is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration of ketoconazole 200 mg twice daily with a single 300-mg dose of fedratinib increased the fedratinib AUC(inf) by 3-fold. The expected steady-state fedratinib AUC increase is 2-fold when fedratinib 400 mg/day is coadministered with ketoconazole 400 mg/day based on pharmacokinetic modeling and simulations.
    Felodipine: (Contraindicated) 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) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. If ketoconazole is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If ketoconazole is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
    Fesoterodine: (Major) Limit the dose of fesoterodine to 4 mg once daily in adults and pediatric patients weighing more than 35 kg if coadministered with ketoconazole. Avoid use of fesoterodine and ketoconazole in pediatric patients weighing 25 to 35 kg. Concurrent use may increase fesoterodine exposure. Fesoterodine is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole led to approximately a doubling of the overall exposure of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine.
    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.
    Finerenone: (Contraindicated) Concomitant use of finerenone and ketoconazole is contraindicated. Concomitant use may increase finerenone exposure and the risk for finerenone-related adverse reactions. Finerenone is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased overall exposure to finerenone by more than 400%.
    Fingolimod: (Moderate) Exercise caution when administering fingolimod concomitantly with ketoconazole as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Ketoconazole has been associated with prolongation of the QT interval.
    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: (Contraindicated) 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: (Moderate) Use fluoxetine with caution in combination with ketoconazole. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Ketoconazole has also been associated with prolongation of the QT interval.
    Fluoxetine; Olanzapine: (Moderate) Use fluoxetine with caution in combination with ketoconazole. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Ketoconazole has also been associated with prolongation of the QT interval. (Moderate) Use ketoconazole with caution in combination with olanzapine as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    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 inhaled fluticasone propionate and ketoconazole is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with ketoconazole increased plasma fluticasone exposure by 1.9-fold with a 45% decrease in plasma cortisol AUC, but had no effect on urinary excretion of cortisol. Ketoconazole increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
    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 inhaled fluticasone propionate and ketoconazole is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with ketoconazole increased plasma fluticasone exposure by 1.9-fold with a 45% decrease in plasma cortisol AUC, but had no effect on urinary excretion of cortisol. Ketoconazole increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
    Fluticasone; Umeclidinium; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and ketoconazole is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with ketoconazole increased plasma fluticasone exposure by 1.9-fold with a 45% decrease in plasma cortisol AUC, but had no effect on urinary excretion of cortisol. Ketoconazole increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (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 inhaled fluticasone propionate and ketoconazole is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with ketoconazole increased plasma fluticasone exposure by 1.9-fold with a 45% decrease in plasma cortisol AUC, but had no effect on urinary excretion of cortisol. Ketoconazole increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (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: (Moderate) Use ketoconazole with caution in combination with fluvoxamine as concurrent use may increase the risk of QT prolongation. 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. (Moderate) Coadministration of mometasone with ketoconazole may cause elevated mometasone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Mometasone is a CYP3A4 substrate; ketoconazole is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
    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.
    Fostamatinib: (Moderate) Monitor for fostamatinib toxicities that may require fostamatinib dose reduction (i.e., elevated hepatic enzymes, neutropenia, high blood pressure, severe diarrhea) if given concurrently with a strong CYP3A4 inhibitor. Concomitant use of fostamatinib with a strong CYP3A4 inhibitor increases exposure to the major active metabolite, R406, which may increase the risk of adverse reactions. R406 is extensively metabolized by CYP3A4; ketoconazole is a strong CYP3A4 inhibitor. Coadministration of fostamatinib with ketoconazole increased R406 AUC by 102% and Cmax by 37%.
    Fostemsavir: (Moderate) Use ketoconazole with caution in combination with fostemsavir. Ketoconazole has been associated with prolongation of the QT interval. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
    Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ketoconazole is necessary. Gefitinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
    Gemifloxacin: (Moderate) Use ketoconazole with caution in combination with gemifloxacin as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    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.
    Gilteritinib: (Major) Consider an alternative to ketoconazole during treatment with gilteritinib due to increased gilteritinib exposure and the potential for additive QT prolongation. If coadministration is required, frequently monitor for gilteritinib-related adverse effects and cardiac toxicity. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. Both drugs have been associated with QT prolongation.
    Glasdegib: (Major) Consider an alternative to ketoconazole during treatment with glasdegib due to the potential for additive QT prolongation and increased glasdegib exposure. If coadministration cannot be avoided, monitor for increased glasdegib-related adverse events and for increased risk of QT prolongation with more frequent ECG monitoring. Glasdegib is a CYP3A4 substrate that may cause QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Ketoconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Coadministration of ketoconazole increased the glasdegib AUC by 2.4-fold in a drug interaction study.
    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: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks of QT prolongation in patients receiving ketoconazole as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Granisetron: (Moderate) Use ketoconazole with caution in combination with granisetron as concurrent use may increase the risk of QT prolongation. Ketoconazole and granisetron have been associated with prolongation of the QT interval.
    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: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ketoconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ketoconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    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.
    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: (Moderate) Use ketoconazole with caution in combination with haloperidol as concurrent use may increase the risk of QT prolongation and haloperidol-related adverse effects. A haloperidol dose reduction may be necessary. Ketoconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Haloperidol is a CYP3A4 substrate; QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. Mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with CYP3A4 inhibitors.
    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.
    Histrelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving ketoconazole as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ketoconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ketoconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ketoconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ketoconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ketoconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ketoconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ketoconazole can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ketoconazole is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydroxychloroquine: (Major) Avoid coadministration of ketoconazole and hydroxychloroquine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Ketoconazole and hydroxychloroquine have been associated with prolongation of the QT interval.
    Hydroxyzine: (Moderate) Caution is recommended if hydroxyzine is administered with ketoconazole due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP. Ketoconazole has been associated with prolongation of the QT interval.
    Ibrexafungerp: (Major) Decrease the ibrexafungerp dose to 150 mg PO every 12 hours for 1 day if administered concomitantly with ketoconazole. In a drug interaction study, the AUC and Cmax of ibrexafungerp increased by 5.8-fold and 2.5-fold, respectively, when coadministered with ketoconazole. Ibrexafungerp is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor.
    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: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. If ketoconazole is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like ketoconazole can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ketoconazole is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    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.
    Idelalisib: (Contraindicated) 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: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with ketoconazole is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Ketoconazole is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    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 strong 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) Use ketoconazole with caution in combination with tricyclic antidepressants (TCAs) as concurrent use may increase the risk of QT prolongation and increased TCA-related adverse effects. 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.
    Infigratinib: (Major) Avoid concomitant use of infigratinib and ketoconazole. Coadministration may increase infigratinib exposure, increasing the risk for adverse effects. Infigratinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC of infigratinib by 622%.
    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.
    Ipratropium; 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.
    Irinotecan Liposomal: (Major) Avoid administration of ketoconazole during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a UGT1A1 substrate. Ketoconazole is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased exposure to both irinotecan and SN-38.
    Irinotecan: (Major) Avoid administration of ketoconazole during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a UGT1A1 substrate. Ketoconazole is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased exposure to both irinotecan and SN-38.
    Isavuconazonium: (Contraindicated) 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.
    Istradefylline: (Major) Do not exceed 20 mg once daily of istradefylline if administered with ketoconazole as istradefylline exposure and adverse effects may increase. Ketoconazole is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with ketoconazole in a drug interaction study.
    Itraconazole: (Major) Typically ketoconazole and itraconazole would not be used in combination due to similar mechanisms of action and indications for use (duplicate therapies). Both itraconazole and ketoconazole are substrates and inhibitors of CYP3A4; taking these drugs together may increase the serum concentrations of both drugs. Furthermore, all systemic azole antifungal agents have been associated with prolongation of the QT interval. Coadministration would increase the risk of QT prolongation.
    Ivabradine: (Contraindicated) 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. Ivacaftor is a CYP3A substrate. Coadministration with ketoconazole, a strong CYP3A inhibitor, increased ivacaftor exposure by 8.5-fold.
    Ivosidenib: (Major) Do not coadminister ivosidenib with ketoconazole due to decreased exposure to ketoconazole and loss of antifungal efficacy. Additionally, ivosidenib exposure may increase which increases the risk of QT prolongation. If a patient has received ketoconazole, reduce the initial dose of ivosidenib to 250 mg PO once daily and wait at least 5 half-lives of ketoconazole after stopping therapy before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and inducer, and has been associated with QTc prolongation as well as ventricular arrhythmias. Ketoconazole is a CYP3A4 substrate and strong inhibitor that has also been associated with QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax. Because ivosidenib induces CYP3A4, it is also expected to decrease steady-state exposure to CYP3A4 substrates, such as ketoconazole, to a clinically relevant extent.
    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.
    Lamivudine; 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.
    Lamotrigine: (Moderate) Consider a dose reduction of lamotrigine, as clinically appropriate, if adverse reactions occur when administered with ketoconazole. Increased lamotrigine exposure is possible. Lamotrigine is a UGT2B7 substrate. Ketoconazole is a UGT2B7 inhibitor.
    Lapatinib: (Major) Avoid coadministration of lapatinib with ketoconazole due to increased plasma concentrations of lapatinib; QT prolongation may also occur. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. Monitor for evidence of QT prolongation and torsade de pointes (TdP). If ketoconazole is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate that has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have also been reported in postmarketing experience. Ketoconazole is a strong CYP3A4 inhibitor that has also been associated with QT prolongation. Concomitant use with ketoconazole increased lapatinib exposure by 3.6-fold and increased the half-life of lapatinib by 1.7-fold.
    Larotrectinib: (Major) Avoid coadministration of larotrectinib with ketoconazole due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If ketoconazole is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of ketoconazole. Larotrectinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Lefamulin: (Major) Avoid coadministration of lefamulin with ketoconazole as concurrent use may increase the risk of QT prolongation; concurrent use may also increase exposure from lefamulin tablets which may increase the risk of adverse effects. Lefamulin is a CYP3A4 and P-gp substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Ketoconazole is a P-gp and strong CYP3A4 inhibitor that is also associated with QT prolongation. Coadministration of ketoconazole increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
    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.
    Lemborexant: (Major) Avoid coadministration of lemborexant and ketoconazole as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration of lemborexant with another strong CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with ketoconazole due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Ketoconazole has also been associated with prolongation of the QT interval.
    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.
    Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of ketoconazole may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, monitor closely for increased or prolonged pharmacologic effects of ketoconazole; the ketoconazole dose should be decreased as deemed necessary. When appropriate, ketoconazole plasma concentrations should be measured. Ketoconazole is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor; therefore, the magnitude of the interaction may be amplified.
    Leuprolide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving ketoconazole as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Androgen deprivation therapy may also prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving ketoconazole as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Androgen deprivation therapy may also prolong the QT/QTc interval.
    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.
    Levamlodipine: (Moderate) Ketoconazole may decrease the clearance of calcium-channel blockers, including amlodipine, via inhibition of CYP3A4 metabolism.
    Levofloxacin: (Moderate) Use ketoconazole with caution in combination with levofloxacin. Ketoconazole has been associated with prolongation of the QT interval as concurrent use may increase the risk of QT prolongation. Levofloxacin has been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of 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.
    Levonorgestrel; 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.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (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.
    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.
    Lidocaine; Prilocaine: (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: (Moderate) Use ketoconazole with caution in combination with lithium as concurrent use may increase the risk of QT prolongation. Ketoconazole and lithium have been associated with prolongation of the QT interval.
    Lofexidine: (Major) Monitor ECG if lofexidine is coadministered with ketoconazole due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Ketoconazole has been associated with prolongation of the QT interval.
    Lomitapide: (Contraindicated) 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.
    Lonafarnib: (Contraindicated) Coadministration of lonafarnib and ketoconazole is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate, a CYP2C9 substrate, and strong CYP3A4 inhibitor. Ketoconazole is a CYP3A4 substrate, a weak CYP2C9 inhibitor, and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
    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) Avoid coadministration of lopinavir with ketoconazole due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Both drugs have been associated with 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).
    Lorlatinib: (Major) Avoid coadministration of lorlatinib with ketoconazole due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions of lorlatinib. If concomitant use is unavoidable, decrease the starting dose of lorlatinib from 100 mg PO once daily to 75 mg PO once daily. In patients who have already had a dose reduction to 75 mg PO once daily due to adverse reactions, reduce the dose of lorlatinib to 50 mg PO once daily. If ketoconazole is discontinued, increase the dose of lorlatinib after 3 plasma half-lives of ketoconazole to the dose that was used before starting ketoconazole. Lorlatinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of lorlatinib by 42% and 24%, respectively.
    Lovastatin: (Contraindicated) 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: (Contraindicated) 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. Ivacaftor is a CYP3A substrate. Coadministration with ketoconazole, a strong CYP3A inhibitor, increased ivacaftor exposure by 8.5-fold.
    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 or 1 packet of oral granules every other day 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 another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
    Lumateperone: (Major) Avoid coadministration of lumateperone and ketoconazole as concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lumateperone exposure by approximately 4-fold. In addition, lumateperone is a UGT substrate and ketoconazole is a UGT inhibitor. The manufacturer of lumateperone recommends avoiding concomitant use of lumateperone with UGT inhibitors.
    Lurasidone: (Contraindicated) 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.
    Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and ketoconazole due to the risk of increased lurbinectedin exposure which may increase the incidence of lurbinectedin-related adverse reactions. Lurbinectedin is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as ketoconazole. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Ketoconazole has been associated with prolongation of the QT interval.
    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; children weighing 2 to 9 kg: use not recommended.
    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: (Contraindicated) 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%.
    Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with ketoconazole is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and ketoconazole is a weak CYP2C9 inhibitor.
    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: (Moderate) Use ketoconazole with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    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; Repaglinide: (Moderate) Coadministration of ketoconazole and repaglinide increases the AUC of repaglinide by 15%; if coadministration is necessary, consider a dose reduction of repaglinide and increased frequency of glucose monitoring. Ketoconazole is a CYP3A4 inhibitor and repaglinide is a CYP3A4 substrate. The possibility of an increased risk of hypoglycemia should be considered during concomitant use of ketoconazole and repaglinide.
    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: (Contraindicated) 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: (Contraindicated) 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: (Contraindicated) 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: (Moderate) Concomitant use of metronidazole and ketoconazole may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Midazolam: (Contraindicated) 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: (Major) Avoid coadministration of mifepristone with ketoconazole due to the risk of additive QT prolongation; the exposure of both drugs may also be increased. If concomitant use of mifepristone is necessary for the treatment of Cushing's syndrome in a patient already receiving ketoconazole, initiate mifepristone at a dose of 300 mg and titrate to a maximum of 900 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 900 mg, reduce dose of mifepristone to 600 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with ketoconazole is initiated in a patient already receiving 1,200 mg, reduce the mifepristone dose to 900 mg. Both mifepristone and ketoconazole are substrates and strong inhibitors of CYP3A4 that are associated with QT prolongation.
    Mirtazapine: (Contraindicated) 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.
    Mometasone: (Moderate) Coadministration of mometasone with ketoconazole may cause elevated mometasone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Mometasone is a CYP3A4 substrate; ketoconazole is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
    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: (Contraindicated) Concomitant use of naloxegol with ketoconazole is contraindicated. Naloxegol is metabolized primarily by CYP3A. 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.
    Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with ketoconazole is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. In vitro, coadministration with ketoconazole increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
    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 ketoconazole increased neratinib exposure by 381%.
    Netupitant, Fosnetupitant; 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: (Contraindicated) 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) Use ketoconazole and nicardipine with caution due to additive negative inotropic effect and increased risk of edema and congestive heart failure. Concomitant administration may cause several-fold increases in nicardipine plasma concentrations.
    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) Ketoconaozle, a dual inhibitor of P-glycoprotein (P-gp) and CYP3A4, increases the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Ketoconazole is a potent inhibitor of CYP3A4 and a moderate P-gp inhibitor; nintedanib is a P-gp substrate and a minor substrate of CYP3A4. In drug interaction studies, the use of ketoconazole increased nintedanib AUC by 60% and the Cmax by 1.83-fold.
    Nisoldipine: (Contraindicated) 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.
    Norethindrone; 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.
    Norethindrone; Ethinyl Estradiol; 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.
    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.
    Norgestimate; 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.
    Nortriptyline: (Minor) Use ketoconazole with caution in combination with tricyclic antidepressants (TCAs) as concurrent use may increase the risk of QT prolongation and increased TCA-related adverse effects. 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: (Moderate) Use octreotide with caution in combination with ketoconazole. Ketoconazole has been associated with prolongation of the QT interval. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes (TdP), the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Moderate) Use ketoconazole with caution in combination with ofloxacin as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Quinolones have been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Moderate) Use ketoconazole with caution in combination with olanzapine as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Olaparib: (Major) Avoid coadministration of olaparib with ketoconazole due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 100 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after ketoconazole is discontinued. Olaparib is a CYP3A substrate and ketoconazole is a strong CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with another strong CYP3A inhibitor increased the olaparib Cmax by 42% and the AUC by 170%.
    Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and ketoconazole is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and ketoconazole may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If ketoconazole is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 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).
    Omeprazole; Amoxicillin; 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.
    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.
    Osilodrostat: (Major) Reduce the dose of osilodrostat by one-half and consider more frequent ECG monitoring during coadministration of ketoconazole; concurrent use may increase osilodrostat exposure and the risk of osilodrostat-related adverse reactions, including QT prolongation. Osilodrostat is a CYP3A4 substrate that is associated with dose-dependent QT prolongation; ketoconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval.
    Osimertinib: (Major) Avoid coadministration of ketoconazole with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy 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: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. If ketoconazole is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like ketoconazole can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ketoconazole is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Ozanimod: (Major) In general, do not initiate ozanimod in patients taking ketoconazole due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Ketoconazole has been associated with prolongation of the QT interval.
    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 if possible due to the potential for additive effects on the QT interval. Both paliperidone and ketoconazole are associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of paliperidone overdose. According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to prolong the QT interval. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, 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: (Moderate) Use caution when using pasireotide in combination with ketoconazole as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses. Ketoconazole has been associated with prolongation of the QT interval.
    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.
    Pemigatinib: (Major) Avoid coadministration of pemigatinib and ketoconazole due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If ketoconazole is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of ketoconazole. Pemigatinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased pemigatinib exposure by 88%.
    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: (Contraindicated) 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) Use ketoconazole with caution in combination with perphenazine as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Perphenazine; Amitriptyline: (Minor) Use ketoconazole with caution in combination with perphenazine as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation. (Minor) Use ketoconazole with caution in combination with tricyclic antidepressants (TCAs) as concurrent use may increase the risk of QT prolongation and increased TCA-related adverse effects. 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.
    Pexidartinib: (Major) Avoid coadministration of pexidartinib with ketoconazole as concurrent use may increase pexidartinib exposure. If concurrent use cannot be avoided, reduce the dose of pexidartinib. If ketoconazole is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of ketoconazole. Additionally, monitor for evidence of hepatotoxicity if coadministration is necessary. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease. Dose adjustments are as follows: 800 mg/day or 600 mg/day of pexidartinib, reduce to 200 mg twice daily; 400 mg/day of pexidartinib, reduce to 200 mg once daily. Pexidartinib is a CYP3A4 and UGT substrate; ketoconazole is a strong CYP3A4 inhibitor and a UGT inhibitor. Coadministration of another strong CYP3A4 inhibitor increased pexidartinib exposure by 70%; coadministration with another UGT inhibitor increased pexidartinib exposure by 60%.
    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 if possible 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 10 mg once daily. 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 pimavanserin-related adverse effects including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation.
    Pimozide: (Contraindicated) 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.
    Pioglitazone; Metformin: (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.
    Pitolisant: (Major) Avoid coadministration of pitolisant with ketoconazole as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Ketoconazole has been associated with prolongation of the QT interval.
    Polatuzumab Vedotin: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of ketoconazole due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; ketoconazole is a strong CYP3A4 inhibitor. Ketoconazole is predicted to increase the exposure of MMAE by 45%.
    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) Avoid coadministration of ponatinib and ketoconazole due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of ketoconazole and consider alternative therapy. After ketoconazole has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting ketoconazole. Ponatinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the ponatinib AUC by 78%.
    Ponesimod: (Major) In general, do not initiate ponesimod in patients taking ketoconazole due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Ketoconazole has been associated with prolongation of the QT interval.
    Porfimer: (Major) Avoid coadministration of porfimer with ketoconazole foam due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like ketoconazole foam may increase the risk of a photosensitivity reaction.
    Pralsetinib: (Major) Avoid coadministration of ketoconazole with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is unavoidable, reduce the dose of pralsetinib to 200 mg once daily for patients taking a daily dose of 400 mg or 300 mg, and to 100 mg once daily for patients taking a daily dose of 200 mg. After ketoconazole has been discontinued for 3 to 5 elimination half-lives, resume the pralsetinib dose taken prior to initiating ketoconazole. Pralsetinib is a CYP3A and P-glycoprotein (P-gp) substrate and ketoconazole is a combined P-gp and strong CYP3A inhibitor. Coadministration with another combined P-gp and strong CYP3A inhibitor increased the AUC of pralsetinib by 251%.
    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: (Moderate) Use ketoconazole with caution in combination with primaquine. Both ketoconazole and primaquine have been associated with QT prolongation.
    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) Use ketoconazole with caution in combination with prochlorperazine as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Progesterone: (Moderate) Use caution if coadministration of ketoconazole with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Ketoconazole is a strong CYP3A4 inhibitor. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
    Promethazine: (Moderate) Use ketoconazole with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Promethazine; Dextromethorphan: (Moderate) Use ketoconazole with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Promethazine; Phenylephrine: (Moderate) Use ketoconazole with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation. Ketoconazole has been associated with prolongation of the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    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) Use ketoconazole with caution in combination with tricyclic antidepressants (TCAs) as concurrent use may increase the risk of QT prolongation and increased TCA-related adverse effects. 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: (Contraindicated) 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: (Contraindicated) 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: (Contraindicated) 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.
    Regorafenib: (Major) Avoid coadministration of regorafenib with ketoconazole due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration of ketoconazole increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
    Relugolix: (Major) Avoid concomitant use of relugolix and oral ketoconazole. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer ketoconazole at least 6 hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of ketoconazole is required; if treatment is interrupted for more than 7 days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. Ketoconazole has been associated with prolongation of the QT interval. Relugolix is a P-glycoprotein (P-gp) substrate and ketoconazole is a P-gp inhibitor.
    Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral ketoconazole. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer ketoconazole at least 6 hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of ketoconazole is required; if treatment is interrupted for more than 7 days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval. Ketoconazole has been associated with prolongation of the QT interval. Relugolix is a P-glycoprotein (P-gp) substrate and ketoconazole is a P-gp inhibitor. (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.
    Repaglinide: (Moderate) Coadministration of ketoconazole and repaglinide increases the AUC of repaglinide by 15%; if coadministration is necessary, consider a dose reduction of repaglinide and increased frequency of glucose monitoring. Ketoconazole is a CYP3A4 inhibitor and repaglinide is a CYP3A4 substrate. The possibility of an increased risk of hypoglycemia should be considered during concomitant use of ketoconazole and repaglinide.
    Retapamulin: (Moderate) Coadministration of retapamulin with strong CYP3A4 inhibitors, such as ketoconazole, in patients younger than 24 months is not recommended. Systemic exposure of topically administered retapamulin may be higher in patients younger than 24 months than in patients 2 years and older. Retapamulin is a CYP3A4 substrate.
    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. Both ketoconazole and ribociclib are CYP3A4 substrates and strong inhibitors that have been reported to prolong the QT interval. Concomitant use may increase the risk for QT prolongation.
    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. Both ketoconazole and ribociclib are CYP3A4 substrates and strong inhibitors that have been reported to prolong the QT interval. Concomitant use may increase the risk for QT prolongation.
    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) The use of rifapentine within 2 weeks of ketoconazole therapy is not recommended. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole and increase the dose of ketoconazole as necessary. Ketoconazole is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer.
    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.
    Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and ketoconazole. Concomitant use may increase the risk for hepatotoxicity. Discontinue therapy if clinical signs of liver dysfunction are present.
    Rimegepant: (Major) Avoid coadministration of rimegepant with ketoconazole; concurrent use may significantly increase rimegepant exposure. Rimegepant is a CYP3A4 and P-gp substrate; ketoconazole is a strong CYP3A4 inhibitor and P-gp inhibitor. Coadministration of rimegepant with another strong CYP3A4 inhibitor increased rimegepant exposure by 4-fold.
    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.
    Ripretinib: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with ketoconazole. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
    Risperidone: (Moderate) Use risperidone and ketoconazole together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Ketoconazole has also been associated with prolongation of the QT interval.
    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).
    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) Reduce the ruxolitinib dosage during coadministration with ketoconazole as increased ruxolitinib exposure and toxicity may occur. In myelofibrosis (MF) patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In polycythemia vera (PV) patients, reduce the initial dose to 5 mg PO twice daily. Avoid the use of ketoconazole or interrupt ruxolitinib treatment during ketoconazole use in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. For patients with MF or PV patient stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. In graft-versus-host disease patients, reduce the dose to 5 mg PO once daily. Additional dose modifications should be made with frequent monitoring of safety and efficacy. Ruxolitinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor.
    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 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.
    Segesterone Acetate; 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.