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  • CLASSES

    Azole Antifungals
    Cortisol Synthesis Inhibitors
    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

    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, Xolegel

    HOW SUPPLIED

    Extina/Ketoconazole/Ketodan Topical Foam: 2%
    Ketoconazole/Kuric/Nizoral Topical Cream: 2%
    Ketoconazole/Nizoral Oral Tab: 200mg
    Ketoconazole/Nizoral Topical Shampoo: 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 dosage 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]

    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.

    For the treatment of Cushing's syndrome†.
    Oral dosage
    Adults

    400 mg to 1,600 mg/day PO, divided into 2 to 3 doses. Guidelines state the reliable effectiveness of ketoconazole as an option in patients with mild disease and no visible tumor on MRI. In selected other cases, ketoconazole may be combined with other treatments. In a study of 200 patients with Cushing's disease, 33 (64.7%) of 51 patients treated for more than 24 months (mean dose 600 mg/day) normalized urinary-free cortisol concentrations, but 15.4% escaped. Increasing doses may be needed to counter escape. Ensure that male patients follow-up for potential hypogonadism. In all patients, chronic use requires periodic liver function test monitoring, and the potential for drug-drug interactions must be regularly reviewed.

    †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.

    Extemporaneous Compounding-Oral

    NOTE: Extemporaneously compounded oral ketoconazole suspension is not FDA-approved.
    Shake well before administering. Measure dosage with calibrated measuring device.
     
    Extemporaneous preparation of 20 mg/mL ketoconazole oral suspension†
    Using a mortar and pestle, grind twelve 200-mg ketoconazole tablets to a fine powder.
    Add 20 mL of vehicle (1:1 mixture of Ora-Plus and Ora-Sweet; 1:1 mixture of Ora-Plus and Ora-Sweet SF; or Cherry Syrup [cherry syrup concentrate diluted 1:4 with simple syrup]) and mix to a uniform paste.
    Add geometric amounts of the base solution and mix well after each addition.
    Transfer the mixture into an amber plastic bottle.
    Add enough vehicle to bring the final volume to 120 mL.
    Label the bottle with 'Shake well before use' and 'Protect from light'.
    Storage: The oral suspension is stable for at least 60 days when stored at room temperature or refrigerated.

    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:
    - Avoid exposure to heat
    - Do not freeze
    - 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 in original container
    Ketodan:
    - Avoid exposure to heat
    - Do not freeze
    - 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 in original container
    Kuric:
    - Keep away from heat and flame
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in a cool, well ventilated, dry place
    Nizoral:
    - Keep away from heat and flame
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in a cool, well ventilated, dry place
    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. Wait at least 24 hours after ketoconazole has been discontinued before resuming acalabrutinib at the previous dosage. 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; 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) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. If ketoconazole is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Ketoconazole is a strong CYP3A inhibitor, an isoenzyme partially responsible for the metabolism of dihydrocodeine. 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. (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; Pyrilamine: (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.
    Aclidinium; Formoterol: (Moderate) Formoterol, as with other long-acting beta-agonists, should be administered with extreme caution to patients being treated with drugs known to prolong the QTc interval like ketoconazole because the effect of adrenergic agonists on the cardiovascular system may be potentiated. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias. Ketoconazole has been associated with prolongation of the QT interval and torsade de pointes (TdP).
    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.
    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) Coadministration of alfuzosin with ketoconazole is contraindicated as potentially increased alfuzosin concentrations can result in hypotension, and potentially life-threatening cardiac arrhythmia. Alfuzosin is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. 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) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ketoconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    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) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ketoconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    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) The maximum recommended starting dose of almotriptan is 6.25 mg if coadministration with ketoconazole is necessary; do not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan and ketoconazole should be avoided in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased almotriptan exposure by approximately 60%.
    Alogliptin; Metformin: (Moderate) Concomitant administration of metformin and ketoconazole may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion (MATE) and OCT2 substrate and ketoconazole is a MATE and OCT2 inhibitor. MATE and OCT2 inhibitors may decrease metformin elimination by blocking renal tubular secretion.
    Alogliptin; Pioglitazone: (Moderate) Monitor blood glucose during concomitant ketoconazole and pioglitazone use. Concomitant use increased ketoconazole exposure and peak concentration by 34% and 14%, respectively.
    Alosetron: (Moderate) Concomitant use of alosetron with ketoconazole may increase exposure of alosetron and increase the risk for adverse reactions. Caution and close monitoring are advised if these drugs are used together. Alosetron is partially metabolized by CYP3A4; ketoconazole is a strong CY3A4 inhibitor. Coadministration of alosetron with ketoconazole increased mean alosetron expsure (AUC) by 29%.
    Alprazolam: (Contraindicated) Coadministration of ketoconazole and alprazolam is contraindicated. Ketoconazole significantly impairs the CYP3A4 metabolism of alprazolam, resulting in significantly elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. Ketoconazole is a potent CYP3A4 inhibitor. 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: (Contraindicated) Use of ketoconazole/levoketoconazole and amiodarone is contraindicated due to an increased risk for ventricular arrhythmias, torsade de pointes (TdP) and QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. Concomitant use may also increase the exposure of amiodarone, further increasing the risk for adverse events. Amiodarone is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    Amisulpride: (Contraindicated) Avoid concomitant use of ketoconazole and amisulpride due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ketoconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    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 CYP3A and P-gp-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) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ketoconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amlodipine; Benazepril: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ketoconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amlodipine; Celecoxib: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ketoconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amlodipine; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ketoconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amlodipine; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ketoconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ketoconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Amoxicillin; Clarithromycin; Omeprazole: (Contraindicated) Avoid concomitant use of ketoconazole and clarithromycin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of both drugs, further increasing the risk for adverse events. Both ketoconazole and clarithromycin are CYP3A substrates and strong CYP3A inhibitors.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Moderate) In vitro and in vivo animal studies of the combination of amphotericin B and imidazoles suggest that imidazole antifungal agents may induce fungal resistance to amphotericin B. Combination therapy should be administered with caution, especially in immunocompromised patients.
    Amphotericin B lipid complex (ABLC): (Moderate) In vitro and in vivo animal studies of the combination of amphotericin B and imidazoles suggest that imidazole antifungal agents may induce fungal resistance to amphotericin B. Combination therapy should be administered with caution, especially in immunocompromised patients.
    Amphotericin B liposomal (LAmB): (Moderate) In vitro and in vivo animal studies of the combination of amphotericin B and imidazoles suggest that imidazole antifungal agents may induce fungal resistance to amphotericin B. Combination therapy should be administered with caution, especially in immunocompromised patients.
    Amphotericin B: (Moderate) In vitro and in vivo animal studies of the combination of amphotericin B and imidazoles suggest that imidazole antifungal agents may induce fungal resistance to amphotericin B. Combination therapy should be administered with caution, especially in immunocompromised patients.
    Anagrelide: (Contraindicated) Avoid concomitant use of ketoconazole and anagrelide due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Antacids: (Moderate) Administer antacids at least 1 hour before or 2 hours after taking ketoconazole. Antacids can impair the absorption of ketoconazole.
    Apalutamide: (Major) Avoid apalutamide for 2 weeks prior to and during treatment with apalutamide. Concomitant use may decrease exposure of ketoconazole and reduce its efficacy. The exposure of apalutamide may also be increased. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole and/or increased apalutamide-related adverse effects; adjust dosage for both drugs as needed. Ketoconazole is a CYP3A substrate and strong CYP3A inhibitor; apalutamide is a CYP3A substrate and strong CYP3A 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: (Contraindicated) Avoid concomitant use of ketoconazole and apomorphine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Aprepitant, Fosaprepitant: (Major) Avoid coadministration use of aprepitant/fosaprepitant in patients taking ketoconazole or levoketoconazole due to substantially increased exposure of aprepitant. Fosaprepitant is rapidly converted to aprepitant; therefore, a similar interaction is likely. Aprepitant is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the aprepitant AUC and mean terminal half-life by approximately 5-fold and 3-fold, respectively.
    Arformoterol: (Moderate) Arformoterol, as with other long-acting beta-agonists, should be administered with extreme caution to patients being treated with drugs known to prolong the QTc interval like ketoconazole because the effect of adrenergic agonists on the cardiovascular system may be potentiated. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias. Ketoconazole has been associated with prolongation of the QT interval and torsade de pointes (TdP).
    Aripiprazole: (Contraindicated) Avoid concomitant use of aripiprazole and ketoconazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase aripiprazole exposure and other aripiprazole-related adverse effects. Ketoconazole is a strong CYP3A4 inhibitor. If concomitant use is medically necessary, reduce the oral aripiprazole dosage by one-half (50%) of the usual dose and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Reduce the oral aripiprazole dosage to one-quarter (25%) of the usual dose in patients also receiving a CYP2D6 inhibitor or who are CYP2D6 poor metabolizers. Avoid concurrent use of Aristada Initio and ketoconazole because the dose of Aristada Initio cannot be modified. For other long-active aripiprazole injectables (e.g., Ability Maintena, Aristada), dose adjustments are recommended with combined strong CYP2D6/CYP3A inhibitors; consult the product label as the recommendations are dependent on the IM dosage, the product given, and the duration of treatment with the concomitant inhibitors.
    Armodafinil: (Moderate) Monitor for an increase in armodafinil-related adverse reactions if coadministration with ketoconazole is necessary. 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.
    Arsenic Trioxide: (Contraindicated) Avoid concomitant use of ketoconazole and arsenic trioxide due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Artemether; Lumefantrine: (Contraindicated) Avoid concomitant use of ketoconazole and artemether due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Artemether is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration of ketoconazole (single dose) with artemether has resulted in a moderate increase in artemether and DHA (active metabolite) exposure. (Contraindicated) Avoid concomitant use of ketoconazole and lumefantrine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Lumefantrine is a CYP3A4 substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration of ketoconazole (single dose) with lumefantrine has resulted in moderately increased lumefantrine exposure.
    Asciminib: (Moderate) Closely monitor for asciminib-related adverse reactions if concurrent use of asciminib 200 mg twice daily with ketoconazole is necessary as asciminib exposure may increase. Asciminib is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Asenapine: (Contraindicated) Avoid concomitant use of ketoconazole and asenapine due to an increased risk for torsade de pointes (TdP) and QT/QTc 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; 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) Avoid atazanavir for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of ketoconazole and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for ketoconazole-related adverse reactions; a ketoconazole dose reduction may be necessary. Ketoconazole is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor.
    Atazanavir; Cobicistat: (Major) Avoid atazanavir for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of ketoconazole and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for ketoconazole-related adverse reactions; a ketoconazole dose reduction may be necessary. Ketoconazole is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. (Major) Avoid cobicistat for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of both drugs and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for adverse reactions; a ketoconazole dose reduction may be necessary. Both ketoconazole and cobicistat are CYP3A substrates and strong CYP3A inhibitors.
    Atogepant: (Major) Limit the dose of atogepant to 10 mg PO once daily if coadministered with ketoconazole. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of CYP3A and ketoconazole is a strong CYP3A inhibitor. Coadministration with a strong CYP3A inhibitor resulted in a 5.5-fold increase in atogepant exposure and a 2.15-fold increase in atogepant peak concentration.
    Atomoxetine: (Contraindicated) Avoid concomitant use of ketoconazole and atomoxetine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. QT prolongation has been reported postmarketing with atomoxetine; ketoconazole is associated with QT prolongation and TdP.
    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 CYP3A and P-gp-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 CYP3A and P-gp-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.
    Avacopan: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of ketoconazole is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
    Avanafil: (Major) Do not use avanafil in patients receiving ketoconazole due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the avanafil AUC by 13-fold.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and azithromycin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. If use together is medically 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.
    Barbiturates: (Major) Avoid barbiturates for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may decrease exposure of ketoconazole and reduce its efficacy. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole; a ketoconazole dose increase may be necessary. Ketoconazole is a CYP3A substrate and barbiturates are strong CYP3A inducers.
    Bedaquiline: (Contraindicated) Avoid concomitant use of ketoconazole and bedaquiline due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may increase the exposure of bedaquiline, thereby further increasing the risk for adverse effects. If concomitant use of these drugs is required, monitor patients for signs and symptoms of bedaquiline-related adverse reactions (e.g., QT prolongation and hepatotoxicity). Bedaquiline is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Concurrent use of ketoconazole increased bedaquiline exposure by 22%. In addition, repeated dosing of this drug combination resulted in additive QT prolongation when compared with repeated dosing of the individual drugs.
    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 sedation and 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: (Contraindicated) Avoid concomitant use of ketoconazole and metronidazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval, like ketoconazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Contraindicated) Avoid concomitant use of ketoconazole and metronidazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval, like ketoconazole.
    Bortezomib: (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of ketoconazole is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%.
    Bosentan: (Moderate) Use caution if coadministration of ketoconazole with bosentan is necessary, as the systemic exposure of bosentan may be increased resulting in an increase in bosentan-related adverse reactions; however, a bosentan dose adjustment is not necessary. Administration of bosentan with both ketoconazole and a strong or moderate CYP2C9 inhibitor is not recommended. Bosentan is a CYP3A4 and CYP2C9 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the plasma concentrations of bosentan by approximately 2-fold.
    Bosutinib: (Major) Avoid concomitant use of bosutinib and ketoconazole; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the AUC of bosutinib by 8.6-fold.
    Brentuximab vedotin: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with ketoconazole is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased MMAE exposure by approximately 34%.
    Brexpiprazole: (Major) Reduce the brexpiprazole dose to half the usual dose if coadministered with ketoconazole. Administer one quarter of the usual brexpiprazole dose if the patient is also receiving a strong or moderate CYP2D6 inhibitor or is a known poor metabolizer of CYP2D6. If ketoconazole is discontinued, adjust the brexpiprazole dosage to its original level. Brexpiprazole is a CYP3A4 and CYP2D6 substrate; ketoconazole is a strong CYP3A4 inhibitor. Concomitant use of strong CYP3A4 inhibitors increased the exposure of brexpiprazole compared to use of brexpiprazole alone.
    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.
    Budesonide: (Moderate) Monitor for corticosteroid-related adverse effects during chronic concomitant use of inhaled or nasal budesonide and ketoconazole. Avoid concomitant use of oral budesonide and ketoconazole. Budesonide is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Ketoconazole has been observed to increase the overall exposure of oral budesonide by 8-fold. The total absolute bioavailability of inhaled and nasal budesonide products ranges from 6% to 39% of the labeled dose.
    Budesonide; Formoterol: (Moderate) Formoterol, as with other long-acting beta-agonists, should be administered with extreme caution to patients being treated with drugs known to prolong the QTc interval like ketoconazole because the effect of adrenergic agonists on the cardiovascular system may be potentiated. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias. Ketoconazole has been associated with prolongation of the QT interval and torsade de pointes (TdP). (Moderate) Monitor for corticosteroid-related adverse effects during chronic concomitant use of inhaled or nasal budesonide and ketoconazole. Avoid concomitant use of oral budesonide and ketoconazole. Budesonide is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Ketoconazole has been observed to increase the overall exposure of oral budesonide by 8-fold. The total absolute bioavailability of inhaled and nasal budesonide products ranges from 6% to 39% of the labeled dose.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Formoterol, as with other long-acting beta-agonists, should be administered with extreme caution to patients being treated with drugs known to prolong the QTc interval like ketoconazole because the effect of adrenergic agonists on the cardiovascular system may be potentiated. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias. Ketoconazole has been associated with prolongation of the QT interval and torsade de pointes (TdP). (Moderate) Monitor for corticosteroid-related adverse effects during chronic concomitant use of inhaled or nasal budesonide and ketoconazole. Avoid concomitant use of oral budesonide and ketoconazole. Budesonide is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Ketoconazole has been observed to increase the overall exposure of oral budesonide by 8-fold. The total absolute bioavailability of inhaled and nasal budesonide products ranges from 6% to 39% of the labeled dose.
    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; Epinephrine: (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: (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: (Contraindicated) Avoid concomitant use of ketoconazole and buprenorphine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when ketoconazole is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping ketoconazole, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If ketoconazole is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and ketoconazole is a CYP3A inhibitor.
    Buprenorphine; Naloxone: (Contraindicated) Avoid concomitant use of ketoconazole and buprenorphine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when ketoconazole is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping ketoconazole, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If ketoconazole is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and ketoconazole is a CYP3A inhibitor.
    Buspirone: (Moderate) A low dose of buspirone used cautiously is recommended when coadministered with ketoconazole. If a patient has been titrated to a stable dosage of buspirone, a dose adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone. Administering ketoconazole with buspirone may increase buspirone concentration and risk for adverse events. Buspirone is a sensitive substrate of CYP3A4; ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the buspirone AUC by 19-fold with an increased incidence of buspirone-related adverse effects.
    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.
    Butalbital; Acetaminophen; 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.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and rilpivirine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of rilpivirine, further increasing the risk for adverse effects. Rilpivirine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Cabozantinib: (Major) Avoid concomitant use of cabozantinib and ketoconazole due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with ketoconazole 2 to 3 days after discontinuation of ketoconazole. Cabozantinib is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased 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. (Minor) Ketoconazole has been shown to inhibit the clearance of caffeine by 11 percent. The clinical significance of this interaction 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 1,200 mg/day.
    Calcium Carbonate: (Moderate) Administer calcium carbonate at least 1 hour before or 2 hours after taking ketoconazole. Antacids can impair the absorption of ketoconazole.
    Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Major) Avoid use of H2-blockers with ketoconazole. Medications that increase gastric pH may impair ketoconazole absorption. (Moderate) Administer calcium carbonate at least 1 hour before or 2 hours after taking ketoconazole. Antacids can impair the absorption of ketoconazole.
    Calcium Carbonate; Magnesium Hydroxide: (Moderate) Administer calcium carbonate at least 1 hour before or 2 hours after taking ketoconazole. Antacids can impair the absorption of ketoconazole.
    Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Moderate) Administer calcium carbonate at least 1 hour before or 2 hours after taking ketoconazole. Antacids can impair the absorption of ketoconazole.
    Calcium Carbonate; Risedronate: (Moderate) Administer calcium carbonate at least 1 hour before or 2 hours after taking ketoconazole. Antacids can impair the absorption of ketoconazole.
    Calcium Carbonate; Simethicone: (Moderate) Administer calcium carbonate at least 1 hour before or 2 hours after taking ketoconazole. Antacids can impair the absorption of ketoconazole.
    Calcium; Vitamin D: (Moderate) Administer calcium carbonate at least 1 hour before or 2 hours after taking ketoconazole. Antacids can impair the absorption of ketoconazole.
    Canagliflozin; Metformin: (Moderate) Concomitant administration of metformin and ketoconazole may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion (MATE) and OCT2 substrate and ketoconazole is a MATE and OCT2 inhibitor. MATE and OCT2 inhibitors may decrease metformin elimination by blocking renal tubular secretion.
    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) Avoid carbamazepine for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may decrease exposure of ketoconazole and reduce its efficacy. The exposure of carbamazepine may also be increased. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole and monitor carbamazepine concentrations closely for increased toxicity; adjust dosage for both drugs as clinically indicated. Ketoconazole is a CYP3A substrate and strong CYP3A inhibitor; carbamazepine is a CYP3A substrate and strong CYP3A inducer.
    Cariprazine: (Major) The dose of cariprazine should be reduced in patients also receiving ketoconazole. When 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 patients taking cariprazine 1.5 mg daily, the dosing frequency should be adjusted to every other day. When initiating cariprazine in a patient who is stable on ketoconazole, 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, and then increased to a maximum dose of 3 mg daily. When ketoconazole is withdrawn, the cariprazine dosage may need to be increased. Cariprazine is metabolized by CYP3A4 to its major active metabolite. ketoconazole is a strong CYP3A4 inhibitor. Concurrent use with ketoconazole increased the exposure of cariprazine by about 4-fold; increased the AUC of DDCAR metabolite by about 1.5-fold; and decreased DCAR metabolite AUC by about one-third.
    Celecoxib; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with ketoconazole is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of ketoconazole, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
    Ceritinib: (Contraindicated) Avoid concomitant use of ketoconazole and ceritinib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of both drugs, further increasing the risk for adverse events. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with ketoconazole increased ceritinib exposure by 2.9-fold.
    Chloramphenicol: (Major) Avoid chloramphenicol for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of ketoconazole and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for ketoconazole-related adverse reactions; a ketoconazole dose reduction may be necessary. Ketoconazole is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor.
    Chlordiazepoxide: (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with ketoconazole is necessary; adjust the dose of chlordiazepoxide if necessary. Chlordiazepoxide is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    Chlordiazepoxide; Amitriptyline: (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with ketoconazole is necessary; adjust the dose of chlordiazepoxide if necessary. Chlordiazepoxide is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    Chlordiazepoxide; Clidinium: (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with ketoconazole is necessary; adjust the dose of chlordiazepoxide if necessary. Chlordiazepoxide is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    Chloroquine: (Contraindicated) Avoid concomitant use of ketoconazole and chloroquine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    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) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. If ketoconazole is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Ketoconazole is a strong CYP3A inhibitor, an isoenzyme partially responsible for the metabolism of dihydrocodeine. 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.
    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.
    Chlorpromazine: (Contraindicated) Avoid concomitant use of ketoconazole and chlorpromazine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    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) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with ketoconazole and monitor for an increase in cilostazol-related adverse reactions. Concurrent use may increase cilostazol exposure. Cilostazol is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the cilostazol AUC by 117%.
    Cimetidine: (Major) Avoid use of H2-blockers with ketoconazole. Medications that increase gastric pH may impair ketoconazole absorption.
    Cinacalcet: (Moderate) Dose adjustment of cinacalcet may be required if a patient initiates or discontinues therapy with ketoconazole; closely monitor iPTH and serum calcium concentrations. Cinacalcet is partially metabolized by CYP3A4; ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the exposure (AUC) of cinacalcet by 127%.
    Ciprofloxacin: (Contraindicated) Avoid concomitant use of ketoconazole and ciprofloxacin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval, such as ketoconazole.
    Cisapride: (Contraindicated) Avoid concomitant use of ketoconazole and cisapride due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may increase the exposure of cisapride. Cisapride is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Ketoconazole causes a mean eight-fold increase in cisapride concentrations.
    Citalopram: (Contraindicated) Avoid concomitant use of ketoconazole and citalopram due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use of citalopram with drugs that cause QT prolongation, such as ketoconazole, can cause additional QT prolongation vs. either drug alone. Pharmacokinetic changes have been studied. Combined administration of racemic citalopram (40 mg) and ketoconazole (200 mg) decreased the Cmax and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram.
    Clarithromycin: (Contraindicated) Avoid concomitant use of ketoconazole and clarithromycin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of both drugs, further increasing the risk for adverse events. Both ketoconazole and clarithromycin are CYP3A substrates and strong CYP3A inhibitors.
    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: (Contraindicated) Avoid concomitant use of clofazimine and ketoconazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Clonazepam: (Moderate) Monitor for increased sedation and respiratory depression if clonazepam is coadministered with ketoconazole; adjust the dose of clonazepam if necessary. The systemic exposure of clonazepam may be increased resulting in an increase in treatment-related adverse reactions. Clonazepam is a CYP3A4 substrate and 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) Monitor for an increase in sedation and respiratory depression if coadministration of clorazepate with ketoconazole is necessary. Concurrent use may increase clorazepate exposure. Clorazepate is a prodrug whose active metabolite (N-desmethyldiazepam) is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor.
    Clozapine: (Contraindicated) Avoid concomitant use of ketoconazole and clozapine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may increase the exposure of clozapine, thereby further increasing the risk for adverse events. Clozapine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Cobicistat: (Major) Avoid cobicistat for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of both drugs and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for adverse reactions; a ketoconazole dose reduction may be necessary. Both ketoconazole and cobicistat are CYP3A substrates and strong CYP3A inhibitors.
    Cobimetinib: (Major) Avoid coadministration of ketoconazole with cobimetinib due to the increased risk of cobimetinib-related adverse reactions. Cobimetinib is a sensitive CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased cobimetinib exposure by 6.7-fold.
    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; Guaifenesin; Pseudoephedrine: (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: (Contraindicated) Avoid concomitant use of ketoconazole and promethazine due to an increased risk for QT prolongation and torsade de pointes(TdP). Promethazine has a possible risk for QT prolongation; ketoconazole is known to have a risk for QT prolongation and TdP. If use together is medically necessary it may be advisable to monitor ECG and serum electrolytes. (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; Promethazine: (Contraindicated) Avoid concomitant use of ketoconazole and promethazine due to an increased risk for QT prolongation and torsade de pointes(TdP). Promethazine has a possible risk for QT prolongation; ketoconazole is known to have a risk for QT prolongation and TdP. If use together is medically necessary it may be advisable to monitor ECG and serum electrolytes. (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.
    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 a P-gp and strong CYP3A4 inhibitor like 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 and ketoconazole is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a CYP3A substrate; ketoconazole is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
    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: (Moderate) Use caution if coadministration of ketoconazole with medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A4 and ketoconazole is a strong CYP3A4 inhibitor. (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: (Contraindicated) Avoid concomitant use of ketoconazole and crizotinib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may increase the exposure of crizotinib, further increasing the risk for adverse reactions. If concomitant use is necessary for adults with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), reduce the dose of crizotinib to 250 mg PO once daily. If concomitant use is necessary for young adult or pediatric patients with anaplastic large cell lymphoma or pediatric patients with IMT, 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. Crizotinib is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration ketoconazole increased the AUC of single-dose crizotinib by 216%.
    Cyclosporine: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with ketoconazole is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A4 and P-gp substrate and ketoconazole is a strong CYP3A4 and P-gp inhibitor.
    Dabigatran: (Moderate) Avoid if possible; monitor for dabigatran side effects if use with ketoconazole is necessary. For specific dosage recommendations based on the indication for which dabigatran has been prescribed and the patient's renal function, it is best to consult the product label. P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone. Dabigatran is a P-gp substrate and ketoconazole is a P-gp inhibitor. Coadministration with multiple daily doses of 400 mg ketoconazole increased dabigatran AUC by 153%.
    Dabrafenib: (Major) Avoid coadministration of dabrafenib and ketoconazole due to increased dabrafenib exposure. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity. Dabrafenib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the dabrafenib AUC by 71%, hydroxy-dabrafenib AUC by 82%, and desmethyl-dabrafenib AUC by 68%.
    Daclatasvir: (Major) Reduce the daclatasvir dose to 30 mg PO once daily if coadministered with ketoconazole due to increased daclatasvir exposure. Daclatasvir is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the daclatasvir AUC by 3-fold.
    Dapagliflozin; Metformin: (Moderate) Concomitant administration of metformin and ketoconazole may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion (MATE) and OCT2 substrate and ketoconazole is a MATE and OCT2 inhibitor. MATE and OCT2 inhibitors may decrease metformin elimination by blocking renal tubular secretion.
    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.
    Daridorexant: (Major) Avoid concomitant use of daridorexant and ketoconazole. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
    Darifenacin: (Moderate) Do not exceed a dose of 7.5 mg/day of darifenacin when administered with ketoconazole due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    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: (Major) Avoid darunavir for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of both drugs and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for adverse reactions; a ketoconazole dose reduction may be necessary. Both ketoconazole and darunavir are CYP3A substrates and strong CYP3A inhibitors.
    Darunavir; Cobicistat: (Major) Avoid cobicistat for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of both drugs and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for adverse reactions; a ketoconazole dose reduction may be necessary. Both ketoconazole and cobicistat are CYP3A substrates and strong CYP3A inhibitors. (Major) Avoid darunavir for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of both drugs and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for adverse reactions; a ketoconazole dose reduction may be necessary. Both ketoconazole and darunavir are CYP3A substrates and strong CYP3A inhibitors.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid cobicistat for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of both drugs and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for adverse reactions; a ketoconazole dose reduction may be necessary. Both ketoconazole and cobicistat are CYP3A substrates and strong CYP3A inhibitors. (Major) Avoid darunavir for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of both drugs and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for adverse reactions; a ketoconazole dose reduction may be necessary. Both ketoconazole and darunavir are CYP3A substrates and strong CYP3A inhibitors.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid ritonavir for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of ketoconazole and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for ketoconazole-related adverse reactions; a ketoconazole dose reduction may be necessary. Ketoconazole is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor.
    Dasatinib: (Contraindicated) Avoid concomitant use of ketoconazole and dasatinib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may increase the exposure of dasatinib, further increasing the risk for adverse effects. 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 and ketoconazole is a strong CYP3A4 inhibitor. 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: (Contraindicated) Avoid concomitant use of ketoconazole and androgen deprivation therapy (i.e. degarelix) due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Delavirdine: (Major) Avoid delavirdine for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of ketoconazole and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for ketoconazole-related adverse reactions; a ketoconazole dose reduction may be necessary. Ketoconazole is a CYP3A substrate and delavirdine is a strong CYP3A inhibitor.
    Desflurane: (Contraindicated) Avoid concomitant use of ketoconazole and halogenated anesthetics due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Desogestrel; Ethinyl Estradiol: (Moderate) Monitor for an increase in the incidence and severity of estrogen-related adverse effects during concomitant use of ethinyl estradiol and ketoconazole. Concomitant use may increase ethinyl estradiol exposure. Ethinyl estradiol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Deutetrabenazine: (Contraindicated) Avoid concomitant use of ketoconazole and deutetrabenazine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. The degree of QT prolongation associated with deutetrabenazine is not clinically significant when 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) Avoid concomitant use of ketoconazole and quinidine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with ketoconazole is necessary. Concurrent use increases diazepam exposure. Diazepam is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    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.
    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) Increase monitoring of serum digoxin concentrations and watch for potential signs and symptoms of clinical toxicity when starting, adjusting, or discontinuing ketoconazole. Concurrent use may increase digoxin exposure. Digoxin is a P-gp substrate with a narrow therapeutic index and ketoconazole is a P-gp inhibitor.
    Dihydroergotamine: (Contraindicated) Coadministration of ergot alkaloids and ketoconazole is contraindicated due to the potential for increased ergot exposure. Increased plasma concentrations of ergot alkaloids are associated with risk of acute ergot toxicity which is characterized by peripheral vasospasm and ischemia of the extremities and other tissues. Ergot alkaloids are CYP3A substrates and ketoconazole is a strong CYP3A inhibitor.
    Diltiazem: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with ketoconazole is necessary. Concurrent use may result in elevated diltiazem concentrations. An adjustment in the diltiazem dose may be warranted. Diltiazem is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    Disopyramide: (Contraindicated) Avoid concomitant use of ketoconazole and disopyramide due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    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) Avoid concomitant use of ketoconazole and dofetilide due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of dofetilide, further increasing the risk for adverse effects. Dofetilide is a substrate of OCT2 and ketoconazole is an inhibitor of this drug transporter. CYP3A4 inhibition by ketoconazole may also contribute. Coadministration with ketoconazole for 7 days has been shown to increase dofetilide AUC by 41% in males and 69% in females.
    Dolasetron: (Contraindicated) Avoid concomitant use of ketoconazole and dolasetron due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Dolutegravir; Rilpivirine: (Contraindicated) Avoid concomitant use of ketoconazole and rilpivirine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of rilpivirine, further increasing the risk for adverse effects. Rilpivirine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Donepezil: (Contraindicated) Avoid concomitant use of ketoconazole and donepezil due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may increase the exposure of donepezil, further increasing the risk for adverse effects. Donepezil is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased mean donepezil concentrations by 36%.
    Donepezil; Memantine: (Contraindicated) Avoid concomitant use of ketoconazole and donepezil due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may increase the exposure of donepezil, further increasing the risk for adverse effects. Donepezil is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased mean donepezil concentrations by 36%.
    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) Monitor for an increase in tenofovir-related adverse effects if coadministration with ketoconazole is necessary. Concurrent use may increase tenofovir exposure. Tenofovir disoproxil fumarate is a P-gp substrate and ketoconazole is a P-gp inhibitor. (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 symptoms of hypotension if coadministration of doxazosin and ketoconazole is necessary. Concurrent use may result in increased doxazosin exposure. Doxazosin is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Doxercalciferol: (Moderate) CYP450 inhibitors such as ketoconazole may inhibit the 25-hydroxylation of doxercalciferol and thus reduce the formation of active doxercalciferol moiety, which may reduce efficacy of doxercalciferol. If a patient initiates or discontinues therapy with a CYP450 inhibitor, dose adjustment of doxercalciferol may be necessary. Monitor intact PTH and serum calcium concentrations closely. Doxercalciferol is activated by CYP 27 in the liver to form 1-alpha,25-(OH)2D2 (major metabolite) and 1-alpha,24-dihydroxyvitamin D2 (minor metabolite). Ketoconazole is a strong CYP3A4 inhibitor.
    Doxorubicin Liposomal: (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.
    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: (Moderate) Monitor for increased toxicity (e.g., feeling high, dizziness, confusion, somnolence) of dronabinol if coadministered with ketoconazole. Coadministration may increase the exposure of dronabinol. Dronabinol is a CYP3A4 substrate and ketoconazole is a strong CYP3A inhibitor.
    Dronedarone: (Contraindicated) Avoid concomitant use of ketoconazole and dronedarone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may increase the exposure of dronedarone, further increasing the risk for adverse effects. Dronedarone is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased dronedarone exposure by approximately 17-fold.
    Droperidol: (Contraindicated) Avoid concomitant use of ketoconazole and droperidol due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may increase the exposure of droperidol, further increasing the risk for adverse effects. Droperidol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Drospirenone: (Moderate) Monitor for an increase in drospirenone-related adverse effects if coadministered with ketoconazole. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take drospirenone and ketoconazole long-term. Drospirenone is a CYP3A4 substrate that has antimineralocorticoid effects; the progestin may increase serum potassium. Ketoconazole is a strong inhibitor of CYP3A4; coadministration of ketoconazole with drospirenone resulted in a moderate increase of drospirenone exposure.
    Drospirenone; Estetrol: (Moderate) Monitor for an increase in drospirenone-related adverse effects if coadministered with ketoconazole. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take drospirenone and ketoconazole long-term. Drospirenone is a CYP3A4 substrate that has antimineralocorticoid effects; the progestin may increase serum potassium. Ketoconazole is a strong inhibitor of CYP3A4; coadministration of ketoconazole with drospirenone resulted in a moderate increase of drospirenone exposure.
    Drospirenone; Estradiol: (Moderate) Monitor for an increase in drospirenone-related adverse effects if coadministered with ketoconazole. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take drospirenone and ketoconazole long-term. Drospirenone is a CYP3A4 substrate that has antimineralocorticoid effects; the progestin may increase serum potassium. Ketoconazole is a strong inhibitor of CYP3A4; coadministration of ketoconazole with drospirenone resulted in a moderate increase of drospirenone exposure. (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) Monitor for an increase in drospirenone-related adverse effects if coadministered with ketoconazole. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take drospirenone and ketoconazole long-term. Drospirenone is a CYP3A4 substrate that has antimineralocorticoid effects; the progestin may increase serum potassium. Ketoconazole is a strong inhibitor of CYP3A4; coadministration of ketoconazole with drospirenone resulted in a moderate increase of drospirenone exposure. (Moderate) Monitor for an increase in the incidence and severity of estrogen-related adverse effects during concomitant use of ethinyl estradiol and ketoconazole. Concomitant use may increase ethinyl estradiol exposure. Ethinyl estradiol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Monitor for an increase in drospirenone-related adverse effects if coadministered with ketoconazole. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take drospirenone and ketoconazole long-term. Drospirenone is a CYP3A4 substrate that has antimineralocorticoid effects; the progestin may increase serum potassium. Ketoconazole is a strong inhibitor of CYP3A4; coadministration of ketoconazole with drospirenone resulted in a moderate increase of drospirenone exposure. (Moderate) Monitor for an increase in the incidence and severity of estrogen-related adverse effects during concomitant use of ethinyl estradiol and ketoconazole. Concomitant use may increase ethinyl estradiol exposure. Ethinyl estradiol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Dutasteride: (Moderate) Monitor for dutasteride-related adverse reactions if coadministration with ketoconazole is necessary due to a potential for increased dutasteride exposure. Dutasteride is extensively metabolized in humans by CYP3A4/3A5 isoenzymes. The effect of potent CYP3A4 inhibitors on dutasteride has not been studied. Because of the potential for drug-drug interactions, use caution when prescribing dutasteride to patients taking potent, chronic CYP3A4 enzyme inhibitors like ketoconazole, a strong CYP3A4 inhibitor.
    Dutasteride; Tamsulosin: (Major) Concurrent use of tamsulosin and ketoconazole is not recommended due to the potential for elevated tamsulosin concentrations. Such increases in tamsulosin concentrations are expected to produce clinically significant and potentially serious side effects, such as hypotension, dizziness, and vertigo. Tamsulosin is extensively metabolized by CYP3A4. Coadministration with ketoconazole, a strong CYP3A4 inhibitor, increased the Cmax and AUC of tamsulosin 2.2 and 2.8-fold, respectively. (Moderate) Monitor for dutasteride-related adverse reactions if coadministration with ketoconazole is necessary due to a potential for increased dutasteride exposure. Dutasteride is extensively metabolized in humans by CYP3A4/3A5 isoenzymes. The effect of potent CYP3A4 inhibitors on dutasteride has not been studied. Because of the potential for drug-drug interactions, use caution when prescribing dutasteride to patients taking potent, chronic CYP3A4 enzyme inhibitors like ketoconazole, a strong CYP3A4 inhibitor.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and efavirenz due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may decrease the exposure of ketoconazole, reducing its efficacy. Ketoconazole is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
    Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) Avoid concomitant use of ketoconazole and efavirenz due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may decrease the exposure of ketoconazole, reducing its efficacy. Ketoconazole is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. (Moderate) Monitor for an increase in tenofovir-related adverse effects if coadministration with ketoconazole is necessary. Concurrent use may increase tenofovir exposure. Tenofovir disoproxil fumarate is a P-gp substrate and ketoconazole is a P-gp inhibitor.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Contraindicated) Avoid concomitant use of ketoconazole and efavirenz due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may decrease the exposure of ketoconazole, reducing its efficacy. Ketoconazole is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. (Moderate) Monitor for an increase in tenofovir-related adverse effects if coadministration with ketoconazole is necessary. Concurrent use may increase tenofovir exposure. Tenofovir disoproxil fumarate is a P-gp substrate and ketoconazole is a P-gp inhibitor.
    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. Coadministration may increase elagolix exposure. Elagolix is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the AUC of elagolix by 120%.
    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. Coadministration may increase elagolix exposure. Elagolix is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the AUC of elagolix by 120%. (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) Concomitant use of elbasvir and ketoconazole is not recommended. Use of these drugs together may significantly increase the exposure of elbasvir, resulting in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Elbasvir is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased elbasvir exposure by almost 2-fold. (Major) Concomitant use of grazoprevir and ketoconazole is not recommended. Use of these drugs together may significantly increase the exposure of grazoprevir, resulting in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Grazoprevir is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased grazoprevir exposure by 3-fold.
    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 cobicistat for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of both drugs and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for adverse reactions; a ketoconazole dose reduction may be necessary. Both ketoconazole and cobicistat are CYP3A substrates and strong CYP3A inhibitors. (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 cobicistat for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of both drugs and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for adverse reactions; a ketoconazole dose reduction may be necessary. Both ketoconazole and cobicistat are CYP3A substrates and strong CYP3A inhibitors. (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) Monitor for an increase in tenofovir-related adverse effects if coadministration with ketoconazole is necessary. Concurrent use may increase tenofovir exposure. Tenofovir disoproxil fumarate is a P-gp substrate and ketoconazole is a P-gp inhibitor.
    Empagliflozin; Linagliptin; Metformin: (Moderate) Concomitant administration of metformin and ketoconazole may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion (MATE) and OCT2 substrate and ketoconazole is a MATE and OCT2 inhibitor. MATE and OCT2 inhibitors may decrease metformin elimination by blocking renal tubular secretion.
    Empagliflozin; Metformin: (Moderate) Concomitant administration of metformin and ketoconazole may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion (MATE) and OCT2 substrate and ketoconazole is a MATE and OCT2 inhibitor. MATE and OCT2 inhibitors may decrease metformin elimination by blocking renal tubular secretion.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Contraindicated) Avoid concomitant use of ketoconazole and rilpivirine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of rilpivirine, further increasing the risk for adverse effects. Rilpivirine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Contraindicated) Avoid concomitant use of ketoconazole and rilpivirine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of rilpivirine, further increasing the risk for adverse effects. Rilpivirine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. (Moderate) Monitor for an increase in tenofovir-related adverse effects if coadministration with ketoconazole is necessary. Concurrent use may increase tenofovir exposure. Tenofovir disoproxil fumarate is a P-gp substrate and ketoconazole is a P-gp inhibitor.
    Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse effects if coadministration with ketoconazole is necessary. Concurrent use may increase tenofovir exposure. Tenofovir disoproxil fumarate is a P-gp substrate and ketoconazole is a P-gp inhibitor.
    Enalapril; Felodipine: (Moderate) Concurrent use of felodipine and ketoconazole should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased felodipine AUC and half-life by approximately 8-fold and 2-fold, respectively.
    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.
    Enfortumab vedotin: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with ketoconazole is necessary. Concomitant use may increase unconjugated 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 and P-gp substrate; ketoconazole is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
    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) Avoid enzalutamide for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may decrease exposure of ketoconazole and reduce its efficacy. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole; a ketoconazole dose increase may be necessary. Ketoconazole is a CYP3A substrate and enzalutamide is a strong CYP3A inducer.
    Eplerenone: (Contraindicated) Eplerenone is contraindicated for use with ketoconazole due to increased eplerenone exposure which increases the risk of developing hyperkalemia and hypotension. Eplerenone is a sensitive CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased serum eplerenone concentrations by roughly 5-fold.
    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 and ketoconazole is contraindicated due to the potential for increased ergot exposure. Increased plasma concentrations of ergot alkaloids are associated with risk of acute ergot toxicity which is characterized by peripheral vasospasm and ischemia of the extremities and other tissues. Ergot alkaloids are CYP3A substrates and ketoconazole is a strong CYP3A inhibitor.
    Ergonovine: (Contraindicated) Coadministration of ergot alkaloids and ketoconazole is contraindicated due to the potential for increased ergot exposure. Increased plasma concentrations of ergot alkaloids are associated with risk of acute ergot toxicity which is characterized by peripheral vasospasm and ischemia of the extremities and other tissues. Ergot alkaloids are CYP3A substrates and ketoconazole is a strong CYP3A inhibitor.
    Ergot alkaloids: (Contraindicated) Coadministration of ergot alkaloids and ketoconazole is contraindicated due to the potential for increased ergot exposure. Increased plasma concentrations of ergot alkaloids are associated with risk of acute ergot toxicity which is characterized by peripheral vasospasm and ischemia of the extremities and other tissues. Ergot alkaloids are CYP3A substrates and ketoconazole is a strong CYP3A inhibitor.
    Ergotamine: (Contraindicated) Coadministration of ergot alkaloids and ketoconazole is contraindicated due to the potential for increased ergot exposure. Increased plasma concentrations of ergot alkaloids are associated with risk of acute ergot toxicity which is characterized by peripheral vasospasm and ischemia of the extremities and other tissues. Ergot alkaloids are CYP3A substrates and ketoconazole is a strong CYP3A inhibitor.
    Ergotamine; Caffeine: (Contraindicated) Coadministration of ergot alkaloids and ketoconazole is contraindicated due to the potential for increased ergot exposure. Increased plasma concentrations of ergot alkaloids are associated with risk of acute ergot toxicity which is characterized by peripheral vasospasm and ischemia of the extremities and other tissues. Ergot alkaloids are CYP3A substrates and ketoconazole is a strong CYP3A inhibitor. (Moderate) Ketoconazole has been shown to inhibit the clearance of caffeine by 11 percent. The clinical significance of these interactions has not been determined.
    Eribulin: (Contraindicated) Avoid concomitant use of ketoconazole and eribulin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    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%.
    Ertugliflozin; Metformin: (Moderate) Concomitant administration of metformin and ketoconazole may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion (MATE) and OCT2 substrate and ketoconazole is a MATE and OCT2 inhibitor. MATE and OCT2 inhibitors may decrease metformin elimination by blocking renal tubular secretion.
    Erythromycin: (Contraindicated) Avoid concomitant use of ketoconazole and erythromycin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. In addition, ketoconazole is a strong CYP3A4 inhibitor, and may increase exposure to erythromycin, a CYP3A4 substrate.
    Escitalopram: (Contraindicated) Avoid concomitant use of ketoconazole and escitalopram due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Ketoconazole is associated with a risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been reported postmarketing with escitalopram. Pharmacokinetic interactions are not expected based on studies with citalopram.
    Estazolam: (Moderate) Monitor for estazolam-related adverse reactions, including sedation and respiratory depression, if coadministration with ketoconazole is necessary. Estazolam is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. In vivo drug-drug interaction studies were not conducted between estazolam and inhibitors of CYP3A.
    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: (Moderate) Use caution if coadministration of ketoconazole with medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A4 and ketoconazole is a strong CYP3A4 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.
    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. (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 total dose of eszopiclone should not exceed 2 mg when administered with ketoconazole. Coadministration may increase eszopiclone exposure resulting in increased risk of next-day psychomotor or memory impairment and decreased ability to perform tasks requiring full mental alertness such as driving. CYP3A4 is a primary metabolic pathway for eszopiclone; ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased eszopiclone exposure by 2.2-fold.
    Ethanol: (Major) Advise patients to avoid alcohol consumption while taking ketoconazole. A disulfiram-like reaction has rarely been reported when alcohol was consumed concurrently with ketoconazole. 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. (Major) Due to the risk of hepatotoxicity, alcohol should be avoided during and for at least 48 hours following ketoconazole therapy. In addition, a disulfiram-like reaction has rarely been reported when alcohol was consumed concurrently with ketoconazole. 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.
    Ethinyl Estradiol: (Moderate) Monitor for an increase in the incidence and severity of estrogen-related adverse effects during concomitant use of ethinyl estradiol and ketoconazole. Concomitant use may increase ethinyl estradiol exposure. Ethinyl estradiol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Monitor for an increase in the incidence and severity of estrogen-related adverse effects during concomitant use of ethinyl estradiol and ketoconazole. Concomitant use may increase ethinyl estradiol exposure. Ethinyl estradiol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Monitor for an increase in the incidence and severity of estrogen-related adverse effects during concomitant use of ethinyl estradiol and ketoconazole. Concomitant use may increase ethinyl estradiol exposure. Ethinyl estradiol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Monitor for an increase in the incidence and severity of estrogen-related adverse effects during concomitant use of ethinyl estradiol and ketoconazole. Concomitant use may increase ethinyl estradiol exposure. Ethinyl estradiol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Ethinyl Estradiol; Norgestrel: (Moderate) Monitor for an increase in the incidence and severity of estrogen-related adverse effects during concomitant use of ethinyl estradiol and ketoconazole. Concomitant use may increase ethinyl estradiol exposure. Ethinyl estradiol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Ethosuximide: (Moderate) Monitor for an increase in ethosuximide-related adverse reactions if coadministration with ketoconazole is necessary. Ethosuximide is a CYP3A4 substrate with a narrow therapeutic index and ketoconazole is a strong CYP3A4 inhibitor.
    Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Monitor for an increase in the incidence and severity of estrogen-related adverse effects during concomitant use of ethinyl estradiol and ketoconazole. Concomitant use may increase ethinyl estradiol exposure. Ethinyl estradiol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Etonogestrel: (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as ketoconazole may increase the serum concentration of etonogestrel.
    Etonogestrel; Ethinyl Estradiol: (Moderate) Monitor for an increase in the incidence and severity of estrogen-related adverse effects during concomitant use of ethinyl estradiol and ketoconazole. Concomitant use may increase ethinyl estradiol exposure. Ethinyl estradiol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as ketoconazole may increase the serum concentration of etonogestrel.
    Etravirine: (Moderate) Monitor for an increase in etravirine-related adverse reactions if coadministration with ketoconazole is necessary. Etravirine is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased etravirine exposure by 1.4-fold.
    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 CYP3A 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.
    Famotidine: (Major) Avoid use of H2-blockers with ketoconazole. Medications that increase gastric pH may impair ketoconazole absorption.
    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: (Moderate) Concurrent use of felodipine and ketoconazole should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased felodipine AUC and half-life by approximately 8-fold and 2-fold, respectively.
    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.
    Finasteride; Tadalafil: (Major) Avoid coadministration of tadalafil and ketoconazole for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of ketoconazole for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Concurrent use may increase systemic exposure to tadalafil resulting in adverse effects including hypotension, syncope, visual changes, and prolonged erection. Tadalafil is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole 200 mg and 400 mg daily increased tadalafil AUC by 107% and 312%, respectively.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and fingolimod due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Flecainide: (Contraindicated) Avoid concomitant use of ketoconazole and flecainide due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Flibanserin: (Contraindicated) The concomitant use of flibanserin and strong CYP3A4 inhibitors such as ketoconazole is contraindicated due to increased flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following the use of ketoconazole, start flibanserin at least 2 weeks after the last dose of ketoconazole. If initiating ketoconazole following flibanserin use, begin therapy at least 2 days after the last dose of flibanserin. In cases where the benefit of initiating ketoconazole therapy within 2 days of stopping flibanserin clearly outweighs the risk of flibanserin-related hypotension and syncope, monitor the patient for signs of hypotension and syncope. Coadministration with ketoconazole increased flibanserin exposure by 4.5-fold.
    Fluoxetine: (Contraindicated) Avoid concomitant use of ketoconazole and fluoextine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Ketoconazole has a known risk for QT prolongation and torsade de pointes (TdP). Postmarketing cases of QT interval prolongation and ventricular arrhythmia including TdP have been reported in patients treated with fluoxetine.
    Fluphenazine: (Contraindicated) Avoid concomitant use of ketoconazole and fluphenazine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Flurazepam: (Moderate) Monitor for an increase in flurazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with ketoconazole is necessary. Concurrent use may increase flurazepam exposure. Flurazepam is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    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 concomitant use of salmeterol with ketoconazole. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose. (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. (Moderate) Monitor for an increase in vilanterol-related adverse effects, including increased heart rate and QT prolongation, if coadministered with ketoconazole. Coadministration may increase vilanterol exposure. Vilanterol is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole significantly increased systemic exposure to vilanterol. Vilanterol, as with other long-acting beta-agonists, should be administered with extreme caution to patients being treated with drugs known to prolong the QTc interval like ketoconazole because the effect of adrenergic agonists on the cardiovascular system may be potentiated.
    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. (Moderate) Monitor for an increase in vilanterol-related adverse effects, including increased heart rate and QT prolongation, if coadministered with ketoconazole. Coadministration may increase vilanterol exposure. Vilanterol is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole significantly increased systemic exposure to vilanterol. Vilanterol, as with other long-acting beta-agonists, should be administered with extreme caution to patients being treated with drugs known to prolong the QTc interval like ketoconazole because the effect of adrenergic agonists on the cardiovascular system may be potentiated.
    Fluvoxamine: (Contraindicated) Avoid concomitant use of ketoconazole and fluvoxamine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Fomepizole: (Minor) Drugs that inhibit the cytochrome P450 enzyme system, such as ketoconazole, may decrease the rate of elimination of fomepizole.
    Food: (Major) Advise patients to avoid cannabis use during ketoconazole treatment. Concomitant use may alter the exposure of some cannabinoids and increase the risk for adverse reactions. The cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A substrates and ketoconazole is a strong CYP3A inhibitor. Concomitant use of a cannabinoid product containing THC and CBD at an approximate 1:1 ratio with ketoconazole increased THC, 11-OH-THC, and CBD peak exposures by 1.3-, 3-, and 1.9-fold respectively.
    Formoterol: (Moderate) Formoterol, as with other long-acting beta-agonists, should be administered with extreme caution to patients being treated with drugs known to prolong the QTc interval like ketoconazole because the effect of adrenergic agonists on the cardiovascular system may be potentiated. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias. Ketoconazole has been associated with prolongation of the QT interval and torsade de pointes (TdP).
    Formoterol; Mometasone: (Moderate) Formoterol, as with other long-acting beta-agonists, should be administered with extreme caution to patients being treated with drugs known to prolong the QTc interval like ketoconazole because the effect of adrenergic agonists on the cardiovascular system may be potentiated. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias. Ketoconazole has been associated with prolongation of the QT interval and torsade de pointes (TdP). (Moderate) Monitor for steroid-related adverse reactions if coadministration of mometasone with ketoconazole is necessary, due to increased mometasone exposure; Cushing syndrome and adrenal suppression could potentially occur with long-term use. Mometasone is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    Fosamprenavir: (Moderate) Monitor for increased toxicity of both drugs if fosamprenavir is coadministered with ketoconazole; a ketoconazole dose reduction may be needed for patients receiving more than 400 mg/day. Concurrent use may increase the plasma concentrations of both drugs. Fosamprenavir is a CYP3A substrate and moderate CYP3A inhibitor; ketoconazole is a CYP3A substrate and strong CYP3A inhibitor.
    Foscarnet: (Contraindicated) Avoid concomitant use of ketoconazole and foscarnet due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Fosphenytoin: (Major) The use of fosphenytoin 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. Monitor phenytoin concentrations during concomitant therapy due to risk for phenytoin toxicity. Concomitant use may increase phenytoin concentrations. Ketoconazole is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and fostemsavir due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. The degree of QT prolongation associated with fostemsavir is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 4 times the recommended daily dose.
    Futibatinib: (Major) Avoid concurrent use of futibatinib and ketoconazole. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; ketoconazole is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and gemifloxacin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Gemtuzumab Ozogamicin: (Contraindicated) Avoid concomitant use of ketoconazole and gemtuzumab due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Gilteritinib: (Contraindicated) Avoid concomitant use of ketoconazole and gilteritinib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may increase the exposure of gilteritinib, further increasing the risk for adverse effects. Gilteritinib is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
    Glasdegib: (Contraindicated) Avoid concomitant use of ketoconazole and glasdegib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may increase the exposure of glasdegib, further increasing the risk for adverse effects. Glasdegib is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased the glasdegib AUC by 2.4-fold.
    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) Monitor for an increase in pibrentasvir-related adverse effects if concomitant use of ketoconazole is necessary. Concomitant use may increase pibrentasvir exposure. Pibrentasvir is a substrate of P-gp and ketoconazole is a P-gp inhibitor.
    Glimepiride; 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.
    Glipizide; Metformin: (Moderate) Concomitant administration of metformin and ketoconazole may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion (MATE) and OCT2 substrate and ketoconazole is a MATE and OCT2 inhibitor. MATE and OCT2 inhibitors may decrease metformin elimination by blocking renal tubular secretion.
    Glyburide; Metformin: (Moderate) Concomitant administration of metformin and ketoconazole may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion (MATE) and OCT2 substrate and ketoconazole is a MATE and OCT2 inhibitor. MATE and OCT2 inhibitors may decrease metformin elimination by blocking renal tubular secretion.
    Glycopyrrolate; Formoterol: (Moderate) Formoterol, as with other long-acting beta-agonists, should be administered with extreme caution to patients being treated with drugs known to prolong the QTc interval like ketoconazole because the effect of adrenergic agonists on the cardiovascular system may be potentiated. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias. Ketoconazole has been associated with prolongation of the QT interval and torsade de pointes (TdP).
    Goserelin: (Contraindicated) Avoid concomitant use of ketoconazole and androgen deprivation therapy (i.e. goserelin) due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Granisetron: (Contraindicated) Avoid concomitant use of ketoconazole and granisetron due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice during ketoconazole treatment due to the risk of increased ketoconazole exposure and adverse reactions. Ketoconazole is a CYP3A substrate and grapefruit juice is a strong CYP3A inhibitor.
    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) If coadministration of ketoconazole with extended-release (ER) guanfacine is necessary, it is recommended to reduce the guanfacine dosage to half of the recommended dose for age and weight. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for adverse effects including hypotension, drowsiness, lethargy, and bradycardia. If ketoconazole is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Ketoconazole may significantly increase guanfacine plasma concentrations, as indicated in pharmacokinetic drug interaction studies.
    H2-blockers: (Major) Avoid use of H2-blockers with ketoconazole. Medications that increase gastric pH may impair ketoconazole absorption.
    Halogenated Anesthetics: (Contraindicated) Avoid concomitant use of ketoconazole and halogenated anesthetics due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Haloperidol: (Contraindicated) Avoid concomitant use of ketoconazole and haloperidol due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. The intravenous route may carry a higher risk for haloperidol-induced QT/QTc prolongation than other routes of administration. Additionally, concomitant use may increase the exposure of haloperidol, further increasing the risk for adverse effects. Haloperidol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Histrelin: (Contraindicated) Avoid concomitant use of ketoconazole and androgen deprivation therapy (i.e. histrelin) due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    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; 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: (Contraindicated) Avoid concomitant use of ketoconazole and hydroxychloroquine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Hydroxyzine: (Contraindicated) Avoid concomitant use of ketoconazole and hydroxyzine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Ketoconazole has been associated with QT prolongation and TdP; cases of QT prolongation and TdP have been reported during postmarketing use of hydroxyzine, particularly in patients with other risk factors for QT prolongation/TdP.
    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 concomitant use of ibrutinib and ketoconazole; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of ketoconazole is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when ketoconazole is discontinued. Ibrutinib is a CYP3A4 substrate and 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; Famotidine: (Major) Avoid use of H2-blockers with ketoconazole. Medications that increase gastric pH may impair ketoconazole absorption.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and ibutilide due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Idelalisib: (Major) Avoid idelalisib for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of both drugs and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for adverse reactions (e.g., hepatotoxicity, diarrhea, neutropenia, and infection); a ketoconazole dose reduction may be necessary. Both ketoconazole and idelalisib are CYP3A substrates and strong CYP3A inhibitors. Coadministration with ketoconazole increased increased idelalisib exposure by 1.8-fold.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and iloperidone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may increase the exposure of iloperidone, further increasing the risk for adverse effects. Reduce the iloperidone dose by one-half if concomitant use is necessary. If ketoconazole is discontinued, increase the iloperidone dose to the previous level. Iloperidone is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the AUC of iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively.
    Imatinib: (Moderate) Monitor for an increase in imatinib-related adverse reactions if coadministration with ketoconazole is necessary. Imatinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased imatinib exposure by 40%.
    Indacaterol: (Moderate) Monitor for beta-agonist side effects like tremor, nervousness, or fast, irregular heart rate, if indacaterol is coadministered with ketoconazole. Concurrent use may increase indacaterol exposure, although such increases in indacaterol exposure are unlikely to require any dose adjustment. Indacaterol is a CYP3A4 and P-gp substrate; ketoconazole is a strong CYP3A4 and P-gp inhibitor. In drug interaction studies, coadministration with ketoconazole caused an approximately 2-fold increase in indacaterol exposure.
    Indacaterol; Glycopyrrolate: (Moderate) Monitor for beta-agonist side effects like tremor, nervousness, or fast, irregular heart rate, if indacaterol is coadministered with ketoconazole. Concurrent use may increase indacaterol exposure, although such increases in indacaterol exposure are unlikely to require any dose adjustment. Indacaterol is a CYP3A4 and P-gp substrate; ketoconazole is a strong CYP3A4 and P-gp inhibitor. In drug interaction studies, coadministration with ketoconazole caused an approximately 2-fold increase in indacaterol exposure.
    Indinavir: (Major) Avoid indinavir for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of both drugs and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for adverse reactions; a ketoconazole dose reduction may be necessary. Although specific recommendations are unavailable for use with ketoconazole, a reduced indinavir dose of 600 mg PO every 8 hours is recommended when coadministered with other strong CYP3A4 inhibitors. Both ketoconazole and indinavir are CYP3A substrates and strong CYP3A inhibitors.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and inotuzumab due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    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 and its active metabolite, SN-38, are CYP3A4 substrates. Ketoconazole is a strong CYP3A4 inhibitor. Concomitant use may increase systemic 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 and its active metabolite, SN-38, are CYP3A4 substrates. Ketoconazole is a strong CYP3A4 inhibitor. Concomitant use may increase systemic 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: (Contraindicated) Avoid concomitant use of ketoconazole and halogenated anesthetics due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Isoniazid, INH: (Major) Avoid the concomitant use of isonazid for 2 weeks before and during treatment with ketoconazole. The product labels note that isoniazid may decrease the biovailability of ketoconazole or induce CYP3A4 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 rifampin for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may decrease exposure of ketoconazole and reduce its efficacy. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole; a ketoconazole dose increase may be necessary. Ketoconazole is a CYP3A substrate and rifampin is a strong CYP3A inducer. (Major) Avoid the concomitant use of isonazid for 2 weeks before and during treatment with ketoconazole. The product labels note that isoniazid may decrease the biovailability of ketoconazole or induce CYP3A4 resulting in antifungal treatment failure. If coadministration is necessary, monitor the antifungal activity of ketoconazole and increase the dose as necessary.
    Isoniazid, INH; Rifampin: (Major) Avoid rifampin for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may decrease exposure of ketoconazole and reduce its efficacy. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole; a ketoconazole dose increase may be necessary. Ketoconazole is a CYP3A substrate and rifampin is a strong CYP3A inducer. (Major) Avoid the concomitant use of isonazid for 2 weeks before and during treatment with ketoconazole. The product labels note that isoniazid may decrease the biovailability of ketoconazole or induce CYP3A4 resulting in antifungal treatment failure. If coadministration is necessary, monitor the antifungal activity of ketoconazole and increase the dose as necessary.
    Isradipine: (Moderate) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with ketoconazole is necessary. Concomitant use may increase isradipine exposure. Isradipine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and ivosidenib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. If coadministered, decreased ketoconazole exposure and loss of antifungal efficacy may occur. Additionally, concomitant use may increase the exposure of ivosidenib, further increasing the risk for adverse effects. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If ketoconazole is discontinued, wait at least 5 half-lives of ketoconazole before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. 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) Avoid coadministration of ixabepilone with strong CYP3A4 inhibitors like ketoconazole. If coadministration cannot be avoided, reduce the dose of ixabepilone to 20 mg per meters-squared. Monitor for neuropathy, GI symptoms, and myelosuppression. If the strong inhibitor is discontinued, increase the ixabepilone dose (at 1 week after discontinuing the inhibitor) to that was used before starting the strong inhibitor. Ixabepilone is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased ixabepilone exposure by 79%.
    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) Monitor for an increase in tenofovir-related adverse effects if coadministration with ketoconazole is necessary. Concurrent use may increase tenofovir exposure. Tenofovir disoproxil fumarate is a P-gp substrate and ketoconazole is a P-gp inhibitor.
    Lansoprazole; Amoxicillin; Clarithromycin: (Contraindicated) Avoid concomitant use of ketoconazole and clarithromycin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of both drugs, further increasing the risk for adverse events. Both ketoconazole and clarithromycin are CYP3A substrates and strong CYP3A inhibitors.
    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 ketoconazole with larotrectinib due to the risk of increased larotrectinib exposure which may increase the risk of adverse reactions. If concomitant use is unavoidable, reduce the dose of larotrectinib by 50%. After ketoconazole has been discontinued for 3 to 5 elimination half-lives, resume the larotrectinib dose taken prior to initiating ketoconazole. Larotrectinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the larotrectinib AUC by 4.3-fold.
    Lefamulin: (Contraindicated) Avoid concomitant use of ketoconazole and lefamulin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of lefamulin, further increasing the risk for adverse effects. Lefamulin is a CYP3A4 and P-gp substrate and ketoconazole is a P-gp and strong CYP3A inhibitor. 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: (Contraindicated) Avoid concomitant use of ketoconazole and lenvatinib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and androgen deprivation therapy (i.e. leuprolide) due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Leuprolide; Norethindrone: (Contraindicated) Avoid concomitant use of ketoconazole and androgen deprivation therapy (i.e. leuprolide) due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Levamlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ketoconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Levofloxacin: (Contraindicated) Avoid concomitant use of ketoconazole and levofloxacin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Ketoconazole is associated with QT prolongation and TdP; levofloxacin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia and rare cases of TdP have been spontaneously reported during postmarketing surveillance.
    Levomilnacipran: (Major) Do not exceed a levomilnacipran dose of 80 mg once daily if coadministration with ketoconazole is necessary. Concomitant use may increase levomilnacipran exposure. Levomilnacipran is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased levomilnacipran exposure by about 50%.
    Levonorgestrel; Ethinyl Estradiol: (Moderate) Monitor for an increase in the incidence and severity of estrogen-related adverse effects during concomitant use of ethinyl estradiol and ketoconazole. Concomitant use may increase ethinyl estradiol exposure. Ethinyl estradiol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Monitor for an increase in the incidence and severity of estrogen-related adverse effects during concomitant use of ethinyl estradiol and ketoconazole. Concomitant use may increase ethinyl estradiol exposure. Ethinyl estradiol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    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; Epinephrine: (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.
    Linagliptin; Metformin: (Moderate) Concomitant administration of metformin and ketoconazole may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion (MATE) and OCT2 substrate and ketoconazole is a MATE and OCT2 inhibitor. MATE and OCT2 inhibitors may decrease metformin elimination by blocking renal tubular secretion.
    Lithium: (Contraindicated) Avoid concomitant use of ketoconazole and lithium due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Lithium has been associated with QT prolongation; ketoconazole is associated with QT prolongation and TdP.
    Lofexidine: (Contraindicated) Avoid concomitant use of ketoconazole and lofexidine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    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. Both lonafarnib and ketoconazole are CYP3A substrates and strong CYP3A inhibitors. Coadministration with ketoconazole increased the exposure of lonafarnib by 425%.
    Loperamide: (Contraindicated) Concomitant use of loperamide and ketoconazole is contraindicated due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase loperamide exposure and the risk for other loperamide-related adverse effects; loperamide is a CYP3A and P-gp substrate and ketoconazole is a strong CYP3A and P-gp inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-fold.
    Loperamide; Simethicone: (Contraindicated) Concomitant use of loperamide and ketoconazole is contraindicated due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase loperamide exposure and the risk for other loperamide-related adverse effects; loperamide is a CYP3A and P-gp substrate and ketoconazole is a strong CYP3A and P-gp inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-fold.
    Lopinavir; Ritonavir: (Contraindicated) Avoid concomitant use of ketoconazole and lopinavir; ritonavir due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of both drugs, further increasing the risk for adverse effects. Both lopinavir; ritonavir and ketoconazole are CYP3A substrates and strong CYP3A inhibitors. (Major) Avoid ritonavir for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of ketoconazole and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for ketoconazole-related adverse reactions; a ketoconazole dose reduction may be necessary. Ketoconazole is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor.
    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) Avoid lumacaftor; ivacaftor for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may decrease exposure of ketoconazole and reduce its efficacy. The exposure of lumacaftor; ivacaftor may also be increased. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole; a ketoconazole dose increase may be necessary. 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 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 CYP3A4 to reach steady-state. Ketoconazole is a CYP3A substrate and strong CYP3A inhibitor; ivacaftor is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
    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.
    Lumateperone: (Major) Reduce the dose of lumateperone to 10.5 mg once daily if concomitant use of ketoconazole is necessary. 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 a strong CYP3A4 inhibitor increased lumateperone exposure by approximately 4-fold.
    Lurasidone: (Contraindicated) Coadministration of lurasidone with ketoconazole is contraindicated due to increased plasma concentrations of lurasidone. Lurasidone is a sensitive CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased lurasidone exposure by 9-fold.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and macimorelin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Macitentan: (Major) Avoid coadministration of macitentan with ketoconazole due to the risk of increased macitentan exposure and adverse effects. Consider alternative treatment options for pulmonary hypertension if treatment with ketoconazole is necessary. Macitentan is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased macitentan exposure by approximately 2-fold.
    Maprotiline: (Contraindicated) Avoid concomitant use of ketoconazole and maprotiline due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Maraviroc: (Major) Reduce the dose of maraviroc when coadministration with ketoconazole is necessary, regardless of whether the patient is receiving a concomitant strong CYP3A4 inducer. The effect of ketoconazole on maraviroc exposure is expected to exceed that of the inducer and overall, increased maraviroc concentrations are expected. Coadministration of maraviroc with ketoconazole is contraindicated in patients with CrCl less than 30 mL/minute. Recommendations for reducing the maraviroc dose when administered with ketoconazole (with or without a concomitant CYP3A inducer) are: 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. Maraviroc is a sensitive CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with strong CYP3A4 inhibitors may result in increased maraviroc concentrations.
    Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with ketoconazole due to risk of heart failure due to systolic dysfunction. Concomitant use increases mavacamten exposure. Mavacamten is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Concomitant use of mavacamten 15 mg with ketoconazole 400 mg once daily is predicted to increase mavacamten exposure up to 130%.
    Medroxyprogesterone: (Moderate) Use caution if coadministration of ketoconazole with medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A4 and ketoconazole is a strong CYP3A4 inhibitor.
    Mefloquine: (Contraindicated) Avoid concomitant use of ketoconazole and mefloquine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Ketoconazole should not be administered within 15 weeks of the last dose of mefloquine. Concomitant use may also increase the exposure of mefloquine, further increasing the risk for adverse effects. Mefloquine is a CYP3A4 substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased the exposure of mefloquine by 79%.
    Meperidine; Promethazine: (Contraindicated) Avoid concomitant use of ketoconazole and promethazine due to an increased risk for QT prolongation and torsade de pointes(TdP). Promethazine has a possible risk for QT prolongation; ketoconazole is known to have a risk for QT prolongation and TdP. If use together is medically necessary it may be advisable to monitor ECG and serum electrolytes.
    Metformin: (Moderate) Concomitant administration of metformin and ketoconazole may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion (MATE) and OCT2 substrate and ketoconazole is a MATE and OCT2 inhibitor. MATE and OCT2 inhibitors may decrease metformin elimination by blocking renal tubular secretion.
    Metformin; Repaglinide: (Moderate) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with ketoconazole is necessary. Repaglinide is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased repaglinide exposure by up to 1.5-fold. (Moderate) Concomitant administration of metformin and ketoconazole may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion (MATE) and OCT2 substrate and ketoconazole is a MATE and OCT2 inhibitor. MATE and OCT2 inhibitors may decrease metformin elimination by blocking renal tubular secretion.
    Metformin; Rosiglitazone: (Moderate) Concomitant administration of metformin and ketoconazole may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion (MATE) and OCT2 substrate and ketoconazole is a MATE and OCT2 inhibitor. MATE and OCT2 inhibitors may decrease metformin elimination by blocking renal tubular secretion. (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. (Moderate) Concomitant administration of metformin and ketoconazole may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion (MATE) and OCT2 substrate and ketoconazole is a MATE and OCT2 inhibitor. MATE and OCT2 inhibitors may decrease metformin elimination by blocking renal tubular secretion.
    Metformin; Sitagliptin: (Moderate) Concomitant administration of metformin and ketoconazole may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion (MATE) and OCT2 substrate and ketoconazole is a MATE and OCT2 inhibitor. MATE and OCT2 inhibitors may decrease metformin elimination by blocking renal tubular secretion.
    Methadone: (Contraindicated) Avoid concomitant use of ketoconazole and methadone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of methadone, further increasing the risk for adverse effects, such as respiratory and/or CNS depression. Methadone is a CYP3A4 substrate and ketoconazole is a strong CYP3A inhibitor.
    Methylergonovine: (Contraindicated) Coadministration of ergot alkaloids and ketoconazole is contraindicated due to the potential for increased ergot exposure. Increased plasma concentrations of ergot alkaloids are associated with risk of acute ergot toxicity which is characterized by peripheral vasospasm and ischemia of the extremities and other tissues. Ergot alkaloids are CYP3A substrates and ketoconazole is a strong CYP3A inhibitor.
    Methylprednisolone: (Moderate) Monitor for corticosteroid-related adverse events if methylprednisolone is used with ketoconazole. Concurrent use may increase the exposure of methylprednisolone. Methylprednisolone is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%.
    Metronidazole: (Contraindicated) Avoid concomitant use of ketoconazole and metronidazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval, like ketoconazole.
    Midazolam: (Major) Avoid coadministration of midazolam with ketoconazole. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    Midostaurin: (Contraindicated) Avoid concomitant use of ketoconazole and midostaurin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of midostaurin, further increasing the risk for adverse effects. 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 and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the AUC values of midostaurin and its metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively.
    Mifepristone: (Contraindicated) Avoid concomitant use of ketoconazole and mifepristone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of both drugs, further increasing the risk for adverse effects. When mifepristone is used in the treatment of Cushing's syndrome, coadministration with ketoconazole should be done only when necessary, and in such cases the dose of mifepristone should be limited to a maximum dose of 900 mg per day. In a patient already receiving ketoconazole, initiate mifepristone at a dose of 300 mg and titrate up to a maximum of 900 mg if clinically indicated. If ketoconazole is initiated in a patient already receiving mifepristone 300 mg, dosage adjustments are not required. If ketoconazole is initiated in a patient already receiving mifepristone 600 mg, reduce mifepristone to 300 mg per day and titrate to a maximum of 600 mg if clinically indicated. If ketoconazole is initiated in a patient receiving already receiving 900 mg, reduce mifepristone to 600 mg per day and titrate up to a maximum of 900 mg if clinically indicated. In a patient receiving mifepristone 1,200 mg, reduce the mifepristone dose to 900 mg. Both mifepristone and ketoconazole are substrates and strong inhibitors of CYP3A4.
    Mirtazapine: (Contraindicated) Avoid concomitant use of ketoconazole and mirtazapine if possible due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Decrease the dose of mirtazapine if needed with concomitant strong CYP3A inhibitor use. Conversely, an increase in dosage of mirtazapine may be needed if the CYP3A inhibitor is discontinued. Mirtazapine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased the AUC of mirtazapine by approximately 50%.
    Mirvetuximab Soravtansine: (Moderate) Closely monitor for mirvetuximab soravtansine-related adverse reactions if concomitant use of ketoconazole is necessary. DM4, the cytotoxic component of mirvetuximab soravtansine, is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Concomitant use may increase unconjugated DM4 exposure.
    Mitapivat: (Major) Avoid coadministration of mitapivat with ketoconazole, due to increased risk of adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Ketoconazole increased mitapivat overall and peak exposure by approximately 3.9-fold and 2.4-fold, respectively, after mitapivat 5, 20, or 50 mg twice daily.
    Mitotane: (Major) Avoid mitotane for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may decrease exposure of ketoconazole and reduce its efficacy. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole; a ketoconazole dose increase may be necessary. Ketoconazole is a CYP3A substrate and mitotane is a strong CYP3A inducer.
    Mobocertinib: (Contraindicated) Avoid concomitant use of ketoconazole and mobocertinib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of mobocertinib, further increasing the risk for adverse effects. Mobocertinib is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Use of ketoconazole is predicted to increase the overall exposure of mobocertinib and its active metabolites by 374% to 419%.
    Modafinil: (Moderate) Monitor for an increase in modafinil-related adverse reactions if coadministration with ketoconazole is necessary. Modafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as ketoconazole are possible. However, because modafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict.
    Mometasone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of mometasone with ketoconazole is necessary, due to increased mometasone exposure; Cushing syndrome and adrenal suppression could potentially occur with long-term use. Mometasone is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    Morphine: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression. If coadministration with ketoconazole is necessary, assess the need for morphine dosage reduction as clinically indicated. Morphine is a P-glycoprotein (P-gp) substrate and ketoconazole is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
    Morphine; Naltrexone: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression. If coadministration with ketoconazole is necessary, assess the need for morphine dosage reduction as clinically indicated. Morphine is a P-glycoprotein (P-gp) substrate and ketoconazole is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
    Moxifloxacin: (Contraindicated) Avoid concomitant use of ketoconazole and moxifloxacin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    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.
    Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid coadministration of sirolimus with ketoconazole as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and ketoconazole is a strong CYP3A and P-gp inhibitor. Concomitant use increased sirolimus overall exposure by 10.9-fold.
    Nefazodone: (Major) Avoid nefazodone for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of ketoconazole and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for ketoconazole-related adverse reactions; a ketoconazole dose reduction may be necessary. Ketoconazole is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor.
    Nelfinavir: (Major) Avoid nelfinavir for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of both drugs and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for adverse reactions; a ketoconazole dose reduction may be necessary. Although specific recommendations are unavailable for use with ketoconazole, a reduced nelfinavir dose of 600 mg PO every 8 hours is recommended when coadministered with other strong CYP3A4 inhibitors. Both ketoconazole and nelfinavir are CYP3A substrates and strong CYP3A 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) Monitor for an increase in netupitant-related adverse reactions if coadministration with ketoconazole is necessary. Netupitant is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased netupitant exposure by 140%; however, no dosage adjustment is necessary.
    Nevirapine: (Major) Avoid coadministration of nevirapine and ketoconazole. Concurrent use may result in decreases in ketoconazole plasma concentrations that may reduce efficacy of the drug. If concurrent use cannot be avoided, monitor for decreased efficacy of ketoconazole and increase the dose of ketoconazole as necessary. Additionally, monitor for an increase in nevirapine-related adverse reactions if coadministration with ketoconazole is necessary. Ketoconazole is a CYP3A substrate and strong CYP3A inhibitor; nevirapine is a CYP3A substrate and CYP3A inducer. Coadministration results in a 15% to 30% increase in nevirapine plasma concentrations and a 63% reduction in ketoconazole AUC.
    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 CYP3A 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) Careful monitoring and dose adjustment of nifedipine may be necessary if administered with ketoconazole as nifedipine exposure and adverse effects may be increased. Consider initiating nifedipine at the lowest dose. Nifedipine is a CYP3A4 substrate; ketoconazole is a strong/moderate CYP3A4 inhibitor.
    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: (Major) Avoid coadministration of nimodipine with ketoconazole due to the risk of significant hypotension. If concomitant use is unavoidable, monitor blood pressure and reduce the dose of nimodipine as clinically appropriate. Nimodipine is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    Nintedanib: (Moderate) Monitor for nintedanib-related adverse reactions if concomitant use of ketoconazole is necessary. Concomitant use may increase nintedanib exposure. Nintedanib is a P-gp substrate, and a minor substrate of CYP3A4 and ketoconazole is a dual P-gp and CYP3A4 inhibitor. Coadministration with ketoconazole increased nintedanib AUC by 60%.
    Nirmatrelvir; Ritonavir: (Major) Avoid ritonavir for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of ketoconazole and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for ketoconazole-related adverse reactions; a ketoconazole dose reduction may be necessary. Ketoconazole is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with ketoconazole due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and ketoconazole is a CYP3A4 inhibitor. Coadministration with ketoconazole increased the AUC of nisoldipine by 24-fold.
    Nizatidine: (Major) Avoid use of H2-blockers with ketoconazole. Medications that increase gastric pH may impair ketoconazole absorption.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Monitor for an increase in the incidence and severity of estrogen-related adverse effects during concomitant use of ethinyl estradiol and ketoconazole. Concomitant use may increase ethinyl estradiol exposure. Ethinyl estradiol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Norethindrone; Ethinyl Estradiol: (Moderate) Monitor for an increase in the incidence and severity of estrogen-related adverse effects during concomitant use of ethinyl estradiol and ketoconazole. Concomitant use may increase ethinyl estradiol exposure. Ethinyl estradiol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Monitor for an increase in the incidence and severity of estrogen-related adverse effects during concomitant use of ethinyl estradiol and ketoconazole. Concomitant use may increase ethinyl estradiol exposure. Ethinyl estradiol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Norgestimate; Ethinyl Estradiol: (Moderate) Monitor for an increase in the incidence and severity of estrogen-related adverse effects during concomitant use of ethinyl estradiol and ketoconazole. Concomitant use may increase ethinyl estradiol exposure. Ethinyl estradiol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and octreotide due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Octreotide has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and other conduction disturbances which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
    Ofloxacin: (Contraindicated) Avoid concomitant use of ketoconazole and ofloxacin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Ketoconazole is associated with a risk for QT prolongation and TdP. Some quinolones, including ofloxacin, have been associated with prolongation of the QT interval on the ECG and infrequent cases of arrhythmia. Rare cases ofTdP have been spontaneously reported during postmarketing surveillance in patients receiving quinolones, including ofloxacin.
    Olanzapine: (Contraindicated) Avoid concomitant use of ketoconazole and olanzapine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Olanzapine; Fluoxetine: (Contraindicated) Avoid concomitant use of ketoconazole and fluoextine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Ketoconazole has a known risk for QT prolongation and torsade de pointes (TdP). Postmarketing cases of QT interval prolongation and ventricular arrhythmia including TdP have been reported in patients treated with fluoxetine. (Contraindicated) Avoid concomitant use of ketoconazole and olanzapine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Olanzapine; Samidorphan: (Contraindicated) Avoid concomitant use of ketoconazole and olanzapine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    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.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ketoconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Olodaterol: (Moderate) Monitor for an increase in olodaterol-related adverse effects, including increased heart rate and QT prolongation, if coadministered with ketoconazole. Coadministration may increase olodaterol exposure. No dose adjustment of olodaterol is necessary. In a drug interaction study using the strong dual CYP and P-gp inhibitor ketoconazole, a 1.7-fold increase of olodaterol inhalation maximum plasma concentrations and AUC was observed. No dose adjustment is necessary. Olodaterol, as with other long-acting beta-agonists, should be administered with extreme caution to patients being treated with drugs known to prolong the QTc interval like ketoconazole because the effect of adrenergic agonists on the cardiovascular system may be potentiated.
    Olopatadine; Mometasone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of mometasone with ketoconazole is necessary, due to increased mometasone exposure; Cushing syndrome and adrenal suppression could potentially occur with long-term use. Mometasone is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid ritonavir for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of ketoconazole and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for ketoconazole-related adverse reactions; a ketoconazole dose reduction may be necessary. Ketoconazole is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and ondansetron due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Ketoconazole is associated with an established risk for QT prolongation and TdP. Electrocardiogram (ECG) monitoring is recommended in patients at risk if use together cannot be avoided and is medically necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and osilodrostat due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of osilodrostat, further increasing the risk for adverse effects. If concomitant use is necessary, reduce the dose of osilodrostat by half. Osilodrostat is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Osimertinib: (Contraindicated) Avoid concomitant use of ketoconazole and osimertinib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Ospemifene: (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with ketoconazole is necessary. Ospemifene is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased ospemifene systemic exposure by 1.4-fold.
    Oxaliplatin: (Contraindicated) Avoid concomitant use of ketoconazole and oxaliplatin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Oxybutynin: (Moderate) Monitor for an increase in oxybutynin-related adverse reactions if coadministration with ketoconazole is necessary. Oxybutynin is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased mean oxybutynin plasma concentrations by approximately 2-fold.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and ozanimod due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Ozanimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
    Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of paclitaxel with ketoconazole is necessary due to the risk of increased plasma concentrations of paclitaxel. Paclitaxel is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors 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.
    Pacritinib: (Contraindicated) Concurrent use of pacritinib with ketoconazole is contraindicated due to increased pacritinib exposure which increases the risk of adverse reactions. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de pointes (TdP). Pacritinib is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and paliperidone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Panobinostat: (Contraindicated) Avoid concomitant use of ketoconazole and panobinostat due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of panobinostat, further increasing the risk for adverse effects. If concomitant use is necessary, reduce the starting dose of panobinostat to 10 mg. Panobinostat is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased the AUC of panobinostat by 73%.
    Paricalcitol: (Moderate) Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with both paricalcitol and ketoconazole, or during periods of dose titration. If hypercalcemia occurs, the dose of paricalcitol should be reduced or withheld until these parameters are normalized. Paricalcitol is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole approximately doubled the exposure of paricalcitol.
    Pasireotide: (Contraindicated) Avoid concomitant use of ketoconazole and pasireotide due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Pazopanib: (Contraindicated) Avoid concomitant use of ketoconazole and pazopanib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of pazopanib, further increasing the risk for adverse effects. If concurrent use is unavoidable, reduce the pazopanib dose to 400 mg PO once daily; further dose adjustments may be necessary if adverse effects occur. Pazopanib is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Concurrent use with ketoconazole increased the AUC of pazopanib by 1.7-fold.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and systemic pentamidine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    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.
    Perindopril; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ketoconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Perphenazine: (Contraindicated) Avoid concomitant use of ketoconazole and perphenazine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Perphenazine; Amitriptyline: (Contraindicated) Avoid concomitant use of ketoconazole and perphenazine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    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 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased pexidartinib exposure by 70%.
    Phenytoin: (Major) The use of phenytoin 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. Monitor phenytoin concentrations during concomitant therapy due to risk for phenytoin toxicity. Concomitant use may increase phenytoin concentrations. Ketoconazole is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer.
    Pimavanserin: (Contraindicated) Avoid concomitant use of ketoconazole and pimavanserin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of pimavanserin, further increasing the risk for adverse effects. If concurrent use is unavoidable, reduce the dose of pimavanserin to 10 mg PO once daily and monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation if coadministration with ketoconazole is necessary. Concurrent use may increase pimavanserin exposure. Pimavanserin is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased exposure to pimavanserin by 3-fold.
    Pimozide: (Contraindicated) Avoid concomitant use of ketoconazole and pimozide due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of pimozide, further increasing the risk for adverse effects. Pimozide is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Pioglitazone: (Moderate) Monitor blood glucose during concomitant ketoconazole and pioglitazone use. Concomitant use increased ketoconazole exposure and peak concentration by 34% and 14%, respectively.
    Pioglitazone; Glimepiride: (Moderate) Monitor blood glucose during concomitant ketoconazole and pioglitazone use. Concomitant use increased ketoconazole exposure and peak concentration by 34% and 14%, respectively.
    Pioglitazone; Metformin: (Moderate) Concomitant administration of metformin and ketoconazole may increase metformin exposure and increase the risk for lactic acidosis. If these drugs are given together, monitor for signs of metformin toxicity; metformin dose adjustments may be needed. Metformin is a human multidrug and toxic extrusion (MATE) and OCT2 substrate and ketoconazole is a MATE and OCT2 inhibitor. MATE and OCT2 inhibitors may decrease metformin elimination by blocking renal tubular secretion. (Moderate) Monitor blood glucose during concomitant ketoconazole and pioglitazone use. Concomitant use increased ketoconazole exposure and peak concentration by 34% and 14%, respectively.
    Pitolisant: (Contraindicated) Avoid concomitant use of ketoconazole and pitolisant due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and ponesimod due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Ponesimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc 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) Monitor for corticosteroid-related adverse events if prednisolone is used with ketoconazole. Concurrent use may increase the exposure of prednisolone. Prednisolone is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%.
    Prednisone: (Moderate) Monitor for corticosteroid-related adverse events if prednisone is used with ketoconazole. Concurrent use may increase the exposure of prednisone. Prednisone is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%. In a study, ketoconazole inhibited 6 beta-hydroxylase and increased the exposure of biologically active unbound prednisolone after oral prednisone administration.
    Pretomanid: (Major) Avoid coadministration of pretomanid with ketoconazole, especially in patients with impaired hepatic function, due to increased risk for hepatotoxicity. Monitor for evidence of hepatotoxicity if coadministration is necessary. If new or worsening hepatic dysfunction occurs, discontinue hepatotoxic medications.
    Primaquine: (Contraindicated) Avoid concomitant use of ketoconazole and primaquine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Probenecid; 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 a P-gp and strong CYP3A4 inhibitor like 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.
    Procainamide: (Contraindicated) Avoid concomitant use of ketoconazole and procainamide due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Prochlorperazine: (Contraindicated) Avoid concomitant use of ketoconazole and prochlorperazine due to an increased risk for torsade de pointes (TdP) and QT/QTc 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.
    Promethazine: (Contraindicated) Avoid concomitant use of ketoconazole and promethazine due to an increased risk for QT prolongation and torsade de pointes(TdP). Promethazine has a possible risk for QT prolongation; ketoconazole is known to have a risk for QT prolongation and TdP. If use together is medically necessary it may be advisable to monitor ECG and serum electrolytes.
    Promethazine; Dextromethorphan: (Contraindicated) Avoid concomitant use of ketoconazole and promethazine due to an increased risk for QT prolongation and torsade de pointes(TdP). Promethazine has a possible risk for QT prolongation; ketoconazole is known to have a risk for QT prolongation and TdP. If use together is medically necessary it may be advisable to monitor ECG and serum electrolytes.
    Promethazine; Phenylephrine: (Contraindicated) Avoid concomitant use of ketoconazole and promethazine due to an increased risk for QT prolongation and torsade de pointes(TdP). Promethazine has a possible risk for QT prolongation; ketoconazole is known to have a risk for QT prolongation and TdP. If use together is medically necessary it may be advisable to monitor ECG and serum electrolytes.
    Propafenone: (Contraindicated) Avoid concomitant use of ketoconazole and propafenone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Drugs that inhibit CYP3A4 (such as ketoconazole) can be expected to cause increased plasma levels of propafenone. The combination may increase the risk of adverse reactions, including proarrhythmia. Propafenone is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    Proton pump inhibitors: (Major) Avoid use of proton pump inhibitors (PPIs) with ketoconazole. Medications that increase gastric pH may impair oral ketoconazole absorption.
    Quazepam: (Moderate) Monitor for an increase in quazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with ketoconazole is necessary; reduce the dose of quazepam if clinically appropriate. Concurrent use may increase the concentrations of quazepam. Quazepam is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    Quetiapine: (Contraindicated) Avoid concomitant use of ketoconazole and quetiapine due to an increased risk for QT prolongation and a risk for torsade de pointes (TdP). Concomitant use may also increase the exposure of quetiapine, further increasing the risk for adverse effects. If concomitant use is necessary, reduce the dose of quetiapine to one-sixth the original dose; consider monitoring ECG and serum electrolytes. Quetiapine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased the exposure of quetiapine by approximately 6-fold.
    Quinidine: (Contraindicated) Avoid concomitant use of ketoconazole and quinidine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Quinine: (Contraindicated) Avoid concomitant use of ketoconazole and quinine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of quinine, further increasing the risk for adverse effects. Quinine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased the exposure of quinine by 45% and decreased the clearance by 31%.
    Ramelteon: (Moderate) Monitor for an increase in ramelteon-related adverse reactions if coadministration with ketoconazole is necessary. Ramelteon is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased ramelteon exposure by 84%.
    Ranitidine: (Major) Avoid use of H2-blockers with ketoconazole. Medications that increase gastric pH may impair ketoconazole absorption.
    Ranolazine: (Contraindicated) Avoid concomitant use of ketoconazole and ranolazine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of ranolazine, further increasing the risk for adverse effects. Ranolazine is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased ranolazine exposure by 220%.
    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.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and relugolix due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of relugolix, further increasing the risk for adverse effects. If concomitant use is unavoidable, administer ketoconazole at least six 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 seven days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Relugolix is a P-gp substrate and ketoconazole is a P-gp inhibitor.
    Relugolix; Estradiol; Norethindrone acetate: (Contraindicated) Avoid concomitant use of ketoconazole and relugolix due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of relugolix, further increasing the risk for adverse effects. If concomitant use is unavoidable, administer ketoconazole at least six 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 seven days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Relugolix is a 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) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with ketoconazole is necessary. Repaglinide is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased repaglinide exposure by up to 1.5-fold.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and ribociclib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of both drugs, further increasing the risk for adverse effects. If coadministration cannot be avoided, reduce the dose of ribociclib to 400 mg once daily. If ketoconazole is discontinued, resume the previous ribociclib dose after at least 5 half-lives of ketoconazole. Both ribociclib and ketoconazole are CYP3A substrates and strong CYP3A inhibitors. Coadministration with another strong inhibitor increased the ribociclib AUC by 3.2-fold.
    Ribociclib; Letrozole: (Contraindicated) Avoid concomitant use of ketoconazole and ribociclib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of both drugs, further increasing the risk for adverse effects. If coadministration cannot be avoided, reduce the dose of ribociclib to 400 mg once daily. If ketoconazole is discontinued, resume the previous ribociclib dose after at least 5 half-lives of ketoconazole. Both ribociclib and ketoconazole are CYP3A substrates and strong CYP3A inhibitors. Coadministration with another strong inhibitor increased the ribociclib AUC by 3.2-fold.
    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) Avoid rifampin for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may decrease exposure of ketoconazole and reduce its efficacy. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole; a ketoconazole dose increase may be necessary. Ketoconazole is a CYP3A substrate and rifampin is a strong CYP3A inducer.
    Rifapentine: (Major) Avoid rifapentine for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may decrease exposure of ketoconazole and reduce its efficacy. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole; a ketoconazole dose increase may be necessary. Ketoconazole is a CYP3A substrate and rifapentine is a strong CYP3A inducer.
    Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with ketoconazole is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and ketoconazole is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
    Rilpivirine: (Contraindicated) Avoid concomitant use of ketoconazole and rilpivirine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of rilpivirine, further increasing the risk for adverse effects. Rilpivirine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and risperidone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Ritonavir: (Major) Avoid ritonavir for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of ketoconazole and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for ketoconazole-related adverse reactions; a ketoconazole dose reduction may be necessary. Ketoconazole is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor.
    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: (Contraindicated) Avoid concomitant use of ketoconazole and romidepsin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of romidepsin, further increasing the risk for adverse effects. Romidepsin is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased romidepsin AUC by approximately 25%.
    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 when coadministered with ketoconazole in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur. No dose adjustments are necessary for patients with graft-versus-host disease; however, monitor blood counts more frequently for toxicity and adjust ruxolitinib dosage for adverse reactions. In 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 PV patients, reduce the initial dose to 5 mg PO twice daily. In MF or PV patients 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. Avoid the use of ketoconazole in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily; alternatively, ruxolitinib therapy may be interrupted for the duration of ketoconazole use. Ruxolitinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased ruxolitinib overall exposure by 91%.
    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 concomitant use of salmeterol with ketoconazole. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
    Saquinavir: (Contraindicated) Avoid concomitant use of ketoconazole and saquinavir due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of both drugs, further increasing the risk for adverse effects. Both saquinavir and ketoconazole are CYP3A substrates and strong CYP3A inhibitors. Coadministration with ketoconazole 200 mg/day increased saquinavir exposure by 168%.
    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) Monitor for an increase in the incidence and severity of estrogen-related adverse effects during concomitant use of ethinyl estradiol and ketoconazole. Concomitant use may increase ethinyl estradiol exposure. Ethinyl estradiol is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. (Minor) Coadministration of segesterone, a CYP3A4 substrate and a strong CYP3A4 inhibitor, such as ketoconazole may increase the serum concentration of segesterone.
    Selpercatinib: (Contraindicated) Avoid concomitant use of ketoconazole and selpercatinib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of selpercatinib, further increasing the risk for adverse effects. If coadministration is unavoidable, reduce the dose of selpercatinib to 40 mg PO twice daily if original dose was 120 mg twice daily, and to 80 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If ketoconazole is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of ketoconazole. Selpercatinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased selpercatinib exposure by 133%.
    Selumetinib: (Major) Avoid coadministration of selumetinib and ketoconazole due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If ketoconazole is discontinued, resume the original selumetinib dose after 3 elimination half-lives of ketoconazole. Selumetinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
    Sertraline: (Contraindicated) Avoid concomitant use of ketoconazole and sertraline due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Ketoconazole has a well established risk for QT prolongation and TdP. QTc prolongation and TdP have been reported during postmarketing use of sertraline; most cases had confounding risk factors; the risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Sertraline has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure).
    Sevoflurane: (Contraindicated) Avoid concomitant use of ketoconazole and halogenated anesthetics due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Sibutramine: (Major) The hepatic CYP450 3A4-mediated metabolism of sibutramine may be inhibited by ketoconazole, a CYP3A4 inhibitor.
    Sildenafil: (Major) Coadministration of ketoconazole is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving ketoconazole. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Ketoconazole is a strong CYP3A4 inhibitor; sildenafil is a sensitive CYP3A4 substrate. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
    Silodosin: (Contraindicated) Concurrent use of silodosin and ketoconazole is contraindicated. Silodosin is extensively metabolized by CYP3A4 and is a P-glycoprotein (P-gp) substrate; ketoconazole inhibits CYP3A4 and P-gp. Coadministration may cause significant increases in silodosin plasma concentrations. In one study, coadministration resulted in a 3.8-fold increase in maximum plasma silodosin concentrations and a 3.2-fold increase in silodosin AUC.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and ketoconazole. Inhibition of CYP3A4 by ketoconazole may significantly increase the plasma concentrations of simeprevir, resulting in adverse effects.
    Simvastatin: (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 CYP3A inhibitors such as ketoconazole. If therapy with ketoconazole is unavoidable, simvastatin therapy must be suspended during the course of ketoconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin.
    Simvastatin; Sitagliptin: (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 CYP3A 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.
    Siponimod: (Contraindicated) Avoid concomitant use of ketoconazole and siponimod due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of siponimod, further increasing the risk for adverse effects. Siponimod is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    Sirolimus: (Major) Avoid coadministration of sirolimus with ketoconazole as concurrent use may increase sirolimus exposure and risk of toxicity. Alternative agents with lesser interaction potential with sirolimus should be considered. Sirolimus is a CYP3A and P-gp substrate and ketoconazole is a strong CYP3A and P-gp inhibitor. Concomitant use increased sirolimus overall exposure by 10.9-fold.
    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.
    Sodium Stibogluconate: (Contraindicated) Avoid concomitant use of sodium stibogluconate and ketoconazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with ketoconazole. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); ketoconazole is an inhibitor of P-gp. Ketoconazole is also a potent inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Use caution when administering velpatasvir with ketoconazole. Taking these drugs together may increase the plasma concentrations of velpatasvir, potentially resulting in adverse events. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); ketoconazole is an inhibitor of P-gp. Ketoconazole is also a potent inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
    Solifenacin: (Contraindicated) Avoid concomitant use of ketoconazole and solifenacin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of solifenacin, further increasing the risk for adverse effects. If concomitant use is necessary, do not exceed a dose of 5 mg per day of solifenacin in adults; do not exceed the initial solifenacin starting dose in pediatric patients. Solifenacin is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased solifenacin exposure by 2.7-fold.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and ketoconazole; sonidegib exposure was significantly increased in healthy subjects who received ketoconazole and sonidegib compared with sonidegib only. This interaction may result in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
    Sorafenib: (Contraindicated) Avoid concomitant use of ketoconazole and sorafenib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Sotalol: (Contraindicated) Avoid concomitant use of ketoconazole and sotalol due to an increased risk for QT/QTc prolongation and torsade de pointes (TdP).
    St. John's Wort, Hypericum perforatum: (Major) Avoid St. John's Wort for 2 weeks before and during treatment with ketoconazole. Concomitant use may decrease ketoconazole exposure and reduce ketoconazole efficacy. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole. Ketoconazole is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer.
    Sucralfate: (Moderate) Avoid use of sucralfate with ketoconazole. If concomitant use is necessary, separate administration of ketoconazole and sucralfate by at least 2 hours. Sucralfate is expected to impair ketoconazole absorption. Coadministration of sucralfate decreased ketoconazole bioavailability by approximately 20%.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if ketoconazole must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of ketoconazole is necessary. If ketoconazole is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like ketoconazole can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If ketoconazole is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
    Sunitinib: (Contraindicated) Avoid concomitant use of ketoconazole and sunitinib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of sunitinib, further increasing the risk for adverse effects. If concomitant use is unavoidable, monitor the QT interval more frequently and consider reducing the daily dose of sunitinib to a minimum of 37.5 mg for patients with GIST or RCC, and to a minimum of 25 mg for patients with pNET. Sunitinib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased exposure to sunitinib and its primary active metabolite by 51%.
    Suvorexant: (Major) Coadministration of suvorexant and ketoconazole is not recommended due to the potential for significantly increased suvorexant exposure. Suvorexant is a CYP3A4 substrate. Ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the suvorexant AUC by 2.8-fold.
    Tacrolimus: (Contraindicated) Avoid concomitant use of ketoconazole and tacrolimus due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of tacrolimus, further increasing the risk for adverse effects. If concomitant use is unavoidable, decrease tacrolimus dose and closely monitor tacrolimus serum concentrations. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased exposure to tacrolimus and its primary active metabolite by 51%.
    Tadalafil: (Major) Avoid coadministration of tadalafil and ketoconazole for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of ketoconazole for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Concurrent use may increase systemic exposure to tadalafil resulting in adverse effects including hypotension, syncope, visual changes, and prolonged erection. Tadalafil is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole 200 mg and 400 mg daily increased tadalafil AUC by 107% and 312%, respectively.
    Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with ketoconazole is necessary. Talazoparib is a P-glycoprotein (P-gp) substrate and ketoconazole is a P-gp inhibitor. Coadministration with other P-gp inhibitors increased talazoparib exposure by 8% to 45%.
    Tamoxifen: (Contraindicated) Avoid concomitant use of ketoconazole and tamoxifen due to an increased risk for QT/QTc prolongation and torsade de pointes (TdP). Ketoconazole has an established risk for QT prolongation and TdP; QT prolongation with tamoxifen has been reported in the published literature.
    Tamsulosin: (Major) Concurrent use of tamsulosin and ketoconazole is not recommended due to the potential for elevated tamsulosin concentrations. Such increases in tamsulosin concentrations are expected to produce clinically significant and potentially serious side effects, such as hypotension, dizziness, and vertigo. Tamsulosin is extensively metabolized by CYP3A4. Coadministration with ketoconazole, a strong CYP3A4 inhibitor, increased the Cmax and AUC of tamsulosin 2.2 and 2.8-fold, respectively.
    Tasimelteon: (Moderate) Avoid concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as ketoconazole, if possible. Tasimelteon is partially metabolized via CYP3A4, and an increase in exposure of tasimelteon with the potential for adverse reactions is possible if a strong CYP3A4 inhibitor is coadministered. During administration of ketoconazole 40 mg/day for 5 days, tasimelteon exposure increased by about 50%.
    Tazemetostat: (Major) Avoid coadministration of tazemetostat with ketoconazole as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. Tazemetostat is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
    Telavancin: (Contraindicated) Avoid concomitant use of ketoconazole and telavancin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Telbivudine: (Moderate) The risk of myopathy may be increased if ketoconazole is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Telithromycin: (Contraindicated) Avoid concomitant use of ketoconazole and telithromycin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of both drugs, further increasing the risk for adverse effects. Both ketoconazole and telithromycin are CYP3A substrates and strong CYP3A inhibitors.
    Telmisartan; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ketoconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
    Temsirolimus: (Major) Avoid coadministration of ketoconazole with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of ketoconazole before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole did not significantly affect temsirolimus exposure, but decreased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively.
    Tenofovir Alafenamide: (Minor) According to the manufacturer, interactions are not expected during coadministration of ketoconazole and tenofovir alafenamide; however based on the metabolic pathways of these medications, monitoring for tenofovir-associated adverse reactions should be considered if these drugs are given together. Ketoconazole is an inhibitor of the drug transporter P-glycoprotein (P-gp). Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tenofovir Disoproxil Fumarate: (Moderate) Monitor for an increase in tenofovir-related adverse effects if coadministration with ketoconazole is necessary. Concurrent use may increase tenofovir exposure. Tenofovir disoproxil fumarate is a P-gp substrate and ketoconazole is a P-gp inhibitor.
    Tepotinib: (Major) Avoid concomitant use of tepotinib and ketoconazole due to increased plasma concentrations of tepotinib, which may increase the incidence and severity of adverse reactions. Tepotinib is a CYP3A and P-gp substrate; ketoconazole is a dual strong CYP3A and P-gp inhibitor.
    Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering ketoconazole. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may substantially increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP3A4; ketoconazole is a CYP3A4 inhibitor. Monitor patients for adverse reactions if these drugs are coadministered.
    Tetrabenazine: (Contraindicated) Avoid concomitant use of ketoconazole and tetrabenazine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    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 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.
    Theophylline, Aminophylline: (Minor) Ketoconazole has been reported to decrease theophylline serum concentrations when theophylline was administered orally as sustained-release tablets, however, no interaction was noted when theophylline was administered IV. Since ketoconazole is well-known to inhibit the hepatic metabolism of many drugs and theophylline concentrations would be expected to increase, it is suspected that ketoconazole may have interfered with oral bioavailability of theophylline. As these results are based on a single case report, additional clinical data are necessary.
    Thioridazine: (Contraindicated) Avoid concomitant use of ketoconazole and thioridazine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Thiotepa: (Major) Avoid the concomitant use of thiotepa and ketoconazole if possible; reduced metabolism to the active thiotepa metabolite may result in decreased thiotepa efficacy. Consider an alternative agent with no or minimal potential to inhibit CYP3A4. If coadministration is necessary, monitor patients for signs of reduced thiotepa efficacy. In vitro, thiotepa is metabolized via CYP3A4 to the active metabolite, TEPA; ketoconazole is a strong CYP3A4 inhibitor.
    Ticagrelor: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inhibitors, such as ketoconazole. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp) and concomitant use with ketoconazole substantially increases ticagrelor exposure which may increase the bleeding risk.
    Tinidazole: (Major) Ketoconazole is an enzyme inhibitor that can decrease the hepatic metabolism of tinidazole. As a result, elimination can be delayed and serum tinidazole concentrations can increase.
    Tiotropium; Olodaterol: (Moderate) Monitor for an increase in olodaterol-related adverse effects, including increased heart rate and QT prolongation, if coadministered with ketoconazole. Coadministration may increase olodaterol exposure. No dose adjustment of olodaterol is necessary. In a drug interaction study using the strong dual CYP and P-gp inhibitor ketoconazole, a 1.7-fold increase of olodaterol inhalation maximum plasma concentrations and AUC was observed. No dose adjustment is necessary. Olodaterol, as with other long-acting beta-agonists, should be administered with extreme caution to patients being treated with drugs known to prolong the QTc interval like ketoconazole because the effect of adrenergic agonists on the cardiovascular system may be potentiated.
    Tipranavir: (Major) Avoid tipranavir for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of both drugs and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for adverse reactions; a ketoconazole dose reduction may be necessary. Both ketoconazole and tipranavir are CYP3A substrates and strong CYP3A inhibitors.
    Tisotumab Vedotin: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with ketoconazole is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with ketoconazole increased unconjugated MMAE exposure by 34%.
    Tofacitinib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with ketoconazole. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with ketoconazole. Ketoconazole is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with ketoconazole increased tofacitinib exposure by 2-fold.
    Tolterodine: (Contraindicated) Avoid concomitant use of ketoconazole and tolterodine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of both drugs, further increasing the risk for adverse effects. If concomitant use is necessary, reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily. Tolterodine is a CYP3A substrate and ketoconazole is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. Coadministration with ketoconazole increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
    Tolvaptan: (Contraindicated) The concomitant use of tolvaptan and ketoconazole is contraindicated due to increased tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; ketoconazole is a strong inhibitor of CYP3A4. In a drug interaction study, coadministration of ketoconazole 200 mg increased tolvaptan exposure 5-fold; larger ketoconazole doses are expected to produce larger increases in tolvaptan exposure. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
    Topotecan: (Major) Avoid coadministration of ketoconazole with oral topotecan due to increased topotecan exposure; ketoconazole may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and ketoconazole is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Toremifene: (Contraindicated) Avoid concomitant use of ketoconazole and toremifene due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of toremifene, further increasing the risk for adverse effects. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
    Trabectedin: (Major) Avoid the concomitant use of trabectedin with ketoconazole; coadministration resulted in increased trabectedin exposure. If short-term ketoconazole (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg PO twice daily for 7.5 days) increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
    Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with ketoconazole is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of ketoconazole, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
    Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with ketoconazole is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of ketoconazole, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
    Trandolapril; Verapamil: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with ketoconazole. Coadministration may increase the exposure of verapamil. Verapamil is a CYP3A substrate and ketoconazole is a strong CYP3A4 inhibitor. Clinically significant interactions have been reported with inhibitors of CYP3A4 causing elevation of plasma levels of verapamil. Hypotension, bradyarrhythmias, and other side effects have been observed with some combinations.
    Trazodone: (Contraindicated) Avoid concomitant use of ketoconazole and trazodone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of trazodone, further increasing the risk for adverse effects. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Tretinoin, ATRA: (Moderate) Patients should be closely monitored for tretinoin toxicity if concurrent therapy with ketoconazole is necessary. In a small study of patients stabilized on oral tretinoin therapy, a 72% increase in mean tretinoin plasma AUC was observed when ketoconazole (400 mg to 1,200 mg PO) was given 1 hour before the tretinoin dose.
    Triamcinolone: (Moderate) Monitor for an increase in triamcinolone-related adverse effects, such as fluid retention, electrolyte disturbances, and adrenal suppression, if concomitant use of ketoconazole is necessary. Concomitant use may increase triamcinolone exposure. Triamcinolone is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%.
    Triazolam: (Contraindicated) Concomitant use of ketoconazole with triazolam is contraindicated due to the risk of serious adverse events, such as prolonged hypnotic and/or sedative effects. Triazolam is a sensitive CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Consider safer alternatives if a benzodiazepine must be administered in combination with ketoconazole. Benzodiazepines not metabolized by the CYP3A4 enzyme (e.g., lorazepam, oxazepam) are less likely to be affected by strong CYP3A4 inhibitors.
    Triclabendazole: (Contraindicated) Avoid concomitant use of ketoconazole and triclabendazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Trifluoperazine: (Contraindicated) Avoid concomitant use of ketoconazole and trifluoperazine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Triptorelin: (Contraindicated) Avoid concomitant use of ketoconazole and androgen deprivation therapy (i.e. triptorelin) due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Trospium: (Moderate) Antimuscarinic drugs, including trospium, can raise intragastric pH. This effect may decrease the oral bioavailability of ketoconazole. In addition, because both trospium and ketoconazole are eliminated by active tubular secretion, concurrent use may result in increased effects of either drug; however, studies have not been conducted,
    Tucatinib: (Major) Avoid tucatinib for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of ketoconazole and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for ketoconazole-related adverse reactions; a ketoconazole dose reduction may be necessary. Ketoconazole is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor.
    Ubrogepant: (Contraindicated) Coadministration of ubrogepant and ketoconazole is contraindicated as concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole resulted in a 9.7-fold increase in the exposure of ubrogepant.
    Ulipristal: (Minor) Ulipristal is a substrate of CYP3A4 and ketoconazole is a CYP3A4 inhibitor. Concomitant use may increase the plasma concentration of ulipristal resulting in an increased risk for adverse events.
    Umeclidinium; Vilanterol: (Moderate) Monitor for an increase in vilanterol-related adverse effects, including increased heart rate and QT prolongation, if coadministered with ketoconazole. Coadministration may increase vilanterol exposure. Vilanterol is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole significantly increased systemic exposure to vilanterol. Vilanterol, as with other long-acting beta-agonists, should be administered with extreme caution to patients being treated with drugs known to prolong the QTc interval like ketoconazole because the effect of adrenergic agonists on the cardiovascular system may be potentiated.
    Upadacitinib: (Major) Do not exceed an upadacitinib induction dose of 30 mg PO once daily for 8 weeks and a maintenance dose of 15 mg once daily if coadministered with ketoconazole in patients with Ulcerative Colitis. Do not exceed an upadacitinib dose of 15 mg PO once daily if coadministered with ketoconazole in patients with arthritis or dermatitis. Monitor closely for adverse reactions. Concurrent use may increase upadacitinib exposure. Upadacitinib is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Concurrent use of upadacitinib with ketoconazole 400 mg once daily for 6 day increased upadacitinib exposure by 75%.
    Valbenazine: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with ketoconazole is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant. Valbenazine is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased both valbenazine and NBI-98782 exposure by approximately 2-fold.
    Vandetanib: (Contraindicated) Avoid concomitant use of ketoconazole and vandetanib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Vardenafil: (Contraindicated) Avoid concomitant use of ketoconazole and vardenafil due to an increased risk for QT/QTc prolongation and torsade de pointes (TdP). Concomitant use may also increase the exposure of vardenafil, further increasing the risk for adverse effects, such as hypotension and syncope. If concomitant use of ketoconazole and vardenafil oral tablets is required, the maximum single vardenafil oral tablet dose is 5 mg every 24 hours for patients receiving ketoconazole 200 mg daily and 2.5 mg every 24 hours for patients receiving ketoconazole 400 mg daily. Do not use vardenafil orally disintegrating tablets (ODTs) with ketoconazole. Vardenafil is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased the AUC of vardenafil by 10-fold.
    Vemurafenib: (Contraindicated) Avoid concomitant use of ketoconazole and vemurafenib due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of vemurafenib, further increasing the risk for adverse effects. Vemurafenib is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
    Venetoclax: (Major) Coadministration of ketoconazole with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of ketoconazole. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Coadministration of ketoconazole, a strong CYP3A, P-gp, and BCRP inhibitor increased the venetoclax AUC by 540% in a drug interaction study.
    Venlafaxine: (Contraindicated) Avoid concomitant use of ketoconazole and venlafaxine due to an increased risk for QT/QTc prolongation and torsade de pointes (TdP).
    Verapamil: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with ketoconazole. Coadministration may increase the exposure of verapamil. Verapamil is a CYP3A substrate and ketoconazole is a strong CYP3A4 inhibitor. Clinically significant interactions have been reported with inhibitors of CYP3A4 causing elevation of plasma levels of verapamil. Hypotension, bradyarrhythmias, and other side effects have been observed with some combinations.
    Verteporfin: (Moderate) Use caution if coadministration of verteporfin with ketoconazole foam is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like ketoconazole foam may increase the risk of a photosensitivity reaction.
    Vilazodone: (Major) Do not exceed a vilazodone dose of 20 mg once daily if coadministration with ketoconazole is necessary; the original dose of vilazodone can be resumed if ketoconazole is discontinued. Vilazodone is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vilazodone exposure by 50%.
    Vinblastine: (Moderate) Avoid coadministration of vinblastine with ketoconazole due to increased plasma concentrations of vinblastine, resulting in an earlier onset and/or increased severity of neuromuscular, myelosuppressive, or other side effects. Vinblastine is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Enhanced toxicity has been reported in patients receiving a concomitant moderate CYP3A4 inhibitor.
    Vincristine Liposomal: (Major) Avoid coadministration of vincristinewith ketoconazole if possible due to increased plasma concentrations of vincristine. Monitor for an earlier onset and/or increased severity of neuromuscular, myelosuppressive, or other side effects. Vincristine is a substrate of P-glycoprotein (P-gp) in vitro and ketoconazole is a P-gp inhibitor. Vincristine is also a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    Vincristine: (Major) Avoid coadministration of vincristinewith ketoconazole if possible due to increased plasma concentrations of vincristine. Monitor for an earlier onset and/or increased severity of neuromuscular, myelosuppressive, or other side effects. Vincristine is a substrate of P-glycoprotein (P-gp) in vitro and ketoconazole is a P-gp inhibitor. Vincristine is also a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with ketoconazole is necessary. Vinorelbine is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
    Voclosporin: (Contraindicated) Avoid concomitant use of ketoconazole and voclosporin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. The degree of QT prolongation associated with voclosporin is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose. Concomitant use may also increase the exposure of voclosporin, further increasing the risk for adverse effects. Voclosporin is a sensitive CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased voclosporin exposure by approximately 19-fold.
    Vonoprazan; Amoxicillin: (Major) Avoid concomitant use of ketoconazole and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of ketoconazole reducing its efficacy.
    Vonoprazan; Amoxicillin; Clarithromycin: (Contraindicated) Avoid concomitant use of ketoconazole and clarithromycin due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of both drugs, further increasing the risk for adverse events. Both ketoconazole and clarithromycin are CYP3A substrates and strong CYP3A inhibitors. (Major) Avoid concomitant use of ketoconazole and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of ketoconazole reducing its efficacy.
    Vorapaxar: (Major) Avoid coadministration of vorapaxar with ketoconazole due to increased plasma concentrations of vorapaxar and the risk of treatment-related adverse reactions. Vorapaxar is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased vorapaxar exposure by 2-fold; the bleeding risk for a change in exposure of this magnitude is not known.
    Vorinostat: (Contraindicated) Avoid concomitant use of ketoconazole and vorinostat due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with ketoconazole is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Ketoconazole is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
    Zaleplon: (Moderate) Monitor for an increase in zaleplon-related adverse reactions, including excessive sedation and confusion, if coadministered with ketoconazole. Routine dosage adjustments of zaleplon are not required. CYP3A4 is a minor metabolic pathway for zaleplon elimination as sum of desethylzaleplon (formed via CYP3A4) and its metabolites (5-oxo-desethylzaleplon and 5-oxo-desethylzaleplon glucuronide) account for only 9% of the urinary recovery of a zaleplon dose. Use of a strong, selective CYP3A4 inhibitor produced a 34% increase in zaleplon's Cmax and a 20% increase in the exposure. Other strong selective CYP3A4 inhibitors such as ketoconazole can be expected to have similar effects.
    Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO once daily if coadministered with ketoconazole. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Interrupt zanubrutinib therapy as recommended for adverse reactions. After discontinuation of ketoconazole, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. The AUC of zanubrutinib was increased by 278% when coadministered with another strong CYP3A4 inhibitor.
    Ziprasidone: (Contraindicated) Avoid concomitant use of ketoconazole and ziprasidone due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of ziprasidone, further increasing the risk for adverse effects. Ziprasidone is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with ketoconazole increased the AUC of ziprasidone by approximately 35% to 40%.
    Zolpidem: (Moderate) Consider decreasing the dose of zolpidem if coadministration with ketoconazole is necessary. Zolpidem is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the AUC (exposure) of zolpidem by 70% and also increased the pharmacodynamic effects of zolpidem (e.g., sedation and psychomotor impairment).

    PREGNANCY AND LACTATION

    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]

    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.

    MECHANISM OF ACTION

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

    PHARMACOKINETICS

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

    Oral Route

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

    Topical Route

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