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  • CLASSES

    Protein Kinase Inhibitors

    BOXED WARNING

    Alcoholism, angina, bradycardia, cardiac arrhythmias, coronary artery disease, diabetes mellitus, geriatric, hypertension, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, mortality, QT prolongation, thyroid disease

    Concentration-dependent QT prolongation and prolonged cardiac ventricular repolarization possibly leading to sudden cardiac death and mortality have been reported with nilotinib use; QT prolongation increases the risk of torsade de pointes. Use nilotinib with caution in patients with a history of cardiac arrhythmias; patients with unstable angina and significant bradycardia were excluded from clinical trials. Nilotinib use is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Use nilotinib with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including heart failure, myocardial infarction, hypertension, coronary artery disease, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Women, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction may also be at increased risk for QT prolongation. Avoid concomitant use of nilotinib with other medicines known to prolong the QT interval or that are strong CYP3A4 inhibitors as coadministration with these agents may increase the risk of a significantly prolonged QT interval. Evaluate electrolytes at baseline and monitor periodically during therapy. Correct electrolyte abnormalities prior to starting nilotinib. Obtain an electrocardiogram at baseline, after 7 days on therapy, after dose adjustments, and periodically as clinically indicated. Hold nilotinib therapy in patients who develop a QTc more than 480 milliseconds; additionally, a nilotinib dosage adjustment and/or therapy discontinuation may be necessary.

    DEA CLASS

    Rx

    DESCRIPTION

    BCR-ABL tyrosine kinase inhibitor
    Used in certain types of Philadelphia chromosome-positive chronic myelogenous leukemia
    May cause QT prolongation; sudden death has been reported

    COMMON BRAND NAMES

    Tasigna

    HOW SUPPLIED

    Nilotinib/Tasigna Oral Cap: 50mg, 150mg, 200mg

    DOSAGE & INDICATIONS

    For the treatment of Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).
    NOTE: Nilotinib has been designated an orphan drug by the FDA for the treatment of CML.
    For the treatment of chronic phase Ph+ CML in patients resistant or intolerant to prior therapy that included imatinib.
    Oral dosage
    Adults

    400 mg orally twice daily (approximately 12 hours apart) on an empty stomach. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Temporary interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects.Patients who have received nilotinib for a minimum of 3 years and have achieved a sustained molecular response (MR4.5) may be considered for treatment discontinuation. If nilotinib is discontinued, patients must be frequently monitored by a FDA-authorized test to detect possible loss of remission; re-initiation of therapy may be necessary. At a minimum follow-up of 24 months, treatment with nilotinib resulted in a major cytogenic response rate (primary end point) of 59% in patients with Ph+CML in a multicenter, single-arm trial (n = 321). Of the 126 patients with chronic phase Ph+ CML who received nilotinib following prior imatinib therapy and entered the TFR phase after achieving a sustained molecular response (MR4.5) during consolidation with nilotinib in an open-label, multicenter, single-arm trial (ENESTop trial; n = 163), 58 patients (46%) had a loss of MMR. Of the 56 patients who re-initiated nilotinib, 92.9% of patients achieved a MR4.5 at the 96-week assessment.

    For the treatment of newly diagnosed chronic phase Ph+ CML.
    Oral dosage
    Adults

    300 mg orally twice daily (approximately 12 hours apart) on an empty stomach. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Temporary interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. Patients who have received nilotinib for a minimum of 3 years and have achieved a sustained molecular response (MR4.5) may be considered for treatment discontinuation. If nilotinib is discontinued, patients must be frequently monitored by a FDA-authorized test to detect possible loss of remission; re-initiation of therapy may be necessary. The primary end point of major molecular response (MMR) rate at 12 months was significantly improved with nilotinib 300 mg twice daily (44%) and nilotinib 400 mg twice daily (43%) compared with imatinib 400 mg once daily (22%; p < 0.001 for both comparisons) in patients with newly diagnosed chronic phase Philadelphia chromosome–positive chronic myelogenous leukemia in a multicenter, randomized, phase III trial (the ENESTnd trial; n = 846). Additionally, the 12-month complete cytogenetic response rates were significantly higher for nilotinib (600 mg/day, 80%; 800 mg/day, 78%) compared with imatinib (65%; p < 0.001 for both comparisons). At a minimum follow-up of 24 months, the 24-month MMR rates continued to be significantly higher for nilotinib (600 mg/day, 71%; 800 mg/day, 67%) compared with imatinib (44%; p < 0.0001 for both comparisons). At a follow-up of 60 months, the median overall survival (OS) time had not been reached in any study arm; the estimated OS rate was 93.7% in the nilotinib 600-mg/day arm and 91.7% in the imatinib arm. The MMR rate continued to be higher in patients who received nilotinib therapy (77% vs. 60%). Of the 190 patients with newly diagnosed chronic phase Ph+ CML who entered the treatment-free remission (TFR) phase after achieving a MR4.5 during consolidation with nilotinib in an open-label, single-arm trial (the ENESTfreedom trial; n = 215), 91 patients (47.9%) had a loss of MMR. Of the 88 patients who re-initiated nilotinib, 98.9% and 92% of patients achieved a MMR and MR4.5, respectively, at the 96-week assessment.

    Adolescents and Children

    230 mg/m2 orally twice daily (approximately 12 hours apart) on an empty stomach until disease progression or unacceptable toxicity. Round the dose to the nearest 50 mg to a maximum single dose of 400 mg. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Temporary interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. The cumulative major molecular response (MMR) rate was 64% by cycle 12 in a cohort of pediatric patients aged 2 to less than 18 years with newly diagnosed chronic-phase chronic myelogenous leukemia (n = 25) who received nilotinib therapy in an open-label, single-arm, multicenter trial. The median time to first MMR was 5.6 months (range, 2.7 to 16.6 months). Additionally, 28% of patients had a sustained molecular response (MR4.5), defined as a 4.5-log reduction in BCR-ABL transcripts (BCR-ABL/ABL of 0.0032% IS or less). At a median follow-up time of 11.1 months, 1 patient had a confirmed loss of MMR occurring 3 months after a response was achieved.

    For the treatment of accelerated phase Ph+ CML in patients resistant or intolerant to prior therapy that included imatinib.
    Oral dosage
    Adults

    400 mg orally twice daily (approximately 12 hours apart) on an empty stomach. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Temporary interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. At a minimum follow-up of 24 months, treatment with nilotinib resulted in a hematologic response rate (primary end point) of 55% in patients with accelerated phase Ph+ CML in a multicenter, single-arm trial (n = 137).

    For the treatment of chronic phase Ph+ CML in patients resistant or intolerant to prior tyrosine-kinase inhibitor therapy.
    Oral dosage
    Adolescents and Children

    230 mg/m2 orally twice daily (approximately 12 hours apart) on an empty stomach until disease progression or unacceptable toxicity. Round the dose to the nearest 50 mg to a maximum single dose of 400 mg. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Temporary interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. In a pooled analysis from 2 open-label, single-arm, multi-center studies, the cumulative major molecular response (MMR) rate was 47.7% in pediatric patients aged 2 to less than 18 years with imatinib or dasatinib resistant or intolerant chronic-phase chronic myelogenous leukemia (CML) (n = 44) who received nilotinib therapy. The median time to first MMR was 2.8 months (range, 0 to 11.3 months). Additionally, 4.5% of patients had a sustained molecular response (MR4.5), defined as a 4.5-log reduction in BCR-ABL transcripts (BCR-ABL/ABL of 0.0032% IS or less). At a median follow-up time of 11.3 months, no patient had experienced a confirmed loss of MMR but 1 patient progressed to accelerated/blast phase CML at about 10 months from starting nilotinib treatment.

    MAXIMUM DOSAGE

    Adults

    800 mg/day PO.

    Geriatric

    800 mg/day PO.

    Adolescents

    230 mg/m2 twice daily, not to exceed 400 mg/dose.

    Children

    230 mg/m2 twice daily, not to exceed 400 mg/dose.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment (adults only)
    Newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML)
    Any hepatic impairment: Initiate nilotinib at 200 mg PO twice daily. Escalate dosage to the recommended dosage of 300 mg twice daily based on individual patient tolerability.
    Resistant or intolerant Ph+ CML
    Mild or Moderate hepatic impairment (Child-Pugh class A or B): Initiate nilotinib at 300 mg PO twice daily. Escalate dosage to the recommended dosage of 400 mg twice daily based on individual patient tolerability.
    Severe hepatic impairment (Child-Pugh class C): Initiate nilotinib at 200 mg PO twice daily. Escalate dosage to 300 mg twice daily and then to the recommended dosage of 400 mg twice daily based on individual patient tolerability.
     
    Dosage Adjustments due to Treatment-Related Toxicity
    Adults
    Grade 3 or higher elevated bilirubin or transaminase levels: Hold nilotinib therapy. Once toxicity is resolved to grade 1 or less, resume nilotinib at 400 mg PO once daily.
    Pediatric Patients
    Grade 2 or higher elevated bilirubin level OR grade 3 or higher transaminase levels: Hold nilotinib therapy. Once toxicity is resolved to grade 1 or less, resume nilotinib at 230 mg/m2 PO once daily if previous dosage was nilotinib 230 mg/m2 PO twice daily. Discontinue therapy in pediatric patients who were receiving a previous dose of nilotinib 230 mg/m2 PO once daily and recovery to grade 1 or less takes longer than 28 days.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Take nilotinib on an empty stomach; no food should be consumed for at least 1 hour after the dose is taken or for at least 2 hours before the dose is taken.
    For twice daily dosing, separate doses by approximately 12 hours.
    In pediatric patients, dose should be rounded to the nearest 50 mg dose (maximum single dose, 400 mg); different strength capsules may need to be combined to make the dose.
    Do not drink grapefruit juice during treatment.
    Take H2-blockers 10 hours before taking nilotinib or 2 hours after; separate the nilotinib dose from antacids by at least 2 hours.
    If a dose is missed, take the next scheduled dose at the regular time; do not take 2 doses at the same time.

    Oral Solid Formulations

    Swallow capsules whole with water.

    Extemporaneous Compounding-Oral

    For patients unable to swallow capsules, capsule contents may be dispersed in 1 teaspoonful (5 mL) of applesauce.
    Take the mixture immediately or within 15 minutes; do not store for future use.

    STORAGE

    Tasigna:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Cardiac disease, cerebrovascular disease, heart failure, myocardial infarction, occlusive vascular disease

    Serious cardiac and vascular events, including arterial occlusive vascular disease, ischemic heart disease, peripheral arterial occlusive disease, and ischemic cerebrovascular disease have been reported with nilotinib use. Use nilotinib with caution in patients with cardiac disease; patients with recent myocardial infarction and congestive heart failure were excluded from clinical trials. Evaluate patients for cardiovascular disease prior to therapy and monitor risk factors. Patients should seek immediate medical attention if cardiovascular or cerebrovascular symptoms occur. Cardiovascular and cerebrovascular events should be managed according to standard guidelines.

    Anemia, neutropenia, thrombocytopenia

    Myelosuppression including severe anemia, neutropenia, and thrombocytopenia has been reported with nilotinib therapy. Monitor complete blood counts every 2 weeks for the first 2 months of nilotinib treatment and then monthly thereafter or as clinically indicated. Myelosuppression is generally reversible and is managed by holding or dose reducing nilotinib therapy.

    Alcoholism, angina, bradycardia, cardiac arrhythmias, coronary artery disease, diabetes mellitus, geriatric, hypertension, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, mortality, QT prolongation, thyroid disease

    Concentration-dependent QT prolongation and prolonged cardiac ventricular repolarization possibly leading to sudden cardiac death and mortality have been reported with nilotinib use; QT prolongation increases the risk of torsade de pointes. Use nilotinib with caution in patients with a history of cardiac arrhythmias; patients with unstable angina and significant bradycardia were excluded from clinical trials. Nilotinib use is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Use nilotinib with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including heart failure, myocardial infarction, hypertension, coronary artery disease, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Women, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction may also be at increased risk for QT prolongation. Avoid concomitant use of nilotinib with other medicines known to prolong the QT interval or that are strong CYP3A4 inhibitors as coadministration with these agents may increase the risk of a significantly prolonged QT interval. Evaluate electrolytes at baseline and monitor periodically during therapy. Correct electrolyte abnormalities prior to starting nilotinib. Obtain an electrocardiogram at baseline, after 7 days on therapy, after dose adjustments, and periodically as clinically indicated. Hold nilotinib therapy in patients who develop a QTc more than 480 milliseconds; additionally, a nilotinib dosage adjustment and/or therapy discontinuation may be necessary.

    Pancreatitis

    Elevated lipase levels have been reported with nilotinib use; therefore, use nilotinib with caution in patients with a history of pancreatitis. Evaluate lipase and amylase levels monthly or as clinically indicated. In patients who have abdominal pain and elevated lipase levels, hold nilotinib and evaluate for pancreatitis. Therapy interruption and a dosage reduction are recommended in patients who develop grade 3 or higher lipase or amylase level elevations during nilotinib therapy.

    Hepatic disease

    Hepatotoxicity (e.g., elevated hepatic enzymes (AST/ALT), hyperbilirubinemia, and increased alkaline phosphatase levels) has been reported with nilotinib therapy. Grade 3 or 4 elevated bilirubin, AST, and ALT levels were reported at a higher frequency in pediatric patients compared with adults. In a pharmacogenetic analysis, patients with polymorphisms in UGT1A1, specifically polymorphism UGT1A1*28, had a significantly higher risk of hyperbilirubinemia. Use nilotinib with caution in patients with hepatic disease; consider alternative therapies in patients with hepatic impairment. If nilotinib treatment is warranted, an initial dosage adjustment is necessary. Closely monitor patients with hepatic impairment for QT prolongation as nilotinib systemic exposure may be increased in these patients. Obtain liver function tests monthly or as clinically indicated. Therapy interruption and a dosage reduction are recommended in patients who develop grade 3 or higher bilirubin or transaminase level elevations during nilotinib therapy.

    Galactose-free diet, lactase deficiency

    Nilotinib capsules contain lactose and are not recommended for patients with rare hereditary problems of galactose intolerance (requiring a galactose-free diet), severe lactase deficiency, or glucose-galactose malabsorption.

    Gelatin hypersensitivity

    Nilotinib capsules contain gelatin and may be inappropriate for use by patients with a gelatin hypersensitivity.

    Total gastrectomy

    The exposure of nilotinib is reduced in patients with total gastrectomy. Consider more frequent follow-up of these patients. Also, consider nilotinib dose increase or alternative therapy in patients with total gastrectomy.

    Dehydration, leukocytosis, tumor lysis syndrome (TLS)

    Tumor lysis syndrome (TLS) has been reported in patients who received nilotinib therapy for resistant or intolerant chronic myelogenous leukemia. Malignant disease progression, high white blood cell counts (leukocytosis), and/or dehydration were present in many of the cases. Maintain adequate hydration and correct uric acid concentrations prior to initiating nilotinib therapy.

    Ascites, edema, pericardial effusion, pleural effusion, pulmonary edema

    Fluid retention/edema has been reported in patients with newly diagnosed chronic myelogenous leukemia who received nilotinib in a randomized trial. Pleural effusion, pericardial effusion, ascites, and pulmonary edema also occurred in this trial. Monitor patients for signs of fluid retention such as rapid weight gain or swelling and symptoms of respiratory or cardiac compromise such as shortness of breath. Manage patients as medically indicated.

    Hypercholesterolemia, hyperlipidemia, hypertriglyceridemia

    Hypercholesterolemia, hypertriglyceridemia, and hyperlipidemia have been reported with nilotinib therapy in patients with chronic myelogenous leukemia in clinical studies. Obtain a lipid profile at baseline, periodically during the first year, and at least once yearly in patients receiving chronic nilotinib therapy. Patients may require lipid lowering therapy; however, use HMG-CoA reductase inhibitors with caution and evaluate the potential for CYP3A4-mediated drug interactions.

    Hyperglycemia, hypoglycemia

    Hyperglycemia and rare cases of hypoglycemia have been reported with nilotinib therapy in patients with chronic myelogenous leukemia in clinical studies. Assess blood glucose levels at baseline, periodically during the first year, and at least once yearly in patients receiving chronic nilotinib therapy. Treat patients who develop blood glucose changes using current standards of practice.

    Bleeding

    Serious bleeding has been reported with nilotinib therapy; some cases were fatal. Monitor patients for signs and symptoms of bleeding; manage bleeding events as medically appropriate.

    Children, growth inhibition, infants, neonates

    Growth inhibition has been reported in children and adolescents who received other BCR-ABL tyrosine kinase inhibitors; therefore, monitor bone growth and development in pediatric patients. Additionally, in clinical trials, hyperbilirubinemia and elevated AST/ALT concentrations were more reported at a higher frequency in pediatric patients as compared to adults. Nilotinib has not been studied in neonates and infants.

    Pregnancy

    Nilotinib may cause fetal harm when administered during pregnancy, based on its mechanism of action and animal studies. Females of reproductive potential should avoid pregnancy during and after treatment. Discuss the potential hazard to the fetus if nilotinib is used during pregnancy or if a patient becomes pregnant while taking this drug. In animals studies, embryo-fetal toxicities including skeletal variations (e.g., incomplete ossification, fused sternebra), cleft palate, and dilated ureters and small renal papilla were observed following nilotinib administration during organogenesis at doses that resulted in drug exposures approximately 0.5-times (rabbits) and 2-times (rats) the exposures achieved at the highest recommended human dose.

    Contraception requirements, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during nilotinib treatment. Females of reproductive potential should undergo pregnancy testing prior to nilotinib therapy. These patients should avoid pregnancy and use effective contraception during and for 14 days after the last nilotinib dose.

    Breast-feeding

    It is not known if nilotinib or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during nilotinib therapy and for 14 days after the last dose.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 12.0-42.0
    thrombocytopenia / Delayed / 10.0-42.0
    anemia / Delayed / 4.0-27.0
    hypophosphatemia / Delayed / 8.0-17.0
    hyperbilirubinemia / Delayed / 4.0-13.0
    hyperglycemia / Delayed / 6.0-12.0
    pancytopenia / Delayed / 1.0-10.0
    atrial fibrillation / Early / 1.0-10.0
    bradycardia / Rapid / 1.0-10.0
    atrial flutter / Early / 1.0-10.0
    AV block / Early / 1.0-10.0
    eczema vaccinatum / Delayed / 1.0-10.0
    exfoliative dermatitis / Delayed / 1.0-10.0
    pancreatitis / Delayed / 1.0-10.0
    hyperkalemia / Delayed / 1.0-10.0
    ocular hemorrhage / Delayed / 1.0-10.0
    elevated hepatic enzymes / Delayed / 1.0-9.0
    hypokalemia / Delayed / 0-9.0
    hyponatremia / Delayed / 0-7.0
    GI bleeding / Delayed / 0-5.1
    hypocalcemia / Delayed / 0-5.0
    hypoalbuminemia / Delayed / 3.0-4.0
    fluid retention / Delayed / 3.9-3.9
    abdominal pain / Early / 0-3.0
    diarrhea / Early / 1.0-3.0
    headache / Early / 1.0-3.0
    fatigue / Early / 0-3.0
    nausea / Early / 0-2.0
    hypertension / Early / 0-2.0
    dyspnea / Early / 2.0-2.0
    rash / Early / 0-2.0
    back pain / Delayed / 0-2.0
    arthralgia / Delayed / 0-2.0
    myalgia / Early / 0-2.0
    bone pain / Delayed / 0-2.0
    fever / Early / 0-2.0
    bleeding / Early / 0-1.8
    vomiting / Early / 0-1.0
    dyspepsia / Early / 0-1.0
    anorexia / Delayed / 0-1.0
    constipation / Delayed / 0-1.0
    pulmonary edema / Early / 0.1-1.0
    pleural effusion / Delayed / 0.1-1.0
    pericardial effusion / Delayed / 0.1-1.0
    peripheral edema / Delayed / 0-1.0
    cyanosis / Early / 0.1-1.0
    myocardial infarction / Delayed / 0.1-1.0
    hypertensive crisis / Early / 0.1-1.0
    heart failure / Delayed / 0.1-1.0
    cough / Rapid / 0-1.0
    pruritus / Rapid / 0-1.0
    night sweats / Early / 0-1.0
    angioedema / Rapid / 0-1.0
    pharyngitis / Delayed / 0-1.0
    infection / Delayed / 0-1.0
    musculoskeletal pain / Early / 0-1.0
    stroke / Early / 0.1-1.0
    dizziness / Early / 0-1.0
    intracranial bleeding / Delayed / 0.1-1.0
    visual impairment / Early / 0.1-1.0
    insomnia / Early / 1.0-1.0
    asthenia / Delayed / 0-1.0
    ascites / Delayed / 0-0.7
    enterocolitis / Delayed / 0-0.1
    peptic ulcer / Delayed / 0-0.1
    GI perforation / Delayed / 0-0.1
    hearing loss / Delayed / 0-0.1
    thrombosis / Delayed / 0-0.1
    pericarditis / Delayed / 0-0.1
    pulmonary hypertension / Delayed / 0-0.1
    skin atrophy / Delayed / 0-0.1
    erythema nodosum / Delayed / 0-0.1
    erythema multiforme / Delayed / 0-0.1
    optic neuritis / Delayed / 0-0.1
    cerebral edema / Early / 0-0.1
    hematemesis / Delayed / 0-0.1
    retroperitoneal bleeding / Delayed / 0-0.1
    renal failure (unspecified) / Delayed / 0-0.1
    papilledema / Delayed / 0-0.1
    alopecia / Delayed / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known

    Moderate

    leukopenia / Delayed / 1.0-54.0
    lymphopenia / Delayed / 1.0-32.0
    hypercholesterolemia / Delayed / 1.0-28.0
    hypertriglyceridemia / Delayed / 1.0-12.0
    eosinophilia / Delayed / 1.0-10.0
    QT prolongation / Rapid / 1.0-10.0
    palpitations / Early / 1.0-10.0
    angina / Early / 1.0-10.0
    chest pain (unspecified) / Early / 1.0-10.0
    sinus tachycardia / Rapid / 1.0-10.0
    dysphonia / Delayed / 1.0-10.0
    erythema / Early / 1.0-10.0
    flank pain / Delayed / 1.0-10.0
    peripheral neuropathy / Delayed / 1.0-10.0
    hyperamylasemia / Delayed / 1.0-10.0
    diabetes mellitus / Delayed / 1.0-10.0
    hypercalcemia / Delayed / 1.0-10.0
    hyperphosphatemia / Delayed / 1.0-10.0
    hypomagnesemia / Delayed / 1.0-10.0
    hyperlipidemia / Delayed / 1.0-10.0
    conjunctivitis / Delayed / 1.0-10.0
    depression / Delayed / 1.0-10.0
    oral ulceration / Delayed / 0.1-1.0
    stomatitis / Delayed / 0.1-1.0
    gastritis / Delayed / 0.1-1.0
    melena / Delayed / 0.1-1.0
    hypothyroidism / Delayed / 0.1-1.0
    hyperthyroidism / Delayed / 0.1-1.0
    hepatitis / Delayed / 0.1-1.0
    jaundice / Delayed / 0.1-1.0
    candidiasis / Delayed / 0.1-1.0
    migraine / Early / 0.1-1.0
    hyperesthesia / Delayed / 0.1-1.0
    hematoma / Early / 0.1-1.0
    dysuria / Early / 0.1-1.0
    gout / Delayed / 0.1-1.0
    dehydration / Delayed / 0.1-1.0
    conjunctival hyperemia / Early / 0-1.0
    hyperemia / Delayed / 0.1-1.0
    photopsia / Delayed / 0.1-1.0
    blurred vision / Early / 0.1-1.0
    impotence (erectile dysfunction) / Delayed / 0.1-1.0
    thrombocytosis / Delayed / 0-0.1
    esophagitis / Delayed / 0-0.1
    hemorrhoids / Delayed / 0-0.1
    hypotension / Rapid / 0-0.1
    wheezing / Rapid / 0-0.1
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 0-0.1
    skin ulcer / Delayed / 0-0.1
    psoriasis / Delayed / 0-0.1
    hepatomegaly / Delayed / 0-0.1
    cholestasis / Delayed / 0-0.1
    hypoglycemia / Early / 0-0.1
    urinary incontinence / Early / 0-0.1
    hematuria / Delayed / 0-0.1
    hyperuricemia / Delayed / 0-0.1
    photophobia / Early / 0-0.1
    blepharitis / Early / 0-0.1
    amnesia / Delayed / 0-0.1
    dysphoria / Early / 0-0.1
    confusion / Early / 0-0.1
    edema / Delayed / Incidence not known

    Mild

    influenza / Delayed / 13.0-13.0
    xerosis / Delayed / 12.0-12.0
    dysgeusia / Early / 1.0-10.0
    flatulence / Early / 1.0-10.0
    vertigo / Early / 1.0-10.0
    epistaxis / Delayed / 1.0-10.0
    weight gain / Delayed / 1.0-10.0
    weight loss / Delayed / 1.0-10.0
    hyperhidrosis / Delayed / 1.0-10.0
    acne vulgaris / Delayed / 1.0-10.0
    flushing / Rapid / 1.0-10.0
    urticaria / Rapid / 1.0-10.0
    folliculitis / Delayed / 1.0-10.0
    weakness / Early / 1.0-10.0
    hypoesthesia / Delayed / 1.0-10.0
    paresthesias / Delayed / 1.0-10.0
    increased urinary frequency / Early / 1.0-10.0
    xerophthalmia / Early / 1.0-10.0
    ocular pruritus / Rapid / 1.0-10.0
    anxiety / Delayed / 1.0-10.0
    malaise / Early / 1.0-10.0
    gastroesophageal reflux / Delayed / 0.1-1.0
    xerostomia / Early / 0.1-1.0
    throat irritation / Early / 0.1-1.0
    ecchymosis / Delayed / 0.1-1.0
    syncope / Early / 0.1-1.0
    tremor / Early / 0.1-1.0
    urinary urgency / Early / 0.1-1.0
    nocturia / Early / 0.1-1.0
    appetite stimulation / Delayed / 0.1-1.0
    blepharedema / Early / 1.0-1.0
    ocular irritation / Rapid / 0.1-1.0
    gynecomastia / Delayed / 0.1-1.0
    mastalgia / Delayed / 0.1-1.0
    chills / Rapid / 0.1-1.0
    leukocytosis / Delayed / 0-0.1
    gingivitis / Delayed / 0-0.1
    otalgia / Early / 0-0.1
    tinnitus / Delayed / 0-0.1
    skin hyperpigmentation / Delayed / 0-0.1
    hyperkeratosis / Delayed / 0-0.1
    photosensitivity / Delayed / 0-0.1
    petechiae / Delayed / 0-0.1
    skin discoloration / Delayed / 0-0.1
    dysesthesia / Delayed / 0-0.1
    restless legs syndrome (RLS) / Delayed / 0-0.1
    lethargy / Early / 0-0.1
    ocular pain / Early / 0-0.1
    diplopia / Early / 0-0.1
    menorrhagia / Delayed / 0-0.1

    DRUG INTERACTIONS

    Acalabrutinib: (Major) Decrease the acalabrutinib dose to 100 mg PO once daily if coadministered with nilotinib. Coadministration may result in increased acalabrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Acalabrutinib is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. In physiologically based pharmacokinetic (PBPK) simulations, the Cmax and AUC values of acalabrutinib were increased by 2- to almost 3-fold when acalabrutinib was coadministered with moderate CYP3A inhibitors.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with nilotinib 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 nilotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nilotinib 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. Nilotinib is a moderate inhibitor of CYP3A4.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with nilotinib 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 nilotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nilotinib 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. Nilotinib is a moderate inhibitor of CYP3A4.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with nilotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Nilotinib is a moderate inhibitor of CYP3A4.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of oxycodone with nilotinib may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4. nilotinib is a moderate inhibitor of CYP3A4.
    Acetaminophen; Tramadol: (Major) The concomitant use of nilotinib and tramadol may reduce the clearance of tramadol and increase the risk for serious adverse events including seizures and serotonin syndrome. If coadministration of these drugs is required, consider reducing the dose of tramadol and monitor patients for signs of toxicity. Nilotinib is a moderate CYP3A4 inhibitor and tramadol is a CYP3A4 substrate.
    Albuterol: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Albuterol; Ipratropium: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Alfentanil: (Major) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and alfentanil, a CYP3A4 substrate with a narrow therapeutic range, may result in increased alfentanil levels. Monitor for oversedation, respiratory depression, and hypotension. An alfentanil dose reduction may be necessary if these drugs are used together.
    Alfuzosin: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as alfuzosin. Additionally, nilotinib is a moderate inhibitor of CYP3A4 and alfuzosin is a substrate of CYP3A4; administering these drugs together may result in increased alfuzosin levels. If the use of alfuzosin is necessary, hold nilotinib therapy. If these drugs are used together, consider an alfuzosin dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Aliskiren; Amlodipine: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Alprazolam: (Major) Nilotinib is a competitive inhibitor of CYP3A4. Alprazolam is a CYP3A4 substrate. Coadminister these drugs with caution. Increased alprazolam serum concentrations may occur, leading to an increased risk of alprazolam-related adverse reactions. Monitor patients carefully, as the alprazolam dosage may need to be decreased.
    Aluminum Hydroxide: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
    Aluminum Hydroxide; Magnesium Carbonate: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
    Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
    Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
    Amiodarone: (Major) Avoid the concomitant use of nilotinib with amiodarone as significant prolongation of the QT interval may occur. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Sudden deaths and QT prolongation have been reported with nilotinib therapy. Both amiodarone and nilotinib are moderate inhibitors and substrates of CYP3A4; therefore, levels of either agent may be increased resulting in increased toxicity.
    Amlodipine: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Amlodipine; Atorvastatin: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required. (Moderate) Monitor for evidence of myopathy if atorvastatin is coadministered with nilotinib. Concurrent use may result in increased atorvastatin exposure. Nilotinib is a moderate CYP3A4 inhibitor; atorvastatin is a CYP3A4 substrate.
    Amlodipine; Benazepril: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Amlodipine; Olmesartan: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Amlodipine; Telmisartan: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Amlodipine; Valsartan: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time. (Major) Avoid the concomitant use of nilotinib with clarithromycin as significant prolongation of the QT interval may occur. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Sudden deaths and QT prolongation have been reported with nilotinib therapy.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time. (Major) Avoid the concomitant use of nilotinib with clarithromycin as significant prolongation of the QT interval may occur. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Sudden deaths and QT prolongation have been reported with nilotinib therapy.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Moderate) Administration of amphotericin B [lipid complex (ABLC), cholesteryl sulfate complex (ABCD), and liposomal (LAmB)] with antineoplastic agents may increase the potential for nephrotoxicity, bronchospasm, and hypotension. Amphotericin B-induced hypokalemia can result in interactions with other drugs.
    Amphotericin B lipid complex (ABLC): (Moderate) Administration of amphotericin B [lipid complex (ABLC), cholesteryl sulfate complex (ABCD), and liposomal (LAmB)] with antineoplastic agents may increase the potential for nephrotoxicity, bronchospasm, and hypotension. Amphotericin B-induced hypokalemia can result in interactions with other drugs.
    Amphotericin B liposomal (LAmB): (Moderate) Administration of amphotericin B [lipid complex (ABLC), cholesteryl sulfate complex (ABCD), and liposomal (LAmB)] with antineoplastic agents may increase the potential for nephrotoxicity, bronchospasm, and hypotension. Amphotericin B-induced hypokalemia can result in interactions with other drugs.
    Amphotericin B: (Moderate) Administration of amphotericin B [lipid complex (ABLC), cholesteryl sulfate complex (ABCD), and liposomal (LAmB)] with antineoplastic agents may increase the potential for nephrotoxicity, bronchospasm, and hypotension. Amphotericin B-induced hypokalemia can result in interactions with other drugs.
    Anagrelide: (Major) Avoid the concomitant use of nilotinib with anagrelide as significant prolongation of the QT interval may occur. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Sudden deaths and QT prolongation have been reported with nilotinib therapy.
    Antacids: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
    Apalutamide: (Major) Avoid the concomitant use of nilotinib and apalutamide; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and apalutamide is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
    Apomorphine: (Major) Avoid the concomitant use of nilotinib and other drugs with a known potential to prolong the QT interval such as apomorphine; significant prolongation of the QT interval may occur. Sudden death and QT interval prolongation have been reported in patients who received nilotinib therapy. Limited data indicate that QT prolongation is possible with apomorphine administration.
    Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of nilotinib with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant; increased nilotinib exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in nilotinib- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. Nilotinib is a moderate CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Nilotinib is also a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may additionally increase plasma concentrations of nilotinib. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Arformoterol: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Pharmacokinetic interactions may occur with some LABAs.
    Aripiprazole: (Major) Avoid the concomitant use of nilotinib with aripiprazole as significant prolongation of the QT interval may occur. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Sudden deaths and QT prolongation have been reported with nilotinib therapy.
    Arsenic Trioxide: (Major) Avoid the concomitant use of nilotinib and arsenic trioxide; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Torsade de pointes, QT prolongation, and complete atrioventricular block have occurred with arsenic trioxide use.
    Artemether; Lumefantrine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as artemether; lumefantrine. Additionally, nilotinib is a moderate inhibitor of CYP3A4 and artemether; lumefantrine is a substrate of CYP3A4; administering these drugs together may result in increased artemether; lumefantrine levels. If the use of artemether; lumefantrine is necessary, hold nilotinib therapy. If these drugs are used together, consider an artemether; lumefantrine dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Asenapine: (Major) Coadministration of nilotinib and a drug that prolongs the QT interval, such as asenapine, is not advised; nilotinib prolongs the QT interval. Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as asenapine. Additionally, nilotinib is a moderate inhibitor of CYP3A4 and asenapine is a substrate of CYP3A4; administering these drugs together may result in increased asenapine levels. If the use of asenapine is necessary, hold nilotinib therapy. If these drugs are used together, consider an asenapine dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with nilotinib 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 nilotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nilotinib 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. Nilotinib is a moderate inhibitor of CYP3A4.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with nilotinib 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 nilotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nilotinib 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. Nilotinib is a moderate inhibitor of CYP3A4.
    Aspirin, ASA; Omeprazole: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
    Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of oxycodone with nilotinib may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4. nilotinib is a moderate inhibitor of CYP3A4.
    Atazanavir: (Major) Avoid the concomitant use of nilotinib, a substrate and moderate inhibitor of CYP3A4, with atazanavir, a substrate and strong inhibitor of CYP3A4; levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and atazanavir 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Atazanavir; Cobicistat: (Major) Avoid the concomitant use of nilotinib and cobicistat; plasma exposure of both drugs may be increased. If coadministration is required, monitor closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If the strong inhibitor is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a moderate CYP3A4 inhibitor and cobicistat is a strong CYP3A4 inhibitor; both drugs are CYP3A4 substrates. (Major) Avoid the concomitant use of nilotinib, a substrate and moderate inhibitor of CYP3A4, with atazanavir, a substrate and strong inhibitor of CYP3A4; levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and atazanavir 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Atomoxetine: (Major) Avoid the concomitant use of nilotinib with atomoxetine as significant prolongation of the QT interval may occur. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Sudden deaths and QT prolongation have been reported with nilotinib therapy.
    Atorvastatin: (Moderate) Monitor for evidence of myopathy if atorvastatin is coadministered with nilotinib. Concurrent use may result in increased atorvastatin exposure. Nilotinib is a moderate CYP3A4 inhibitor; atorvastatin is a CYP3A4 substrate.
    Atorvastatin; Ezetimibe: (Moderate) Monitor for evidence of myopathy if atorvastatin is coadministered with nilotinib. Concurrent use may result in increased atorvastatin exposure. Nilotinib is a moderate CYP3A4 inhibitor; atorvastatin is a CYP3A4 substrate.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid the concomitant use of nilotinib and phenobarbital; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and phenobarbital is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
    Azithromycin: (Major) Avoid the concomitant use of nilotinib and azithromycin; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. There have been case reports of QT prolongation and torsade de pointes with the use of azithromycin in post-marketing reports. Sudden deaths and QT prolongation have been reported with nilotinib therapy.
    Bedaquiline: (Major) Avoid the concomitant use of nilotinib with bedaquiline as significant prolongation of the QT interval may occur. Bedaquiline has been reported to prolong the QT interval. Sudden deaths and QT prolongation have also been reported with nilotinib therapy.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid the concomitant use of nilotinib and phenobarbital; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and phenobarbital is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Avoid the concomitant use of nilotinib and metronidazole; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Potential QT prolongation has been reported with metronidazole use in limited case reports.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Avoid the concomitant use of nilotinib and metronidazole; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Potential QT prolongation has been reported with metronidazole use in limited case reports.
    Brexpiprazole: (Moderate) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Nilotinib is a moderate inhibitor of CYP3A4. If nilotinib is used in combination with brexpiprazole and a moderate to strong CYP2D6 inhibitor, the brexpiprazole dose should be adjusted and the patient should be carefully monitored for brexpiprazole-related adverse reactions. A reduction of the brexpiprazole dose to 25% of the usual dose is also recommended in patients who are poor metabolizers of CYP2D6 and are receiving a moderate CYP3A4 inhibitor.
    Bromocriptine: (Major) When bromocriptine is used for diabetes, do not exceed a dose of 1.6 mg once daily during concomitant use of nilotinib. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; nilotinib is a moderate inhibitor of CYP3A4. Administration of bromocriptine with a moderate inhibitor of CYP3A4 increased the bromocriptine mean AUC and Cmax by 3.7-fold and 4.6-fold, respectively.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with nilotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Nilotinib is a moderate inhibitor of CYP3A4.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with nilotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Nilotinib is a moderate inhibitor of CYP3A4.
    Budesonide; Formoterol: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Pharmacokinetic interactions may occur with some LABAs.
    Bupivacaine; Lidocaine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Systemic lidocaine has been established to have a causal association with QT prolongation and torsade de pointes. Additionally, nilotinib is a moderate CYP3A4 inhibitor and lidocaine is a CYP3A4 substrate; administering these drugs together may result in increased lidocaine levels. If the use of lidocaine is required, hold nilotinib therapy. If the use of nilotinib and lidocaine cannot be avoided, a lidocaine dose reduction may be necessary; close monitoring of the QT interval is recommended.
    Buprenorphine: (Major) Buprenorphine should be avoided in combination with nitlotinib. Nilotinib prolongs the QT interval; coadministration with a drug that prolongs the QT interval is not advised. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, the plasma concentrations of buprenorphine, a CYP3A4 substrate, may be increased when administered concurrently with nilotinib, a CYP3A4 inhibitor, further increasing the risk of toxicity. If co-administration is necessary, monitor patients for QT prolongation, respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
    Buprenorphine; Naloxone: (Major) Buprenorphine should be avoided in combination with nitlotinib. Nilotinib prolongs the QT interval; coadministration with a drug that prolongs the QT interval is not advised. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, the plasma concentrations of buprenorphine, a CYP3A4 substrate, may be increased when administered concurrently with nilotinib, a CYP3A4 inhibitor, further increasing the risk of toxicity. If co-administration is necessary, monitor patients for QT prolongation, respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied.
    Buspirone: (Moderate) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and buspirone, a CYP3A4 substrate, may result in increased buspirone levels. A buspirone dose reduction may be necessary if these drugs are used together.
    Calcium Carbonate: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
    Calcium Carbonate; Magnesium Hydroxide: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
    Calcium Carbonate; Risedronate: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
    Calcium; Vitamin D: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
    Carbamazepine: (Major) Avoid the concomitant use of nilotinib and carbamazepine; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and carbamazepine is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with nilotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Nilotinib is a moderate inhibitor of CYP3A4.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with nilotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Nilotinib is a moderate inhibitor of CYP3A4.
    Cariprazine: (Moderate) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Nilotinib is a moderate inhibitor of CYP3A4 and may reduce the hepatic metabolism of CYP3A4 substrates, although the impact of moderate CYP3A4 inhibitors on cariprazine metabolism has not been studied. Monitoring for adverse effects, such as CNS effects and extrapyramidal symptoms, is advisable during coadministration.
    Ceritinib: (Major) Avoid coadministration of ceritinib with nilotinib due to the potential for QT prolongation; nilotinib concentrations may also increase. If coadministration is unavoidable, closely monitor electrolytes and ECGs; an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib is a CYP3A4 inhibitor that causes concentration-dependent prolongation of the QT interval. Nilotinib is primarily metabolized by CYP3A4 and is also associated with QT prolongation.
    Cevimeline: (Moderate) Concomitant use of nilotinib, an inhibitor of CYP3A4 and CYP2D6, and cevimeline, a CYP3A4 and CYP2D6 substrate, may result in increased cevimeline levels. A cevimeline dose reduction may be necessary if these drugs are used together.
    Chloramphenicol: (Major) Avoid the concomitant use of nilotinib, a CYP3A4 substrate, with chloramphenicol, a strong CYP3A4 inhibitor; nilotinib levels may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and chloramphenicol 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Chloroquine: (Major) Avoid the concomitant use of nilotinib and chloroquine; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes; fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with nilotinib 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 nilotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nilotinib 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. Nilotinib is a moderate inhibitor of CYP3A4.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with nilotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Nilotinib is a moderate inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with nilotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Nilotinib is a moderate inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with nilotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Nilotinib is a moderate inhibitor of CYP3A4.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with nilotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Nilotinib is a moderate inhibitor of CYP3A4.
    Chlorpromazine: (Major) Avoid the concomitant use of nilotinib and chlorpromazine; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Chlorpromazine is associated with an established risk of QT prolongation and torsade de pointes.
    Cilostazol: (Moderate) Concomitant use of nilotinib, an moderate CYP3A4 inhibitor, and cilostazol, a CYP3A4 substrate, may result in increased cilostazol levels. A cilostazol dose reduction may be necessary if these drugs are used together.
    Cimetidine: (Moderate) If concomitant use of these agents is necessary, administer the H2-blocker approximately 10 hours before and approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. The concomitant use of nilotinib and H2-blockers that elevate the gastric pH may reduce the bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when a single 400-mg nilotinib dose was given 10 hours after and 2 hours prior to famotidine.
    Ciprofloxacin: (Major) Avoid the concomitant use of nilotinib and ciprofloxacin; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Rare cases of QT prolongation and TdP have been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Severe) Nilotinib prolongs the QT interval. Because of the potential for torsade de pointes (TdP), use of cisapride with nilotinib is contraindicated.
    Citalopram: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as citalopram. Nilotinib is a CYP3A4 and CYP2D6 inhibitor and citalopram is a substrate of CYP3A4 and CYP2D6; administering these drugs together may result in increased citalopram levels. If the use of citalopram is necessary, hold nilotinib therapy. If these drugs are used together, consider a citalopram dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Clarithromycin: (Major) Avoid the concomitant use of nilotinib with clarithromycin as significant prolongation of the QT interval may occur. Clarithromycin is associated with an established risk for QT prolongation and torsade de pointes (TdP). Sudden deaths and QT prolongation have been reported with nilotinib therapy.
    Clindamycin: (Moderate) Concomitant use of clindamycin and nilotinib may decrease clindamycin clearance and increase the risk of adverse reactions. Clindamycin is a CYP3A4 substrate; nilotinib is a moderate inhibitor of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
    Clonazepam: (Moderate) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and clonazepam, a CYP3A4 substrate, may result in increased clonazepam levels. A clonazepam dose reduction may be necessary if these drugs are used together.
    Clopidogrel: (Major) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor and a CYP2B6 inducer, and clopidogrel, a CYP3A4 and CYP2B6 substrate, may result altered clopidogrel levels. Monitor patients closely for clopidogrel toxicity and efficacy if these drugs are used together; a clopidogrel dose reduction may be necessary.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist. In addition, coadministration of clozapine and nilotinib may result in increased risk of QT prolongation.
    Cobicistat: (Major) Avoid the concomitant use of nilotinib and cobicistat; plasma exposure of both drugs may be increased. If coadministration is required, monitor closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If the strong inhibitor is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a moderate CYP3A4 inhibitor and cobicistat is a strong CYP3A4 inhibitor; both drugs are CYP3A4 substrates.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid the concomitant use of nilotinib and cobicistat; plasma exposure of both drugs may be increased. If coadministration is required, monitor closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If the strong inhibitor is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a moderate CYP3A4 inhibitor and cobicistat is a strong CYP3A4 inhibitor; both drugs are CYP3A4 substrates.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid the concomitant use of nilotinib and cobicistat; plasma exposure of both drugs may be increased. If coadministration is required, monitor closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If the strong inhibitor is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a moderate CYP3A4 inhibitor and cobicistat is a strong CYP3A4 inhibitor; both drugs are CYP3A4 substrates.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with chronic nilotinib therapy due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of nilotinib is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of nilotinib, resume cobimetinib at the previous dose. Use an alternative to nilotinib in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; nilotinib is a moderate inhibitor of both CYP3A and P-gp. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
    Codeine: (Moderate) Concomitant use of codeine with nilotinib 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 nilotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nilotinib 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. Nilotinib is a moderate inhibitor of CYP3A4.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with nilotinib 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 nilotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nilotinib 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. Nilotinib is a moderate inhibitor of CYP3A4.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with nilotinib 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 nilotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nilotinib 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. Nilotinib is a moderate inhibitor of CYP3A4. (Moderate) QT interval prolongation may be additive if nilotinib and promethazine are coadministered. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Promethazine is associated with a possible risk for QT prolongation.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with nilotinib 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 nilotinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If nilotinib 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. Nilotinib is a moderate inhibitor of CYP3A4. (Moderate) QT interval prolongation may be additive if nilotinib and promethazine are coadministered. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Promethazine is associated with a possible risk for QT prolongation.
    Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and nilotinib 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. Nilotinib 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 moderate CYP3A4 inhibitor like nilotinib 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 twice daily or 0.6 mg once daily or if the original dose is 0.6 mg once daily, decrease the dose to 0.3 mg once daily; for treatment of gout flares, give 1.2 mg as a single dose and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed 1.2 mg/day.
    Conivaptan: (Major) Avoid the concomitant use of nilotinib and conivaptan; plasma exposure of both drugs may be increased. According to the manufacturer of conivaptan, treatment with CYP3A substrates such as nilotinib may be initiated no sooner than 1 week after completion of conivaptan therapy. According to the manufacturer of nilotinib, if use of a strong CYP3A4 inhibitor cannot be avoided then monitor closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If the strong inhibitor is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a moderate CYP3A4 inhibitor and conivaptan is a strong CYP3A4 inhibitor; both drugs are CYP3A4 substrates.
    Crizotinib: (Major) Avoid coadministration of nilotinib with crizotinib if possible due to the risk of concentration-dependent QT prolongation; an increase in treatment-related adverse reactions may also occur. If concomitant use is unavoidable, monitor ECGs for QT prolongation and electrolytes. An interruption of crizotinib therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Both drugs are CYP3A4 substrates, CYP3A4 moderate inhibitors, and have been associated with QT prolongation. Additionally, nilotinib is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp.
    Cyclobenzaprine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Cyclobenzaprine is associated with a possible risk for QT prolongation and torsade de pointes. Additionally, nilotinib is a moderate inhibitor of CYP3A4 and cyclobenzaprine is a substrate of CYP3A4; administering these drugs together may result in increased cyclobenzaprine levels. If the use of cyclobenzaprine is necessary, hold nilotinib therapy. If these drugs are used together, consider a cyclobenzaprine dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Cyclophosphamide: (Moderate) Use caution if cyclophosphamide is used concomitantly with nilotinib, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Nilotinib is a CYP2B6 inducer, a CYP3A4 inhibitor, and both an inhibitor and inducer of CYP2C9; conversion of cyclophosphamide to its active or toxic metabolites may be affected. It is not yet clear what effects CYP2C9 inhibitors or CYP450 inducers have on the activation and/or toxicity of cyclophosphamide. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
    Cyclosporine: (Major) Concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), and cyclosporine, a CYP3A4 and P-gp substrate and inhibitor with a narrow therapeutic range, may result in increased nilotinib and/or cyclosporine levels. A dose reduction of either agent may be necessary if these drugs are used together; monitor patients for nilotinib and cyclosporine toxicity (e.g., cyclosporine concentrations to help avoid graft failure or drug-related toxicity and QT interval prolongation).
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with nilotinib, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like nilotinib in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with nilotinib, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Daclatasvir: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with nilotinib, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. In addition, the therapeutic effects of nilotinib, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor. If these drugs are administered together, monitor patients for adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Danazol: (Moderate) Concomitant use of nilotinib, a substrate and moderate CYP3A4 inhibitor, and danazol, a CYP3A4 inhibitor, may result in increased nilotinib levels. Monitor patients for nilotinib toxicity (e.g., QT interval prolongation) if these drugs are used together.
    Dapsone: (Moderate) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and dapsone, a CYP3A4 substrate, may result in increased dapsone levels. A dapsone dose reduction may be necessary if these drugs are used together.
    Darunavir: (Major) When possible, avoid concurrent use of darunavir with nilotinib as there is a potential for elevated concentrations of both drugs. If the use of darunavir is necessary, hold nilotinib therapy. If used together, a decrease in the dose or an adjustment of the dosing internal of nilotinib may be necessary. Consider reducing the dosage to nilotinib 200 mg PO once daily in patients with newly diagnosed Ph+ CML or to nilotinib 300 mg PO once daily in patients with resistant or intolerant Ph+ CML; close monitoring of the QT interval is recommended. If darunavir is discontinued, titrate the nilotinib dosage upward to the recommended dosage following a washout period. All both drugs are CYP3A4 inhibitors/substrates.
    Darunavir; Cobicistat: (Major) Avoid the concomitant use of nilotinib and cobicistat; plasma exposure of both drugs may be increased. If coadministration is required, monitor closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If the strong inhibitor is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a moderate CYP3A4 inhibitor and cobicistat is a strong CYP3A4 inhibitor; both drugs are CYP3A4 substrates. (Major) When possible, avoid concurrent use of darunavir with nilotinib as there is a potential for elevated concentrations of both drugs. If the use of darunavir is necessary, hold nilotinib therapy. If used together, a decrease in the dose or an adjustment of the dosing internal of nilotinib may be necessary. Consider reducing the dosage to nilotinib 200 mg PO once daily in patients with newly diagnosed Ph+ CML or to nilotinib 300 mg PO once daily in patients with resistant or intolerant Ph+ CML; close monitoring of the QT interval is recommended. If darunavir is discontinued, titrate the nilotinib dosage upward to the recommended dosage following a washout period. All both drugs are CYP3A4 inhibitors/substrates.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid the concomitant use of nilotinib and cobicistat; plasma exposure of both drugs may be increased. If coadministration is required, monitor closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If the strong inhibitor is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a moderate CYP3A4 inhibitor and cobicistat is a strong CYP3A4 inhibitor; both drugs are CYP3A4 substrates. (Major) When possible, avoid concurrent use of darunavir with nilotinib as there is a potential for elevated concentrations of both drugs. If the use of darunavir is necessary, hold nilotinib therapy. If used together, a decrease in the dose or an adjustment of the dosing internal of nilotinib may be necessary. Consider reducing the dosage to nilotinib 200 mg PO once daily in patients with newly diagnosed Ph+ CML or to nilotinib 300 mg PO once daily in patients with resistant or intolerant Ph+ CML; close monitoring of the QT interval is recommended. If darunavir is discontinued, titrate the nilotinib dosage upward to the recommended dosage following a washout period. All both drugs are CYP3A4 inhibitors/substrates.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid the concomitant use of nilotinib and dasabuvir; ombitasvir; paritaprevir; ritonavir. Nilotinib should be avoided in patients receiving strong CYP3A4 inhibitors. Nilotinib should also be avoided in patients receiving drugs that prolong the QT interval. Ritonavir is a strong CYP3A4 inhibitor and has also been associated with QT prolongation in clinical trials. If use of dasabuvir; ombitasvir; paritaprevir; ritonavir is necessary, hold nilotinib therapy. If the use of nilotinib and dasabuvir; ombitasvir; paritaprevir; ritonavir cannot be avoided, closely monitor the QT interval and 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). In addition to an increased risk of serious adverse events, such as QT prolongation, elevated plasma concentrations of all 5 drugs may result due to complex drug interactions. Nilotinib is a CYP2D6 inhibitor, a CYP3A4 substrate/inhibitor, a CYP2C8 inhibitor/inducer, and a P-glycoprotein (P-gp) drug transporter substrate/inhibitor. Ritonavir is a CYP3A4 substrate/potent inhibitor, CYP2D6 substrate, and a P-gp substrate/inhibitor. Paritaprevir is a substrate of CYP3A4 and P-gp. Dasabuvir is a substrate of CYP2C8, CYP3A4, and P-gp. Ombitasvir is a P-gp substrate. (Major) Avoid the concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), with ritonavir, a substrate and strong inhibitor of CYP3A4 and a substrate and inhibitor of P-gp; levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and ritonavir 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with nilotinib. 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; nilotinib is a moderate inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
    Degarelix: (Major) Avoid the concomitant use of nilotinib and degarelix; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Additionally, QT prolongation has occurred following degarelix administration.
    Delavirdine: (Major) Avoid the concomitant use of nilotinib, a substrate and inhibitor of CYP3A4, with delavirdine, a substrate and strong inhibitor of CYP3A4; levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and delavirdine cannot be avoided, consider a nilotinib dose reduction (to nilotinib 200 mg PO once daily in patients with newly diagnosed Ph+ CML or to nilotinib 300 mg PO once daily in patients with resistant or intolerant Ph+ CML); close monitoring of the QT interval is recommended. If the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Desflurane: (Major) Avoid the concomitant use of nilotinib and halogenated anesthetics; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Additionally, fatal cases of torsade de pointes have been reported with halogenated anesthetic use.
    Deutetrabenazine: (Major) Avoid the concomitant use of nilotinib and deutetrabenazine; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. For patients taking a deutetrabenazine dosage more than 24 mg/day, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine.
    Dexamethasone: (Major) Avoid the concurrent use of nilotinib, a CYP3A4 substrate and moderate inhibitor and glycoprotein (P-gp) inhibitor, and dexamethasone, a CYP3A4 substrate and strong inducer and P-gp substrate. Decreased nilotinib concentrations are likely and increased dexamethasone levels may occur. Selecting an alternate agent with less potential for CYP3A4 induction is recommended. If use of both of these agents is required, increasing the nilotinib dosage will most likely not account for the loss of exposure based on the nonlinear pharmacokinetics of nilotinib.
    Dexlansoprazole: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
    Dextromethorphan; Promethazine: (Moderate) QT interval prolongation may be additive if nilotinib and promethazine are coadministered. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Promethazine is associated with a possible risk for QT prolongation.
    Dextromethorphan; Quinidine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval such as quinidine. Additionally, nilotinib is a moderate CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor and quinidine is a CYP3A4 and P-gp substrate with a narrow therapeutic range; administering these drugs together may result in increased quinidine exposure. If the use of quinidine is required, hold nilotinib therapy. If the use of both nilotinib and quinidine cannot be avoided, a quinidine dose reduction may be necessary; close monitoring of the QT interval is recommended.
    Dienogest; Estradiol valerate: (Moderate) Nilotinib is a competitive inhibitor of UGT1A1 and CYP3A4. Estradiol is a substrate of UGT1A1. Increased concentrations of estradiol may occur following coadministration with nilotinib.
    Diltiazem: (Major) A nilotinib and/or diltiazem dose reduction may be necessary if these drugs are used together. Monitor patients for nilotinib and/or diltiazem toxicity (e.g., QT interval prolongation, hypotension) if these drugs are used together.The concomitant use of nilotinib, a substrate and inhibitor of CYP3A4, and diltiazem, a substrate and inhibitor of CYP3A4, may result in increased nilotinib and/or diltiazem levels.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with nilotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Nilotinib is a moderate inhibitor of CYP3A4.
    Disopyramide: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Disopyramide has been established to have a causal association with QT prolongation and torsade de pointes. Additionally, nilotinib is a moderate inhibitor of CYP3A4 and disopyramide is a substrate of CYP3A4; administering these drugs together may result in increased disopyramide levels. If the use of disopyramide is necessary, hold nilotinib therapy. If these drugs are used together, consider a disopyramide dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Docetaxel: (Major) Concomitant use of nilotinib, a CYP3A4 and P-glycoprotein (P-gp) inhibitor, and docetaxel, a CYP3A4 and P-gp substrate with a narrow therapeutic range, may result in increased docetaxel levels. A docetaxel dose reduction may be necessary if these drugs are used together.
    Dofetilide: (Severe) Nilotinib prolongs the QT interval. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Because of the potential for TdP, use of dofetilide with nilotinib is contraindicated.
    Dolasetron: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as dolasetron. Nilotinib is a CYP3A4 and CYP2D6 inhibitor and dolasetron is a substrate of CYP3A4 and CYP2D6; administering these drugs together may result in increased dolasetron levels. If the use of dolasetron is necessary, hold nilotinib therapy. If these drugs are used together, consider a dolasetron dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Dolutegravir; Rilpivirine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as rilpivirine. Nilotinib is a moderate inhibitor of CYP3A4 and rilpivirine is a substrate of CYP3A4; administering these drugs together may result in increased rilpivirine levels. If the use of rilpivirine is necessary, hold nilotinib therapy. If these drugs are used together, consider a rilpivirine dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Donepezil: (Major) Avoid administration of nilotinib with donepezil due to the potential for QT prolongation; increased donepezil-related adverse effects are also possible. Nilotinib therapy should be interrupted if treatment with another drug that prolongs the QT interval is required. If interruption of treatment with nilotinib is not possible, closely monitor for evidence of QT prolongation during concurrent use. Both nilotinib and donepezil may prolong the QT interval; donepezil has also been associated with torsade de pointes. In addition, nilotinib inhibits CYP2D6 and CYP3A4, the two isoenzymes involved in the metabolism of donepezil. Increased concentrations of donepezil may occur if it is coadministered with nilotinib.
    Donepezil; Memantine: (Major) Avoid administration of nilotinib with donepezil due to the potential for QT prolongation; increased donepezil-related adverse effects are also possible. Nilotinib therapy should be interrupted if treatment with another drug that prolongs the QT interval is required. If interruption of treatment with nilotinib is not possible, closely monitor for evidence of QT prolongation during concurrent use. Both nilotinib and donepezil may prolong the QT interval; donepezil has also been associated with torsade de pointes. In addition, nilotinib inhibits CYP2D6 and CYP3A4, the two isoenzymes involved in the metabolism of donepezil. Increased concentrations of donepezil may occur if it is coadministered with nilotinib.
    Doxorubicin: (Major) Acute cardiotoxicity can occur during the administration of doxorubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Coadministration of nilotinib and a drug that prolongs the QT interval, such as doxorubicin, is not advised; nilotinib also prolongs the QT interval. If concurrent administration is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation. Nilotinib is an inhibitor of the efflux transporter P-glycoprotein (P-gp, ABCB1) and of cytochrome P450 (CYP) isoenzyme 3A4. Doxorubicin is a P-glycoprotein and CYP3A4 substrate. Increased concentrations of doxorubicin are likely if it is coadministered with nilotinib; exercise caution.
    Dronabinol: (Moderate) Use caution if coadministration of dronabinol with nilotinib is necessary, and monitor for changes in the efficacy or adverse effect profile of dronabinol (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate. Nilotinib is a moderate inhibitor and inducer of CYP2C9 as well as a moderate CYP3A4 inhibitor. Concomitant use may result in altered plasma concentrations of dronabinol.
    Dronedarone: (Severe) Concomitant use of dronedarone and nilotinib is contraindicated. Nilotinib prolongs the QT interval. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Droperidol: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Droperidol has been established to have a causal association with QT prolongation and torsade de pointes. Additionally, nilotinib is a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp) and droperidol is a substrate of CYP3A4 and P-gp; administering these drugs together may result in increased droperidol levels. If the use of droperidol is necessary, hold nilotinib therapy. If these drugs are used together, consider a droperidol dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Drospirenone; Estradiol: (Moderate) Nilotinib is a competitive inhibitor of UGT1A1 and CYP3A4. Estradiol is a substrate of UGT1A1. Increased concentrations of estradiol may occur following coadministration with nilotinib.
    Drospirenone; Ethinyl Estradiol: (Major) Avoid the concomitant use of nilotinib (a substrate and moderate inhibitor of CYP3A4, inhibitor of UGT1A1, and substrate and inhibitor of P-glycoprotein or P-gp), with ethinyl estradiol (a substrate and strong inhibitor of CYP3A4 and a UGT1A1 and P-gp substrate); levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and ethinyl estradiol 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Avoid the concomitant use of nilotinib (a substrate and moderate inhibitor of CYP3A4, inhibitor of UGT1A1, and substrate and inhibitor of P-glycoprotein or P-gp), with ethinyl estradiol (a substrate and strong inhibitor of CYP3A4 and a UGT1A1 and P-gp substrate); levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and ethinyl estradiol 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Efavirenz: (Major) Coadministration of nilotinib and a drug that prolongs the QT interval, such as efavirenz, is not advised; nilotinib prolongs the QT interval. If concurrent administration is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation. In addition, concomitant use of nilotinib, a substrate and an inhibitor of CYP3A4, and efavirenz, a substrate and inducer of CYP3A4, may result in decreased nilotinib plasma concentrations and/or increased efavirenz concentrations. Selecting an alternate agent with less potential for CYP3A4 induction should be considered. Closely monitor patients if these drugs are used together; increasing the nilotinib dosage will most likely not account for the loss of exposure based on the nonlinear pharmacokinetics of nilotinib.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Coadministration of nilotinib and a drug that prolongs the QT interval, such as efavirenz, is not advised; nilotinib prolongs the QT interval. If concurrent administration is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation. In addition, concomitant use of nilotinib, a substrate and an inhibitor of CYP3A4, and efavirenz, a substrate and inducer of CYP3A4, may result in decreased nilotinib plasma concentrations and/or increased efavirenz concentrations. Selecting an alternate agent with less potential for CYP3A4 induction should be considered. Closely monitor patients if these drugs are used together; increasing the nilotinib dosage will most likely not account for the loss of exposure based on the nonlinear pharmacokinetics of nilotinib.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of nilotinib and a drug that prolongs the QT interval, such as efavirenz, is not advised; nilotinib prolongs the QT interval. If concurrent administration is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation. In addition, concomitant use of nilotinib, a substrate and an inhibitor of CYP3A4, and efavirenz, a substrate and inducer of CYP3A4, may result in decreased nilotinib plasma concentrations and/or increased efavirenz concentrations. Selecting an alternate agent with less potential for CYP3A4 induction should be considered. Closely monitor patients if these drugs are used together; increasing the nilotinib dosage will most likely not account for the loss of exposure based on the nonlinear pharmacokinetics of nilotinib.
    Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with nilotinib may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Nilotinib is a substrate and moderate inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
    Eletriptan: (Moderate) Monitor for increased eletriptan-related adverse effects if coadministered with nilotinib. Systemic concentrations of eletriptan may be increased. Eletriptan is a substrate for CYP3A4, and nilotinib is a moderate CYP3A4 inhibitor. Coadministration of other moderate CYP3A4 inhibitors increased the eletriptan AUC by 2 to 4-fold.
    Eliglustat: (Major) Avoid the concomitant use of nilotinib and eliglustat; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as rilpivirine. Nilotinib is a moderate inhibitor of CYP3A4 and rilpivirine is a substrate of CYP3A4; administering these drugs together may result in increased rilpivirine levels. If the use of rilpivirine is necessary, hold nilotinib therapy. If these drugs are used together, consider a rilpivirine dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as rilpivirine. Nilotinib is a moderate inhibitor of CYP3A4 and rilpivirine is a substrate of CYP3A4; administering these drugs together may result in increased rilpivirine levels. If the use of rilpivirine is necessary, hold nilotinib therapy. If these drugs are used together, consider a rilpivirine dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Encorafenib: (Major) Avoid coadministration of encorafenib and nilotinib due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of nilotinib. If nilotinib is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of nilotinib. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation. Nilotinib is a moderate CYP3A4 inhibitor; sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    Enflurane: (Major) Avoid the concomitant use of nilotinib and halogenated anesthetics; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Additionally, fatal cases of torsade de pointes have been reported with halogenated anesthetic use.
    Enzalutamide: (Major) Avoid the concomitant use of nilotinib and enzalutamide; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and enzalutamide is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
    Eplerenone: (Major) Do not exceed an eplerenone dose of 25 mg PO once daily if given concurrently with a CYP3A4 inhibitor in a post-myocardial infarction patient with heart failure. In patients with hypertension receiving a concurrent CYP3A4 inhibitor, initiate eplerenone at 25 mg PO once daily; the dose may be increased to a maximum of 25 mg PO twice daily for inadequate blood pressure response. In addition, measure serum creatinine and serum potassium within 3 to 7 days of initiating a CYP3A4 inhibitor and periodically thereafter. Eplerenone is a CYP3A4 substrate. Nilotinib is a CYP3A4 inhibitor. Coadministration with moderate CYP3A4 inhibitors increased eplerenone exposure by 100% to 190%. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
    Ergot alkaloids: (Moderate) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and ergot alkaloids (e.g., ergotamine, dihydroergotamine), CYP3A4 substrates with a narrow therapeutic range, may result in increased ergot alkaloid levels. Avoid co-use when possible; consider alternative therapy to the ergot medication. Be alert for symptoms of ergot toxicity if these drugs together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together.
    Eribulin: (Major) Avoid the concomitant use of nilotinib and eribulin; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Additionally, QT prolongation has occurred with eribulin use.
    Erlotinib: (Moderate) Use caution if coadministration of erlotinib with nilotinib is necessary due to the risk of increased erlotinib-related adverse reactions, and avoid coadministration with erlotinib if the patient is additionally taking a CYP1A2 inhibitor. If the patient is taking both nilotinib and a CYP1A2 inhibitor and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements; the manufacturer of erlotinib makes the same recommendations for toxicity-related dose reductions in patients taking strong CYP3A4 inhibitors without concomitant CYP1A2 inhibitors. Nilotinib is a moderate CYP3A4 inhibitor in vitro. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. Coadministration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%; coadministration with nilotinib may also increase erlotinib exposure.
    Erythromycin: (Major) Avoid administration of nilotinib with other drugs that may prolong QT interval, such as erythromycin. Nilotinib prolongs the QT interval. According to the manufacturer, nilotinib therapy should be interrupted if treatment with another drug that prolongs the QT interval is required. If interruption of treatment with nilotinib is not possible, closely monitor for evidence of QT prolongation during concurrent use. Additionally, nilotinib is a substrate of CYP3A4 and P-glycoprotein (P-gp) and erythromycin is an inhibitor of CYP3A4 and P-gp; nilotinib concentrations may increase.
    Erythromycin; Sulfisoxazole: (Major) Avoid administration of nilotinib with other drugs that may prolong QT interval, such as erythromycin. Nilotinib prolongs the QT interval. According to the manufacturer, nilotinib therapy should be interrupted if treatment with another drug that prolongs the QT interval is required. If interruption of treatment with nilotinib is not possible, closely monitor for evidence of QT prolongation during concurrent use. Additionally, nilotinib is a substrate of CYP3A4 and P-glycoprotein (P-gp) and erythromycin is an inhibitor of CYP3A4 and P-gp; nilotinib concentrations may increase.
    Escitalopram: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as escitalopram. Nilotinib is a moderate inhibitor of CYP3A4 and escitalopram is a substrate of CYP3A4; administering these drugs together may result in increased escitalopram levels. If the use of escitalopram is necessary, hold nilotinib therapy. If these drugs are used together, consider an escitalopram dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Esomeprazole: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
    Esomeprazole; Naproxen: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
    Estazolam: (Major) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and estazolam, a CYP3A4 substrate, may result in increased estazolam levels. A estazolam dose reduction may be necessary if these drugs are used together.
    Estradiol Cypionate; Medroxyprogesterone: (Moderate) Nilotinib is a competitive inhibitor of UGT1A1 and CYP3A4. Estradiol is a substrate of UGT1A1. Increased concentrations of estradiol may occur following coadministration with nilotinib.
    Estradiol: (Moderate) Nilotinib is a competitive inhibitor of UGT1A1 and CYP3A4. Estradiol is a substrate of UGT1A1. Increased concentrations of estradiol may occur following coadministration with nilotinib.
    Estradiol; Levonorgestrel: (Moderate) Nilotinib is a competitive inhibitor of UGT1A1 and CYP3A4. Estradiol is a substrate of UGT1A1. Increased concentrations of estradiol may occur following coadministration with nilotinib.
    Estradiol; Norethindrone: (Moderate) Nilotinib is a competitive inhibitor of UGT1A1 and CYP3A4. Estradiol is a substrate of UGT1A1. Increased concentrations of estradiol may occur following coadministration with nilotinib.
    Estradiol; Norgestimate: (Moderate) Nilotinib is a competitive inhibitor of UGT1A1 and CYP3A4. Estradiol is a substrate of UGT1A1. Increased concentrations of estradiol may occur following coadministration with nilotinib.
    Ethinyl Estradiol: (Major) Avoid the concomitant use of nilotinib (a substrate and moderate inhibitor of CYP3A4, inhibitor of UGT1A1, and substrate and inhibitor of P-glycoprotein or P-gp), with ethinyl estradiol (a substrate and strong inhibitor of CYP3A4 and a UGT1A1 and P-gp substrate); levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and ethinyl estradiol 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Ethinyl Estradiol; Desogestrel: (Major) Avoid the concomitant use of nilotinib (a substrate and moderate inhibitor of CYP3A4, inhibitor of UGT1A1, and substrate and inhibitor of P-glycoprotein or P-gp), with ethinyl estradiol (a substrate and strong inhibitor of CYP3A4 and a UGT1A1 and P-gp substrate); levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and ethinyl estradiol 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Ethinyl Estradiol; Ethynodiol Diacetate: (Major) Avoid the concomitant use of nilotinib (a substrate and moderate inhibitor of CYP3A4, inhibitor of UGT1A1, and substrate and inhibitor of P-glycoprotein or P-gp), with ethinyl estradiol (a substrate and strong inhibitor of CYP3A4 and a UGT1A1 and P-gp substrate); levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and ethinyl estradiol 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Ethinyl Estradiol; Etonogestrel: (Major) Avoid the concomitant use of nilotinib (a substrate and moderate inhibitor of CYP3A4, inhibitor of UGT1A1, and substrate and inhibitor of P-glycoprotein or P-gp), with ethinyl estradiol (a substrate and strong inhibitor of CYP3A4 and a UGT1A1 and P-gp substrate); levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and ethinyl estradiol 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period. (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as nilotinib may increase the serum concentration of etonogestrel.
    Ethinyl Estradiol; Levonorgestrel: (Major) Avoid the concomitant use of nilotinib (a substrate and moderate inhibitor of CYP3A4, inhibitor of UGT1A1, and substrate and inhibitor of P-glycoprotein or P-gp), with ethinyl estradiol (a substrate and strong inhibitor of CYP3A4 and a UGT1A1 and P-gp substrate); levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and ethinyl estradiol 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Major) Avoid the concomitant use of nilotinib (a substrate and moderate inhibitor of CYP3A4, inhibitor of UGT1A1, and substrate and inhibitor of P-glycoprotein or P-gp), with ethinyl estradiol (a substrate and strong inhibitor of CYP3A4 and a UGT1A1 and P-gp substrate); levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and ethinyl estradiol 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Avoid the concomitant use of nilotinib (a substrate and moderate inhibitor of CYP3A4, inhibitor of UGT1A1, and substrate and inhibitor of P-glycoprotein or P-gp), with ethinyl estradiol (a substrate and strong inhibitor of CYP3A4 and a UGT1A1 and P-gp substrate); levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and ethinyl estradiol 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Ethinyl Estradiol; Norelgestromin: (Major) Avoid the concomitant use of nilotinib (a substrate and moderate inhibitor of CYP3A4, inhibitor of UGT1A1, and substrate and inhibitor of P-glycoprotein or P-gp), with ethinyl estradiol (a substrate and strong inhibitor of CYP3A4 and a UGT1A1 and P-gp substrate); levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and ethinyl estradiol 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Avoid the concomitant use of nilotinib (a substrate and moderate inhibitor of CYP3A4, inhibitor of UGT1A1, and substrate and inhibitor of P-glycoprotein or P-gp), with ethinyl estradiol (a substrate and strong inhibitor of CYP3A4 and a UGT1A1 and P-gp substrate); levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and ethinyl estradiol 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Avoid the concomitant use of nilotinib (a substrate and moderate inhibitor of CYP3A4, inhibitor of UGT1A1, and substrate and inhibitor of P-glycoprotein or P-gp), with ethinyl estradiol (a substrate and strong inhibitor of CYP3A4 and a UGT1A1 and P-gp substrate); levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and ethinyl estradiol 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Ethinyl Estradiol; Norethindrone: (Major) Avoid the concomitant use of nilotinib (a substrate and moderate inhibitor of CYP3A4, inhibitor of UGT1A1, and substrate and inhibitor of P-glycoprotein or P-gp), with ethinyl estradiol (a substrate and strong inhibitor of CYP3A4 and a UGT1A1 and P-gp substrate); levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and ethinyl estradiol 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Avoid the concomitant use of nilotinib (a substrate and moderate inhibitor of CYP3A4, inhibitor of UGT1A1, and substrate and inhibitor of P-glycoprotein or P-gp), with ethinyl estradiol (a substrate and strong inhibitor of CYP3A4 and a UGT1A1 and P-gp substrate); levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and ethinyl estradiol 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Ethinyl Estradiol; Norgestimate: (Major) Avoid the concomitant use of nilotinib (a substrate and moderate inhibitor of CYP3A4, inhibitor of UGT1A1, and substrate and inhibitor of P-glycoprotein or P-gp), with ethinyl estradiol (a substrate and strong inhibitor of CYP3A4 and a UGT1A1 and P-gp substrate); levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and ethinyl estradiol 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Ethinyl Estradiol; Norgestrel: (Major) Avoid the concomitant use of nilotinib (a substrate and moderate inhibitor of CYP3A4, inhibitor of UGT1A1, and substrate and inhibitor of P-glycoprotein or P-gp), with ethinyl estradiol (a substrate and strong inhibitor of CYP3A4 and a UGT1A1 and P-gp substrate); levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and ethinyl estradiol 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Ethosuximide: (Moderate) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and ethosuximide, a CYP3A4 substrate, may result in increased ethosuximide levels. A ethosuximide dose reduction may be necessary if these drugs are used together.
    Etonogestrel: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as nilotinib may increase the serum concentration of etonogestrel.
    Etoposide, VP-16: (Major) Concomitant use of nilotinib, a CYP3A4 and P-glycoprotein (P-gp) inhibitor, and etoposide, VP-16, a CYP3A4 and P-gp substrate with a narrow therapeutic range, may result in increased etoposide levels. An etoposide dose reduction may be necessary if these drugs are used together.
    Ezogabine: (Major) Avoid the concomitant use of nilotinib and ezogabine; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Additionally, QT prolongation has occurred with ezogabine use.
    Famotidine: (Moderate) If concomitant use of these agents is necessary, administer the H2-blocker approximately 10 hours before and approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. The concomitant use of nilotinib and H2-blockers that elevate the gastric pH may reduce the bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when a single 400-mg nilotinib dose was given 10 hours after and 2 hours prior to famotidine.
    Famotidine; Ibuprofen: (Moderate) If concomitant use of these agents is necessary, administer the H2-blocker approximately 10 hours before and approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. The concomitant use of nilotinib and H2-blockers that elevate the gastric pH may reduce the bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when a single 400-mg nilotinib dose was given 10 hours after and 2 hours prior to famotidine.
    Fentanyl: (Major) Nilotinib is a substrate and inhibitor of both CYP3A4 and P-glycoprotein (P-gp). Fentanyl is a substrate of CYP3A4 and P-gp and has a narrow therapeutic range. If these drugs are coadministered, the fentanyl dose may need to be very conservative; consider a fentanyl dose reduction. Patients should be carefully monitored for an extended time period for signs of too much fentanyl such as oversedation, respiratory depression, and hypotension.
    Fesoterodine: (Moderate) Fesoterodine is rapidly hydrolyzed to its active metabolite, 5-hydroxymethyltolterodine, which is metabolized via hepatic CYP2D6 and CYP3A4. Nilotinib is a competitive inhibitor of CYP3A4 and CYP2D6. In theory, the CYP3A4 and 2D6 inhibitory effects of nilotinib may result in an increase in plasma concentrations of 5-hydroxymethyltolterodine. The need for fesoterodine doses greater than 4 mg/day should be carefully evaluated prior to increasing the dose during concurrent use of mild to moderate 3A4 inhibitors.
    Fingolimod: (Major) Avoid the concomitant use of nilotinib and fingolimod; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsade de pointes (TdP). Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
    Flecainide: (Major) Avoid the concomitant use of nilotinib and flecainide; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Flibanserin: (Severe) The concomitant use of flibanserin and moderate CYP3A4 inhibitors, such as nilotinib, is contraindicated. Moderate CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a moderate CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a moderate CYP3A4 inhibitor following flibanserin use, start the moderate CYP3A4 inhibitor at least 2 days after the last dose of flibanserin.
    Fluconazole: (Severe) Due to the risk of life-threatening arrhythmias such as torsade de pointes (TdP), coadministration of fluconazole with drugs that both prolong the QT interval and are CYP3A4 substrates, like nilotinib, is contraindicated. Fluconazole has been associated with QT prolongation and rare cases of TdP. Additonally, fluconazole is an inhibitor of CYP3A4. Coadministration may result in elevated plasma concentrations of nilotinib, causing an increased risk for adverse events such as QT prolongation.
    Fluoxetine: (Major) Avoid the concomitant use of nilotinib and fluoxetine; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Additionally, QT prolongation and torsade de pointes have occurred with fluoxetine use.
    Fluoxetine; Olanzapine: (Major) Avoid the concomitant use of nilotinib and fluoxetine; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Additionally, QT prolongation and torsade de pointes have occurred with fluoxetine use.
    Fluphenazine: (Minor) QT interval prolongation may be additive if nilotinib and fluphenazine are coadministered. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Flurazepam: (Major) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and flurazepam, a CYP3A4 substrate, may result in increased flurazepam levels. A flurazepam dose reduction may be necessary if these drugs are used together.
    Fluticasone; Salmeterol: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Pharmacokinetic interactions may occur with some LABAs.
    Fluticasone; Umeclidinium; Vilanterol: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Pharmacokinetic interactions may occur with some LABAs.
    Fluticasone; Vilanterol: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Pharmacokinetic interactions may occur with some LABAs.
    Fluvoxamine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and nilotinib. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. According to the manufacturer, nilotinib therapy should be interrupted if treatment with another drug that prolongs the QT interval is required. If interruption of treatment with nilotinib is not possible, closely monitor for evidence of QT prolongation during concurrent use. In addition, concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and CYP2D6, and fluvoxamine, a CYP3A4 inhibitor and CYP2D6 substrate, may result in increased nilotinib and/or fluvoxamine levels. Monitor patients for nilotinib and fluvoxamine toxicity (e.g., QT interval prolongation, serotonin-related side effects).
    Food: (Severe) Do not administer Nilotinib with food. Nilotinib needs to be taken at least 1 hour before a meal or 2 hours after a meal. Food increases the bioavailability of nilotinib. Increased nilotinib serum concentrations may occur if the drug is taken with food, possibly resulting in QT porlongation, palpitations, torsade de pointes (TdP) and/or myelotoxicity.
    Formoterol: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Pharmacokinetic interactions may occur with some LABAs.
    Formoterol; Mometasone: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Pharmacokinetic interactions may occur with some LABAs.
    Fosamprenavir: (Major) Fosamprenavir is metabolized to the active drug amprenavir. Avoid the concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp) and an inhibitor of CYP2C9 and CYP2D6, with amprenavir, a substrate and strong inhibitor of CYP3A4 and a substrate of P-gp, CYP2C9, and CYP2D6; levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and fosamprenavir 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Foscarnet: (Major) Avoid the concomitant use of nilotinib and foscarnet; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes.
    Fosphenytoin: (Major) Avoid the concomitant use of nilotinib and fosphenytoin; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and fosphenytoin is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
    Gefitinib: (Moderate) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and gefitinib, a CYP3A4 substrate, may result in increased gefitinib levels. A gefitinib dose reduction may be necessary if these drugs are used together.
    Gemifloxacin: (Major) Avoid the concomitant use of nilotinib and gemifloxacin; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Gemifloxacin may also prolong the QT interval in some patients, with the maximal change in the QTc interval occurring approximately 5 to 10 hours following oral administration. The likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Major) Avoid the concomitant use of nilotinib and gemtuzumab ozogamicin; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Although QT interval prolongation has not been reported with gemtuzumab ozogamicin, it has been reported with other drugs that contain calicheamicin.
    Glycopyrrolate; Formoterol: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Pharmacokinetic interactions may occur with some LABAs.
    Goserelin: (Major) Avoid the concomitant use of nilotinib and goserelin acetate; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Additionally, androgen deprivation therapy (e.g., goserelin) prolongs the QT interval.
    Granisetron: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as granisetron. Additionally, nilotinib is a moderate inhibitor of CYP3A4 and granisetron is a substrate of CYP3A4; administering these drugs together may result in increased granisetron levels. If the use of granisetron is necessary, hold nilotinib therapy. If these drugs are used together, consider a granisetron dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Grapefruit juice: (Severe) Concurrent use of nilotinib and grapefruit or grapefruit juice is not advised. Grapefruit can inhibit intestinal CYP3A4, and nilotinib is a CYP3A4 substrate. Increased nilotinib serum concentrations may occur if grapefruit or grapefruit juice is consumed.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with nilotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Nilotinib is a moderate inhibitor of CYP3A4.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with nilotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Nilotinib is a moderate inhibitor of CYP3A4.
    Guanfacine: (Major) Nilotinib may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. Upon nilotinib discontinuation, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and nilotinib is a moderate CYP3A4 inhibitor.
    H2-blockers: (Moderate) If concomitant use of these agents is necessary, administer the H2-blocker approximately 10 hours before and approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. The concomitant use of nilotinib and H2-blockers that elevate the gastric pH may reduce the bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when a single 400-mg nilotinib dose was given 10 hours after and 2 hours prior to famotidine.
    Halofantrine: (Severe) Nilotinib prolongs the QT interval and coadministration with drugs that also prolong the QT interval (e.g., halofantrine) is not advised. If concurrent administration is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor for QT interval prolongation. Also, nilotinib is an inhibitor of CYP3A4, and halofantrine is a CYP3A4 substrate. Increased concentrations of halofantrine may occur.
    Halogenated Anesthetics: (Major) Avoid the concomitant use of nilotinib and halogenated anesthetics; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Additionally, fatal cases of torsade de pointes have been reported with halogenated anesthetic use.
    Haloperidol: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as haloperidol. Nilotinib is a CYP3A4 and CYP2D6 inhibitor and haloperidol is a substrate of CYP3A4 and CYP2D6; administering these drugs together may result in increased haloperidol levels. If the use of haloperidol is necessary, hold nilotinib therapy. If these drugs are used together, consider a haloperidol dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Halothane: (Major) Avoid the concomitant use of nilotinib and halogenated anesthetics; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Additionally, fatal cases of torsade de pointes have been reported with halogenated anesthetic use.
    Histrelin: (Major) Avoid administration of nilotinib with histrelin due to the risk of QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for evidence of QT prolongation during concurrent use. Additionally, monitor serum electrolytes, correcting any electrolyte abnormalities as needed. Nilotinib prolongs the QT interval. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with nilotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Nilotinib is a moderate inhibitor of CYP3A4.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with nilotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Nilotinib is a moderate inhibitor of CYP3A4.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with nilotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Nilotinib is a moderate inhibitor of CYP3A4.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with nilotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Nilotinib is a moderate inhibitor of CYP3A4.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with nilotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Nilotinib is a moderate inhibitor of CYP3A4.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with nilotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Nilotinib is a moderate inhibitor of CYP3A4.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with nilotinib may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP3A4. Nilotinib is a moderate inhibitor of CYP3A4.
    Hydroxychloroquine: (Major) Avoid the concomitant use of nilotinib and hydroxychloroquine; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Ventricular arrhythmias and torsade de pointes have been reported with the use of hydroxychloroquine.
    Hydroxyzine: (Major) Avoid the concomitant use of nilotinib and hydroxyzine; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Post-marketing data indicate that hydroxyzine causes QT prolongation and torsade de Pointes.
    Ibrutinib: (Major) If coadministered with nilotinib, reduce the ibrutinib dose to 140 mg/day PO for the treatment of B-cell malignancy or 420 mg/day PO for the treatment of chronic graft-versus-host disease. Resume ibrutinib at the previous dose if nilotinib is discontinued. Monitor patients for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection); interruption of ibrutinib therapy or a dose reduction may be necessary in patients who develop severe toxicity. Ibrutinib is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. When ibrutinib was administered with multiple doses of another moderate CYP3A4 inhibitor, the Cmax and AUC values of ibrutinib were increased by 3.4-fold and 3-fold, respectively.
    Ibuprofen; Oxycodone: (Moderate) Concomitant use of oxycodone with nilotinib may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4. nilotinib is a moderate inhibitor of CYP3A4.
    Ibutilide: (Major) Avoid the concomitant use of nilotinib and ibutilide; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Ibutilide administration can cause QT prolongation and torsades de pointes; proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
    Iloperidone: (Major) Avoid the concomitant use of nilotinib and iloperidone; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Additionally, iloperidone has been associated with QT prolongation.
    Imatinib: (Major) The concomitant use of nilotinib and imatinib resulted in increased levels of both drugs in a phase I study. Both nilotinib and imatinib are a substrates and moderate inhibitors of CYP3A4. Following the administration of nilotinib 400 mg twice daily in combination with imatinib 400 mg once daily or imatinib 400 mg twice daily in a phase I study, the AUC values were increased by 30 to 50% for nilotinib and by about 20% for imatinib. These agents may be used together; monitor patients for nilotinib or imatinib toxicity including QT interval prolongation.
    Indacaterol: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Pharmacokinetic interactions may occur with some LABAs.
    Indacaterol; Glycopyrrolate: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Pharmacokinetic interactions may occur with some LABAs.
    Indinavir: (Major) Avoid the concomitant use of nilotinib, a substrate and moderate inhibitor of CYP3A4, with indinavir, a substrate and strong inhibitor of CYP3A4; levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and indinavir 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with nilotinib due to the potential for additive QT prolongation and risk of torsade de pointes. If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment; closely monitor for evidence of QT prolongation during concurrent use. Inotuzumab has been associated with QT interval prolongation. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with nilotinib may result in increased serum concentrations of both drugs. Nilotinib is a substrate and inhibitor of the hepatic isoenzyme CYP3A4 and a substrate of the drug transporter P-gp; isavuconazole, the active moiety of isavuconazonium, is an inhibitor of CYP3A4 and P-gp. Caution and close monitoring for nilotinib and isavuconazole toxicity (e.g. QT interval prolongation and hepatic toxicity) are advised if these drugs are used together.
    Isoflurane: (Major) Avoid the concomitant use of nilotinib and halogenated anesthetics; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Additionally, fatal cases of torsade de pointes have been reported with halogenated anesthetic use.
    Isoniazid, INH: (Major) Avoid the concomitant use of nilotinib, a CYP3A4 substrate, isoniazid, INH, a strong CYP3A4 inhibitor; nilotinib levels may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and isoniazid 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the concomitant use of nilotinib and rifampin; significantly decreased nilotinib exposure was observed in a drug interaction study. Coadministration of these drugs may lead to reduced nilotinib efficacy. Nilotinib is a CYPA4 substrate and rifampin is a strong CYP3A4 inducer. In a drug interaction study, the AUC value of nilotinib was decreased by about 80% following the addition of rifampicin/rifampin 600 mg once daily for 12 days. (Major) Avoid the concomitant use of nilotinib, a CYP3A4 substrate, isoniazid, INH, a strong CYP3A4 inhibitor; nilotinib levels may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and isoniazid 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Isoniazid, INH; Rifampin: (Major) Avoid the concomitant use of nilotinib and rifampin; significantly decreased nilotinib exposure was observed in a drug interaction study. Coadministration of these drugs may lead to reduced nilotinib efficacy. Nilotinib is a CYPA4 substrate and rifampin is a strong CYP3A4 inducer. In a drug interaction study, the AUC value of nilotinib was decreased by about 80% following the addition of rifampicin/rifampin 600 mg once daily for 12 days. (Major) Avoid the concomitant use of nilotinib, a CYP3A4 substrate, isoniazid, INH, a strong CYP3A4 inhibitor; nilotinib levels may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and isoniazid 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Itraconazole: (Major) Avoid nilotinib use during and for 2 weeks after discontinuation of itraconazole. If use of itraconazole is necessary, hold nilotinib therapy. If the use of nilotinib and itraconazole 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 itraconazole is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period. Taking these drugs together may increase concentrations of nilotinib and itraconazole and could result in additive effects on the QT interval. Nilotinib is a substrate and moderate inhibitor of CYP3A4. Itraconazole is a substrate and strong inhibitor of CYP3A4.
    Ivabradine: (Major) Avoid coadministration of ivabradine and nilotinib as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; nilotinib inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with nilotinib due to increased plasma concentrations of ivosidenib and QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. Ivosidenib is a CYP3A4 substrate that has been associated with QTc prolongation and ventricular arrhythmias. Nilotinib is a moderate CYP3A4 inhibitor; sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Coadministration with another moderate CYP3A4 inhibitor is predicted to increase the ivosidenib single-dose AUC to 173% of control based on physiologically-based pharmacokinetic modeling, with no change in Cmax. Multiple doses of the moderate CYP3A4 inhibitor are predicted to increase the ivosidenib steady-state AUC to 152% of control and AUC to 190% of control.
    Ketoconazole: (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.
    Lansoprazole: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
    Lansoprazole; Naproxen: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
    Lapatinib: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval such as lapatinib. nilotinib is a substrate and inhibitor of CYP3A4 and a substrate and inhibitor of P-glycoprotein (P-gp) and lapatinib is an inhibitor and a substrate of CYP3A4 and an inhibitor of P-gp; nilotinib and/or lapatinib levels may increase. If the use of lapatinib is necessary, hold nilotinib therapy. Monitor patients closely for toxicity (e.g., QT interval prolongation) if these drugs are used together.
    Lenvatinib: (Major) Avoid the concomitant use of nilotinib and lenvatinib; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Additionally, QT prolongation has been reported with lenvatinib in clinical trials.
    Letermovir: (Moderate) Coadministration of letermovir and nilotinib may increase nilotinib exposure. Avoid this combination if the patient is also receiving cyclosporine, because the magnitude of the interaction may be increased. If the use of letermovir with cyclosporine is necessary, interrupt nilotinib therapy. If the use of nilotinib with letermovir and cyclosporine 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 letermovir with cyclosporine is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period. Nilotinib is a CYP3A4 substrate and letermovir is a moderate CYP3A4 inhibitor. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Leuprolide: (Major) Avoid the concomitant use of nilotinib and leuprolide acetate; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Androgen deprevation therapy, such as leuprolide, may cause QT prolongation.
    Leuprolide; Norethindrone: (Major) Avoid the concomitant use of nilotinib and leuprolide acetate; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Androgen deprevation therapy, such as leuprolide, may cause QT prolongation.
    Levalbuterol: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Levofloxacin: (Major) Avoid the concomitant use of nilotinib and levofloxacin; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Levofloxacin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Additionally, rare cases of torsade de pointes have been spontaneously reported during postmarketing surveillance in patients receiving levofloxacin.
    Lidocaine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Systemic lidocaine has been established to have a causal association with QT prolongation and torsade de pointes. Additionally, nilotinib is a moderate CYP3A4 inhibitor and lidocaine is a CYP3A4 substrate; administering these drugs together may result in increased lidocaine levels. If the use of lidocaine is required, hold nilotinib therapy. If the use of nilotinib and lidocaine cannot be avoided, a lidocaine dose reduction may be necessary; close monitoring of the QT interval is recommended.
    Lithium: (Major) Avoid the concomitant use of nilotinib and lithium; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Additionally, lithium has been associated with QT prolongation.
    Live Vaccines: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Lofexidine: (Major) Avoid the concomitant use of nilotinib and lofexidine; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes.
    Lomitapide: (Major) Concomitant use of lomitapide and nilotinib may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Nilotinib is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors. In addition, concomitant use may result in increased serum concentrations of nilotinib. According to the manufacturer of lomitapide, dose reduction of nilotinib should be considered during concurrent use. Lomitapide is an inhibitor of P-glycoprotein (P-gp) and nilotinib is a P-gp substrate.
    Long-acting beta-agonists: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Pharmacokinetic interactions may occur with some LABAs.
    Loperamide: (Major) Loperamide should be avoided in combination with nilotinib. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Nilotinib also prolongs the QT interval and the manufacturer advises against use with other drugs that prolong the QT interval. If concurrent administration is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation. In addition, if these drugs are used together, the plasma concentrations of loperamide may increase. Loperamide is metabolized by CYP3A4, CYP2C8, CYP2B6, and CYP2D6, and is a substrate for the drug transporter P-glycoprotein (P-gp). Nilotinib is an inhibitor of all 4 enzymes and P-gp, further increasing the risk of toxicity. Monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Loperamide; Simethicone: (Major) Loperamide should be avoided in combination with nilotinib. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Nilotinib also prolongs the QT interval and the manufacturer advises against use with other drugs that prolong the QT interval. If concurrent administration is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation. In addition, if these drugs are used together, the plasma concentrations of loperamide may increase. Loperamide is metabolized by CYP3A4, CYP2C8, CYP2B6, and CYP2D6, and is a substrate for the drug transporter P-glycoprotein (P-gp). Nilotinib is an inhibitor of all 4 enzymes and P-gp, further increasing the risk of toxicity. Monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS effects.
    Lopinavir; Ritonavir: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as lopinavir; ritonavir. Both nilotinib and lopinavir; ritonavir are substrates and inhibitors of CYP3A4; administering these drugs together may result in increased nilotinib and/or lopinavir; ritonavir levels. If the use of lopinavir; ritonavir is necessary, hold nilotinib therapy. If these drugs are used together, consider a nilotinib and/or lopinavir; ritonavir dose reduction and monitor patients for toxicity (e.g., QT interval prolongation). (Major) Avoid the concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), with ritonavir, a substrate and strong inhibitor of CYP3A4 and a substrate and inhibitor of P-gp; levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and ritonavir 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Lovastatin: (Moderate) Concomitant use of nilotinib and lovastatin may result in increased lovastatin levels. A lovastatin dose reduction may be necessary if these drugs are used together. Be alert for symptoms of statin-induced myopathy. Lovastatin is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor.
    Lovastatin; Niacin: (Moderate) Concomitant use of nilotinib and lovastatin may result in increased lovastatin levels. A lovastatin dose reduction may be necessary if these drugs are used together. Be alert for symptoms of statin-induced myopathy. Lovastatin is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor.
    Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of nilotinib and lumacaftor; ivacaftor because significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
    Lumacaftor; Ivacaftor: (Major) Avoid the concomitant use of nilotinib and lumacaftor; ivacaftor because significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and lumacaftor; ivacaftor is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
    Lurasidone: (Major) Nilotinib is a moderate inhibitor of CYP3A4 and has the potential for interactions with substrates of CYP3A4 such as lurasidone. Concurrent use of these medications may lead to an increased risk of lurasidone-related adverse reactions. If a moderate inhibitor of CYP3A4 is being prescribed and lurasidone is added in an adult patient, the recommended starting dose of lurasidone is 20 mg/day and the maximum recommended daily dose of lurasidone is 80 mg/day. If a moderate CYP3A4 inhibitor is added to an existing lurasidone regimen, reduce the lurasidone dose to one-half of the original dose. Patients should be monitored for efficacy and toxicity.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as nilotinib. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Nilotinib also prolongs the QT interval.
    Magnesium Hydroxide: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
    Maprotiline: (Major) Avoid the concomitant use of nilotinib and maprotiline; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Maraviroc: (Moderate) Use caution if coadministration of maraviroc with nilotinib is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A and P-glycoprotein (P-gp) substrate and nilotinib is a CYP3A4/P-gp inhibitor. Monitor for an increase in adverse effects with concomitant use.
    Mefloquine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval such as mefloquine. Nilotinib is CYP3A4 inhibitor and a P-glycoprotein (P-gp) substrate and inhibitor and mefloquine is a CYP3A4 substrate and a P-gp substrate and inhibitor. Administering these drugs together may result in increased levels of both drugs. If the use of mefloquine is required, hold nilotinib therapy. Monitor patients closely for toxicity (e.g., QT interval prolongation) if these drugs are used together.
    Meperidine; Promethazine: (Moderate) QT interval prolongation may be additive if nilotinib and promethazine are coadministered. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Promethazine is associated with a possible risk for QT prolongation.
    Metaproterenol: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Methadone: (Major) The need to coadminister methadone with drugs known to prolong the QT interval should be done with extreme caution and a careful assessment of treatment risks versus benefits. At high doses, methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses averaging approximately 400 mg/day. In addition, methadone is a substrate for CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Concurrent use of methadone with inhibitors of these enzymes may result in increased serum concentrations of methadone. Drugs with a possible risk for QT prolongation and TdP that inhibit CYP3A4, CYP2D6, and P-gp that should be used cautiously with methadone include nilotinib.
    Methylprednisolone: (Moderate) Concomitant use of nilotinib, a CYP3A4 and P-glycoprotein (P-gp) inhibitor, and methylprednisolone, a CYP3A4 and P-gp substrate, may result in increased methylprednisolone concentrations. A methylprednisolone dose reduction may be necessary if these drugs are used together.
    Metronidazole: (Major) Avoid the concomitant use of nilotinib and metronidazole; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Potential QT prolongation has been reported with metronidazole use in limited case reports.
    Midazolam: (Major) The concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and midazolam, a CYP3A4 substrate, resulted in a 2.6-fold increase in the systemic midazolam exposure in patients with chronic myelogenous leukemia. Consider a midazolam dose reduction if these drugs are used together.
    Midostaurin: (Major) Avoid the concomitant use of nilotinib and midostaurin; significant prolongation of the QT interval may occur. If concomitant use is required, consider ECG monitoring. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
    Mifepristone: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Mifepristone, when used chronically for hormonal conditions such as Cushing's syndrome, has been associated with dose-dependent prolongation of the QT interval. To minimize the risk of QT prolongation, the lowest effect mifepristone dose should always be used. Additionally, nilotinib is a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp) and mifepristone is an inhibitor and a substrate of CYP3A4 and P-gp; the concentrations of either drug may increase. If the use of mifepristone is necessary, consider dose reduction of nilotinib and monitor closely for nilotinib-associated toxicities, including hematologic, hepatic, and non-hematologic effects, including QT prolongation. ECG monitoring is recommended during nilotinib treatment. A dosage reduction of mifepristone may also be necessary; monitor for adrenal infufficiency and other mifepristone-related toxicities. If drug interactions occur, they may be prolonged due to the prolonged action of mifepristone.
    Mirtazapine: (Major) Avoid the concomitant use of nilotinib and mirtazapine; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Cases of QT prolongation, torsade de pointes, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Mitotane: (Major) Avoid the concomitant use of nilotinib and mitotane; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and mitotane is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%
    Moxifloxacin: (Major) Avoid the concomitant use of nilotinib and moxifloxacin; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including torsade de pointes, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
    Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with nilotinib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; nilotinib is a moderate P-gp inhibitor and a moderate CYP3A4 inhibitor.
    Naloxegol: (Major) Avoid concomitant administration of naloxegol and nilotinib due to the potential for increased naloxegol exposure. If coadministration cannot be avoided, decrease the naloxegol dosage to 12.5 mg once daily and monitor for adverse reactions including opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. Naloxegol is a CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. Coadministration with another moderate CYP3A4 inhibitor increased naloxegol exposure by approximately 3.4-fold.
    Nefazodone: (Major) Avoid the concomitant use of nilotinib, a substrate and inhibitor of CYP3A4, with nefazodone, a substrate and strong inhibitor of CYP3A4; levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and nefazodone 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Nelfinavir: (Major) Avoid the concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), with nelfinavir, a substrate and strong inhibitor of CYP3A4 and a substrate and inhibitor of P-gp; levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and nelfinavir 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Neratinib: (Major) Avoid concomitant use of nilotinib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor. The effect of moderate CYP3A4 inhibition on neratinib concentrations has not been studied; however, coadministration with a strong CYP3A4 inhibitor increased neratinib exposure by 481%. Because of the significant impact on neratinib exposure from strong CYP3A4 inhibition, the potential impact on neratinib safety from concomitant use with moderate CYP3A4 inhibitors should be considered as they may also significantly increase neratinib exposure.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Nilotinib is a CYP3A4 and CYP2D6 inhibitor and palonosetron is a substrate of CYP3A4 and CYP2D6; administering these drugs together may result in increased palonosetron levels. If these drugs are used together, monitor patients for serotonin-related side effects.
    Nevirapine: (Moderate) Concomitant use of nilotinib, a substrate and moderate inhibitor of CYP3A4 and a CYP2B6 inducer, and nevirapine, a substrate and inducer of CYP3A4 and a CYP2B6 substrate, may result in decreased nilotinib and/or altered nevirapine levels. Use these agents together with caution; monitor patients for nevirapine side effects or decreased nilotinib or nevirapine efficacy.
    Nintedanib: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as nilotinib, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Nilotinib is a moderate inhibitor of both P-gp and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Nizatidine: (Moderate) If concomitant use of these agents is necessary, administer the H2-blocker approximately 10 hours before and approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. The concomitant use of nilotinib and H2-blockers that elevate the gastric pH may reduce the bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when a single 400-mg nilotinib dose was given 10 hours after and 2 hours prior to famotidine.
    Norfloxacin: (Major) Avoid the concomitant use of nilotinib and norfloxacin; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Quinolones have also been associated with QT prolongation and torsade de pointes (TdP). For norfloxacin specifically, extremely rare cases of TdP were reported during post-marketing surveillance. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Octreotide: (Major) Avoid the concomitant use of nilotinib and octreotide; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy warranting more cautious monitoring during octreotide administration in higher risk patients with cardiac disease. Since bradycardia is a risk factor for development of torsade de pointes (TdP), the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Major) Avoid the concomitant use of nilotinib and ofloxacin; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Quinolones have also been associated with QT prolongation and torsade de pointes (TdP). Additionally, post-marketing surveillance for ofloxacin has identified very rare cases of TdP.
    Olaparib: (Major) Avoid coadministration of olaparib with nilotinib and consider alternative agents with less CYP3A4 inhibition due to increased olaparib exposure. If concomitant use is unavoidable, reduce the dose of olaparib tablets to 150 mg twice daily; reduce the dose of olaparib capsules to 200 mg twice daily. Olaparib is a CYP3A4/5 substrate and nilotinib is a moderate CYP3A4 inhibitor.
    Olodaterol: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Pharmacokinetic interactions may occur with some LABAs.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid the concomitant use of nilotinib and dasabuvir; ombitasvir; paritaprevir; ritonavir. Nilotinib should be avoided in patients receiving strong CYP3A4 inhibitors. Nilotinib should also be avoided in patients receiving drugs that prolong the QT interval. Ritonavir is a strong CYP3A4 inhibitor and has also been associated with QT prolongation in clinical trials. If use of dasabuvir; ombitasvir; paritaprevir; ritonavir is necessary, hold nilotinib therapy. If the use of nilotinib and dasabuvir; ombitasvir; paritaprevir; ritonavir cannot be avoided, closely monitor the QT interval and 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). In addition to an increased risk of serious adverse events, such as QT prolongation, elevated plasma concentrations of all 5 drugs may result due to complex drug interactions. Nilotinib is a CYP2D6 inhibitor, a CYP3A4 substrate/inhibitor, a CYP2C8 inhibitor/inducer, and a P-glycoprotein (P-gp) drug transporter substrate/inhibitor. Ritonavir is a CYP3A4 substrate/potent inhibitor, CYP2D6 substrate, and a P-gp substrate/inhibitor. Paritaprevir is a substrate of CYP3A4 and P-gp. Dasabuvir is a substrate of CYP2C8, CYP3A4, and P-gp. Ombitasvir is a P-gp substrate. (Major) Avoid the concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), with ritonavir, a substrate and strong inhibitor of CYP3A4 and a substrate and inhibitor of P-gp; levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and ritonavir 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Omeprazole: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
    Omeprazole; Sodium Bicarbonate: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time. (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
    Ondansetron: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Ondansetron is associated with a possible risk for QT prolongation and torsade de pointes. Additionally, nilotinib is an inhibitor of P-glycoprotein (P-gp), CYP2D6 and CYP3A4 and ondansetron is a P-gp, CYP3A4, and CYP2D6 substrate; administering these drugs together may result in increased ondansetron levels. If the use of ondansetron is required, hold nilotinib therapy. If the use of nilotinib and ondansetron cannot be avoided, an ondansetron dose reduction may be necessary; close monitoring of the QT interval is recommended.
    Osimertinib: (Major) Avoid the concomitant use of nilotinib and osimertinib; significant prolongation of the QT interval may occur. If concomitant use is unavoidable, closely monitor electrolytes and ECGs for QT prolongation; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib.
    Oxaliplatin: (Major) Avoid the concomitant use of nilotinib and oxaliplatin; significant prolongation of the QT interval may occur. If concomitant use is unavoidable, closely monitor electrolytes and ECGs for QT prolongation; correct electrolyte abnormalities prior to administration of oxaliplatin. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have been reported with oxaliplatin use in post-marketing experience.
    Oxycodone: (Moderate) Concomitant use of oxycodone with nilotinib may increase oxycodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of oxycodone until stable drug effects are achieved. Discontinuation of nilotinib could decrease oxycodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to oxycodone. If nilotinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Oxycodone is a substrate for CYP3A4. nilotinib is a moderate inhibitor of CYP3A4.
    Paclitaxel: (Major) Concomitant use of nilotinib, a substrate and moderate inhibitor of CYP3A4 and P-glycoprotein (P-gp) and an inducer and inhibitor of CYP2C8, and paclitaxel, a CYP3A4, Pgp, and CYP28C substrate with a narrow therapeutic range, may result in altered paclitaxel levels. In vivo, nilotinib inhibited CYP2C8-mediated metabolism of paclitaxel. If these agents are used together, monitor these patients closely for paclitaxel toxicity; a paclitaxel dose adjustment may be necessary.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Palonosetron: (Moderate) Nilotinib is a CYP3A4 and CYP2D6 inhibitor and palonosetron is a substrate of CYP3A4 and CYP2D6; administering these drugs together may result in increased palonosetron levels. If these drugs are used together, monitor patients for serotonin-related side effects.
    Panobinostat: (Major) The co-administration of panobinostat with nilotinib is not recommended; QT prolongation has been reported with both agents. Nilotinib is a CYP3A4 inhibitor and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor. Although an initial panobinostat dose reduction is recommended in patients taking concomitant strong CYP3A4 inhibitors, no dose recommendations with mild or moderate CYP3A4 inhibitors are provided by the manufacturer. If concomitant use of nilotinib and panobinostat cannot be avoided, closely monitor electrocardiograms and for signs and symptoms of panobinostat toxicity such as cardiac arrhythmias, diarrhea, bleeding, infection, and hepatotoxicity. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve.
    Pantoprazole: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
    Paricalcitol: (Moderate) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and paricalcitol, a CYP3A4 substrate, may result in increased paricalcitol levels. A paricalcitol dose reduction may be necessary if these drugs are used together.
    Pasireotide: (Major) Avoid the concomitant use of nilotinib and pasireotide; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. QT prolongation has occurred with therapeutic and subtherapeutic doses of pasireotide.
    Pazopanib: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval such as pazopanib. Nilotinib is a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp) and pazopanib is an inhibitor and substrate of CYP3A4 and a substrate of P-gp; nilotinib and/or pazopanib levels may increase. If the use of pazopanib is necessary, hold nilotinib therapy. Monitor patients for toxicity (e.g., QT interval prolongation) if these drugs are used together.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentamidine: (Major) Avoid the concomitant use of nilotinib and pentamidine; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Systemic pentamidine has been associated with QT prolongation.
    Perindopril; Amlodipine: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required.
    Perphenazine: (Minor) QT interval prolongation may be additive if nilotinib and perphenazine are coadministered. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Perphenazine; Amitriptyline: (Minor) QT interval prolongation may be additive if nilotinib and perphenazine are coadministered. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Phenobarbital: (Major) Avoid the concomitant use of nilotinib and phenobarbital; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and phenobarbital is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
    Phenylephrine; Promethazine: (Moderate) QT interval prolongation may be additive if nilotinib and promethazine are coadministered. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Promethazine is associated with a possible risk for QT prolongation.
    Phenytoin: (Major) Avoid the concomitant use of nilotinib and phenytoin; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and phenytoin is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
    Pimavanserin: (Major) Avoid the concomitant use of nilotinib and pimavanserin; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Pimavanserin may also cause QT prolongation.
    Pimozide: (Severe) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because of the potential for TdP, use of nilotinib with pimozide is contraindicated.
    Pirbuterol: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Ponatinib: (Moderate) Concomitant use of ponatinib, a CYP3A4 substrate, and nilotinib, a CYP3A4 inhibitor, may increase the exposure of ponatinib. The manufacturer recommends a reduced starting ponatinib dose when use of a strong CYP3A4 inhibitor cannot be avoided. Additionally, ponatinib may increase the plasma concentration of P-gp substrates, such as nilotinib.
    Posaconazole: (Severe) The concurrent use of posaconazole and nilotinib is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of nilotinib. These drugs used in combination may result in elevated nilotinib plasma concentrations, causing an increased risk for nilotinib-related adverse events, such as QT prolongation. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as nilotinib.
    Primaquine: (Major) Avoid the concomitant use of nilotinib and primaquine; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Primaquine has the potential to prolong the QT interval.
    Primidone: (Major) Avoid the concomitant use of nilotinib and primidone; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and primidone is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
    Procainamide: (Major) Avoid the concomitant use of nilotinib and procainamide; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes.
    Prochlorperazine: (Minor) QT interval prolongation may be additive if nilotinib and prochlorperazine are coadministered. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Prochlorperazine is associated with a possible risk for QT prolongation.
    Promethazine: (Moderate) QT interval prolongation may be additive if nilotinib and promethazine are coadministered. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Promethazine is associated with a possible risk for QT prolongation.
    Propafenone: (Major) Avoid the concomitant use of nilotinib and propafenone; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Proton pump inhibitors: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
    Quazepam: (Moderate) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and quazepam, a CYP3A4 substrate, may result in increased quazepam levels. A quazepam dose reduction may be necessary if these drugs are used together.
    Quetiapine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as quetiapine. Additionally, nilotinib is a moderate inhibitor of CYP3A4 and quetiapine is a substrate of CYP3A4; administering these drugs together may result in increased quetiapine levels. If the use of quetiapine is necessary, hold nilotinib therapy. If these drugs are used together, consider a quetiapine dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Quinidine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval such as quinidine. Additionally, nilotinib is a moderate CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor and quinidine is a CYP3A4 and P-gp substrate with a narrow therapeutic range; administering these drugs together may result in increased quinidine exposure. If the use of quinidine is required, hold nilotinib therapy. If the use of both nilotinib and quinidine cannot be avoided, a quinidine dose reduction may be necessary; close monitoring of the QT interval is recommended.
    Quinine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval such as quinine. Nilotinib is an inhibitor of CYP3A4 and CYP2D6 and an inhibitor and inducer of CYP2C9. Quinine is a substrate, inhibitor, and inducer of CYP3A4, a CYP2D6 substrate and inhibitor, and a CYP2C9 substrate. Administering these drugs together may result in altered levels of either drug. If the use of quinine is required, hold nilotinib therapy. Monitor patients closely for toxicity (e.g., QT interval prolongation) and efficacy if these drugs are used together.
    Rabeprazole: (Major) Avoid the concomitant use of nilotinib and proton pump inhibitors (PPIs), as PPIs may cause a reduction in nilotinib bioavailability. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. PPIs inhibit gastric acid secretion and elevate the gastric pH. Administration of a single 400-mg nilotinib dose with multiple oral doses of esomeprazole 40 mg/day reduced the nilotinib AUC by 34% in a study in healthy subjects. Increasing the dose is unlikely to compensate for the loss of nilotinib exposure; additionally, separating the administration of these agents may not eliminate the interaction as PPIs affect the pH of the upper GI tract for an extended period of time.
    Ranitidine: (Moderate) If concomitant use of these agents is necessary, administer the H2-blocker approximately 10 hours before and approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. The concomitant use of nilotinib and H2-blockers that elevate the gastric pH may reduce the bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when a single 400-mg nilotinib dose was given 10 hours after and 2 hours prior to famotidine.
    Ranolazine: (Severe) Coadministration of nilotinib and ranolazine is contraindicated. First, ranolazine is primarily metabolized by CYP3A4 and is a substrate of P-glycoprotein and of CYP2D6; nilotinib is an inhibitor of CYP3A4, P-glycoprotein (P-gp), and CYP2D6. Ranolazine use is contraindicated with potent inhibitors of CYP3A isoenzymes such as nilotinib. Coadministration would likely increase ranolazine plasma concentrations, thus increasing the risk of drug toxicity and proarrhythmic effects. Second, nilotinib prolongs the QT interval and coadministration with other drugs that prolong the QT interval is not advised; ranolazine is associated with dose and plasma concentration-related increases in the QTc interval. Finally, increased nilotinib concentrations may also occur, as nilotinib is a substrate of CYP3A4 and of P-gp, and ranolazine is an inhibitor of CYP3A4 and of P-gp.
    Regadenoson: (Major) Avoid the concomitant use of nilotinib and regadenoson; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Regadenoson has been associated with QT prolongation,
    Ribociclib: (Major) Avoid coadministration of ribociclib with nilotinib due to an increased risk for QT prolongation. Additionally, the systemic exposure of nilotinib may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Nilotinib is a CYP3A4 substrate that has also been associated with QT prolongation and sudden death. Concomitant use may increase the risk for QT prolongation.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with nilotinib due to an increased risk for QT prolongation. Additionally, the systemic exposure of nilotinib may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Nilotinib is a CYP3A4 substrate that has also been associated with QT prolongation and sudden death. Concomitant use may increase the risk for QT prolongation.
    Rifampin: (Major) Avoid the concomitant use of nilotinib and rifampin; significantly decreased nilotinib exposure was observed in a drug interaction study. Coadministration of these drugs may lead to reduced nilotinib efficacy. Nilotinib is a CYPA4 substrate and rifampin is a strong CYP3A4 inducer. In a drug interaction study, the AUC value of nilotinib was decreased by about 80% following the addition of rifampicin/rifampin 600 mg once daily for 12 days.
    Rilpivirine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as rilpivirine. Nilotinib is a moderate inhibitor of CYP3A4 and rilpivirine is a substrate of CYP3A4; administering these drugs together may result in increased rilpivirine levels. If the use of rilpivirine is necessary, hold nilotinib therapy. If these drugs are used together, consider a rilpivirine dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Risperidone: (Major) Avoid the concomitant use of nilotinib and risperidone; significant prolongation of the QT interval may occur. If coadministration is required and the patient has risk factors for cardiac disease or arrhythmias, careful monitoring is recommended. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Risperidone has been associated with a possible risk for QT prolongation and/or TdP. Reports of QT prolongation and TdP during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting.
    Ritonavir: (Major) Avoid the concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), with ritonavir, a substrate and strong inhibitor of CYP3A4 and a substrate and inhibitor of P-gp; levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and ritonavir 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Romidepsin: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as romidepsin. Nilotinib is a moderate inhibitor of CYP3A4 and romidepsin is a substrate of CYP3A4; administering these drugs together may result in increased romidepsin levels. If the use of romidepsin is necessary, hold nilotinib therapy. If these drugs are used together, consider a romidepsin dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Salmeterol: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Pharmacokinetic interactions may occur with some LABAs.
    Saquinavir: (Severe) The concurrent use of nilotinib and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening cardiac arrhythmias such as torsades de pointes (TdP). Both saquinavir boosted with ritonavir and nilotinib are inhibitors and substrates of the hepatic isoenzyme CYP3A4. Further, nilotinib is an inhibitor of P-glycoprotein, for which saquinavir is a substrate. This complex interaction may ultimately result in elevated plasma concentrations of both nilotinib and saquinavir, thus increasing the risk of drug toxicity and proarrhythmic effects. Additionally, saquinavir boosted with ritonavir causes dose-dependent QT and PR prolongation; avoid use with other drugs that may prolong the QT or PR interval, such as nilotinib.
    Sertraline: (Major) Avoid the concomitant use of nilotinib and sertraline; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have occurred in patients who received nilotinib therapy. QT prolongation and torsade de pointes have been reported in postmarketing surveillance of sertraline.
    Sevoflurane: (Major) Avoid the concomitant use of nilotinib and halogenated anesthetics; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Additionally, fatal cases of torsade de pointes have been reported with halogenated anesthetic use.
    Short-acting beta-agonists: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Sildenafil: (Moderate) Monitor for an increase in sildenafil-related adverse reactions if coadministration with nilotinib is necessary; a dose reduction of sildenafil may be necessary when prescribed for erectile dysfunction. Sildenafil is a sensitive CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor.
    Sirolimus: (Major) The concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), with sirolimus, a P-gp and CYP3A4 substrate with a narrow therapeutic range, may result in increased sirolimus levels. A sirolimus dose reduction may be necessary if these drugs are used together.
    Sodium Bicarbonate: (Moderate) If concomitant use of these agents is necessary, administer the antacid approximately 2 hours before or approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH; therefore, concomitant use of nilotinib and antacids may result in decreased bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when an antacid (aluminum hydroxide/magnesium hydroxide/simethicone) was administered approximately 2 hours before or approximately 2 hours after a single 400-mg nilotinib dose.
    Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of velpatasvir with nilotinib. Taking these drugs together may significantly alter the plasma concentrations of velpatasvir, potentially resulting in loss of antiviral efficacy or adverse effects. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); nilotinib is a P-gp inhibitor. Velpatasvir is also a substrate for CYP2B6, CYP3A4, and CYP2C8; nilotinib is an inducer of CYP2B6, an inhibitor of CYP3A4, and an inhibitor/inducer of CYP2C8.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of velpatasvir with nilotinib. Taking these drugs together may significantly alter the plasma concentrations of velpatasvir, potentially resulting in loss of antiviral efficacy or adverse effects. Velpatasvir is a substrate of the drug transporter P-glycoprotein (P-gp); nilotinib is a P-gp inhibitor. Velpatasvir is also a substrate for CYP2B6, CYP3A4, and CYP2C8; nilotinib is an inducer of CYP2B6, an inhibitor of CYP3A4, and an inhibitor/inducer of CYP2C8. (Moderate) Plasma concentrations of nilotinib, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with voxilaprevir, a P-gp inhibitor. Monitor patients for increased side effects if these drugs are administered concurrently.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and nilotinib; sonidegib exposure may be significantly increased resulting in increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A substrate and nilotinib is a moderate CYP3A4 inhibitor. Physiologic-based pharmacokinetic (PBPK) simulations indicate a moderate 3A4 inhibitor would increase the sonidegib AUC by 1.8-fold if administered for 14 days and by 2.8-fold if the moderate CYP3A inhibitor is administered with sonidegib for more than 14 days.
    Sorafenib: (Major) Avoid the concomitant use of nilotinib and sorafenib tosylate; significant prolongation of the QT interval may occur. If concomitant use is unavoidable, monitor ECGs for QT prolongation. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Sorafenib has been associated with QT prolongation.
    Sotalol: (Major) Avoid the concomitant use of nilotinib and sotalol; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have occurred in patients who received nilotinib therapy. Sotalol administration is associated with QT prolongation and torsades de pointes. Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
    St. John's Wort, Hypericum perforatum: (Major) Avoid the concomitant use of nilotinib and St. John's Wort; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and St. John's Wort is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
    Streptogramins: (Major) Avoid the concomitant use of nilotinib, a CYP3A4 substrate, with dalfopristin; quinupristin, a strong CYP3A4 inhibitor; nilotinib levels may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and dalfopristin; quinupristin 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Sufentanil: (Major) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and sufentanil, a CYP3A4 substrate with a narrow therapeutic range, may result in increased sufentanil levels. A sufentanil dose reduction may be necessary if these drugs are used together and close monitoring for oversedation, respiratory depression, and hypotension is warranted.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Avoid the concomitant use of nilotinib and sulfamethoxazole; trimethoprim because significant prolongation of the QT interval may occur. Sudden death and QT prolongation have occurred in patients who received nilotinib therapy. QT prolongation resulting in ventricular tachycardia and torsade de pointes have been reported during post-marketing use of sulfamethoxazole; trimethoprim.
    Sunitinib: (Major) Avoid the concomitant use of nilotinib and sunitinib; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have occurred in patients who received nilotinib therapy. Sunitinib can cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including torsades de points.
    Suvorexant: (Major) A dose reduction to 5 mg of suvorexant is recommended during concurrent use with nilotinib. The suvorexant dose may be increased to 10 mg if needed for efficacy. Suvorexant is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased the suvorexant AUC by 2-fold.
    Tacrolimus: (Major) Nilotinib and tacrolimus both prolong the QT interval. Additionally, tacrolimus is metabolized by CYP3A4 and nilotinib inhibits this isoenzyme. Coadministration of nilotinib and a drug that prolongs the QT interval is not advised, as nilotinib prolongs the QT interval. If concurrent administration with tacrolimus is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation. The manufacturer of tacrolimus advises reducing the tacrolimus dose, close monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation when coadministrating tacrolimus with other substrates and/or inhibitors of CYP3A4 that also have the potential to prolong the QT interval such as nilotinib. Tacrolimus concentrations and thus other adverse reactions may also be increased during concomitant administration.
    Tadalafil: (Moderate) Concomitant use of nilotinib, an moderate CYP3A4 inhibitor, and tadalafil, a CYP3A4 substrate, may result in increased tadalafil levels. A tadalafil dose reduction may be necessary if these drugs are used together.
    Tamoxifen: (Major) Avoid coadministration of tamoxifen with nilotinib due to an increased risk of QT prolongation; increased nilotinib and tamoxifen exposure and reduced tamoxifen efficacy are also possible. If interruption of treatment with nilotinib is not possible, closely monitor for evidence of QT prolongation, increased nilotinib and tamoxifen side effects, and decreased tamoxifen efficacy during concurrent use. Nilotinib prolongs the QT interval. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Nilotinib may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2D6, CYP3A4, and CYP2C9. In a clinical trial, there was a significantly higher rate of breast cancer recurrence in patients who had received a CYP2D6 inhibitor with tamoxifen. In another observational study, no clinically significant differences were observed with the addition of a CYP2D6 inhibitor to tamoxifen therapy; however, only 215 patients of 1,990 were administered a CYP2D6 inhibitor. Tamoxifen may also increase exposure to nilotinib via inhibition of P-glycoprotein (P-gp).
    Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and nilotinib. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as nilotinib, may increase exposure to tasimelteon with the potential for adverse reactions.
    Telavancin: (Major) Avoid the concomitant use of nilotinib and telavancin; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have occurred in patients who received nilotinib therapy. Telavancin has been associated with QT prolongation.
    Telithromycin: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Telithromycin has a causal association with QT prolongation and torsade de pointes. Additionally, nilotinib is a CYP3A4 inhibitor and a substrate and inhibitor of P-glycoprotein (P-gp) and telithromycin is a substrate and a strong inhibitor of CYP3A4 and a P-gp inhibitor; nilotinib and/or telithromycin levels may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and telithromycin 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and nilotinib is necessary, as the systemic exposure of nilotinib may be decreased resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of nilotinib as well as an increase in adverse reactions related to telotristat ethyl. Consider increasing the dose of nilotinib if necessary. Nilotinib is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. In healthy subjects receiving a strong CYP3A4 inducer, systemic exposure to nilotinib was decreased approximately 80%. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and nilotinib is a P-gp inhibitor. Exposure to telotristat ethyl may increase.
    Teniposide: (Major) Concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), and teniposide, a P-gp and CYP3A4 substrate with a narrow therapeutic range, may result in increased teniposide levels. A teniposide dose reduction may be necessary if these drugs are used together.
    Terbutaline: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
    Tetrabenazine: (Major) Avoid the concomitant use of nilotinib and tetrabenazine; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have occurred in patients who received nilotinib therapy. Tetrabenazine causes a small increase in the corrected QT interval.
    Tezacaftor; Ivacaftor: (Major) Adjust the tezacaftor; ivacaftor dosing schedule when coadministered with nilotinib; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor 100 mg/ivacaftor 150 mg tablet every other day in the morning and 1 ivacaftor 150 mg tablet every other day in the morning on alternate days (i.e., tezacaftor/ivacaftor tablet on Day 1 and ivacaftor tablet on Day 2). The evening dose of ivacaftor 150 mg should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); nilotinib is a moderate CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased ivacaftor exposure 3-fold. Simulation suggests a moderate inhibitor may increase tezacaftor exposure 2-fold.
    Thioridazine: (Severe) Nilotinib prolongs the QT interval. Because of the potential for torsade de pointes, use of thioridazine with nilotinib is contraindicated.
    Tiotropium; Olodaterol: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Pharmacokinetic interactions may occur with some LABAs.
    Tipranavir: (Major) Avoid the concomitant use of nilotinib, a substrate and inhibitor of CYP3A4, with tipranavir, a substrate and strong inhibitor of CYP3A4; levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and tipranavir 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Tizanidine: (Major) Avoid the concomitant use of nilotinib and telavancin; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have occurred in patients who received nilotinib therapy. Additionally, tizanidine administration may result in QT prolongation.
    Tolterodine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. Nilotinib is an inhibitor of CYP3A4 and CYP2D6 and tolterodine is a CYP3A4 and CYP2D6 substrate; administering these drugs together may result in increased tolterodine levels. If the use of tolterodine is required, hold nilotinib therapy. If the use of nilotinib and tolterodine cannot be avoided, a tolterodine dose reduction may be necessary; close monitoring of the QT interval is recommended.
    Tolvaptan: (Major) Avoid coadministration of nilotinib when tolvaptan is administered for hyponatremia. In patients with autosomal dominant polycystic kidney disease (ADPKD), reduce tolvaptan dosage if administered with nilotinib. In ADPKD patients receiving tolvaptan 90mg every morning and 30 mg every evening, reduce the dose to 45 mg every morning and 15 mg every evening; for those receiving tolvaptan 60 mg every morning and 30 mg every evening, reduce the dose to 30 mg every morning and 15 mg every evening; for those receiving tolvaptan 45 mg every morning and 15 mg every evening, reduce the dose to 15 mg every morning and 15 mg every evening. Consider additional dosage reduction if the reduced dose is not tolerated. Tolvaptan is a sensitive CYP3A4 substrate; nilotinib is a moderate CYP3A4 inhibitor. Coadministration of another moderate CYP3A4 inhibitor increased the tolvaptan AUC by 200%.
    Toremifene: (Major) Avoid coadministration of nilotinib with toremifene due to the risk of additive QT prolongation. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy. Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Trabectedin: (Moderate) Use caution if coadministration of trabectedin and nilotinib is necessary, due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and nilotinib is a moderate CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), a strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone. The manufacturer of trabectedin recommends avoidance of strong CYP3A inhibitors within 1 day before and 1 week after trabectedin administration; there are no recommendations for concomitant use of moderate or weak CYP3A inhibitors.
    Tramadol: (Major) The concomitant use of nilotinib and tramadol may reduce the clearance of tramadol and increase the risk for serious adverse events including seizures and serotonin syndrome. If coadministration of these drugs is required, consider reducing the dose of tramadol and monitor patients for signs of toxicity. Nilotinib is a moderate CYP3A4 inhibitor and tramadol is a CYP3A4 substrate.
    Trandolapril; Verapamil: (Moderate) The concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), and verapamil, a substrate and inhibitor of CYP3A4 and a P-gp inhibitor, may result in increased nilotinib and/or verapamil levels. A nilotinib and/or verapamil dose reduction may be necessary if these drugs are used together. Monitor patients for nilotinib and/or verapamil toxicity (e.g., QT interval prolongation, hypotension) if these drugs are used together.
    Trazodone: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Trazodone can prolong the QT interval at therapeutic doses, and torsade de pointes (TdP) has been reported with post-marketing use. Additionally, nilotinib is a moderate CYP3A4 inhibitor and trazodone is a CYP3A4 substrate; administering these drugs together may result in increased trazodone levels. If the use of trazodone is required, hold nilotinib therapy. If the use of nilotinib and trazodone cannot be avoided, a trazodone dose reduction may be necessary; close monitoring of the QT interval is recommended.
    Triazolam: (Moderate) Concomitant use of nilotinib, a moderate CYP3A4 inhibitor, and triazolam, a CYP3A4 substrate, may result in increased triazolam levels. If coadministration is not avoidable, then a triazolam dose reduction may be necessary.
    Tricyclic antidepressants: (Minor) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Tricyclic antidepressants, when given in excessive doses or overdosage, may have a causal association with QT prolongation and torsade de pointes (TdP). Additionally, nilotinib is an inhibitor of CYP3A4 and CYP2D6 and tricyclic antidepressants are substrates of CYP3A4 and CYP2D6; administering these drugs together may result in increased tricyclic antidepressants levels. If the use of a tricyclic antidepressant is required, hold nilotinib therapy. If the use of nilotinib and a tricyclic antidepressant cannot be avoided, the tricyclic antidepressant dose reduction may be necessary; close monitoring of the QT interval is recommended.
    Trifluoperazine: (Minor) QT interval prolongation may be additive if nilotinib and trifluoperazine are coadministered. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Trifluoperazine is associated with a possible risk of QT prolongation.
    Triptorelin: (Major) Avoid the concomitant use of nilotinib and triptorelin pamoate; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Androgen deprivation therapy, such as triptorelin, may cause QT prolongation.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Umeclidinium; Vilanterol: (Minor) Nilotinib prolongs the QT interval. Coadministration of nilotinib and other drugs that prolong the QT interval, is not advised. The manufacturer recommends interruption of nilotinib treatment as a possible alternative. If concurrent administration is unavoidable, closely monitor the patient for QT interval prolongation. Drugs that should be used with caution with nilotinib include the long-acting beta-agonists (LABAs). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Pharmacokinetic interactions may occur with some LABAs.
    Vandetanib: (Major) Avoid the concomitant use of nilotinib and vandetanib; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have occurred in patients who received nilotinib therapy. Vandetanib can prolong the QT interval in a concentration-dependent manner. Torsade de pointes and sudden death have been reported in patients receiving vandetanib. If coadministration is necessary, an ECG is needed, as well as more frequent monitoring of the QT interval.
    Vardenafil: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as vardenafil. Additionally, nilotinib is a moderate CYP3A4 inhibitor and vardenafil is a CYP3A4 substrate; administering these drugs together may result in increased vardenafil levels. If the use of vardenafil is required, hold nilotinib therapy. If the use of nilotinib and vardenafil cannot be avoided, a vardenafil dose reduction may be necessary; close monitoring of the QT interval is recommended.
    Vemurafenib: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval such as vemurafenib. Nilotinib is a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp) and vemurafenib is a CYP3A4 substrate and an inhibitor and substrate of P-gp; nilotinib and/or vemurafenib levels may increase. If the use of vemurafenib is necessary, hold nilotinib therapy. Monitor patients for toxicity (e.g., QT interval prolongation) if these drugs are used together.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and nilotinib. Venetoclax is a substrate of CYP3A4 and P-glycoprotein (P-gp) and a P-gp inhibitor; nilotinib is a CYP3A4 and P-gp inhibitor and a P-gp substrate. Consider alternative agents. If concomitant use of these drugs is required, reduce the venetoclax dosage by at least 50% (maximum dose of 200 mg/day) and consider administering nilotinib at least 6 hours before venetoclax. If nilotinib is discontinued, wait 2 to 3 days and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were increased by 106% and 78%, respectively, when a P-gp inhibitor was coadministered in healthy subjects.
    Venlafaxine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as venlafaxine. Nilotinib is a CYP3A4 and CYP2D6 inhibitor and venlafaxine is a substrate of CYP3A4 and CYP2D6; administering these drugs together may result in increased venlafaxine levels. If the use of venlafaxine is necessary, hold nilotinib therapy. If these drugs are used together, consider a venlafaxine dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Verapamil: (Moderate) The concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), and verapamil, a substrate and inhibitor of CYP3A4 and a P-gp inhibitor, may result in increased nilotinib and/or verapamil levels. A nilotinib and/or verapamil dose reduction may be necessary if these drugs are used together. Monitor patients for nilotinib and/or verapamil toxicity (e.g., QT interval prolongation, hypotension) if these drugs are used together.
    Vinblastine: (Major) Concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), and vinblastine, a P-gp and CYP3A4 substrate with a narrow therapeutic range, may result in increased vinblastine levels. A vinblastine dose reduction may be necessary if these drugs are used together.
    Vincristine Liposomal: (Major) Concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), and vincristine, a P-gp and CYP3A4 substrate with a narrow therapeutic range, may result in increased vincristine levels. A vincristine dose reduction may be necessary if these drugs are used together.
    Vincristine: (Major) Concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), and vincristine, a P-gp and CYP3A4 substrate with a narrow therapeutic range, may result in increased vincristine levels. A vincristine dose reduction may be necessary if these drugs are used together.
    Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with nilotinib is necessary. Vinorelbine is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor.
    Voriconazole: (Major) Avoid the concomitant use of nilotinib and voriconazole due to the potential for additive effects on the QT interval and increased exposure to both nilotinib and voriconazole. Nilotinib is a substrate and inhibitor of CYP3A4 and an inducer and inhibitor of CYP2C9. Voriconazole is a substrate and strong inhibitor of CYP3A4 and substrate and inhibitor of CYP2C9. Nilotinib and/or voriconazole levels may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and voriconazole 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 the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
    Vorinostat: (Major) Avoid the concomitant use of nilotinib and vorinotat; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have been reported in patients who received nilotinib therapy. Vorinostat therapy is associated with a risk of QT prolongation.
    Warfarin: (Moderate) Concomitant use of nilotinib, a CYP3A4 inhibitor and a CYP2C9 inducer and inhibitor, and warfarin, a CYP3A4 and CYP2C9 substrate with a narrow therapeutic range, does not appear to change the pharmacokinetics (Cmax, AUC values) or pharmacodynamics (PT/INR values) of warfarin. A cross-over study examined the effect of administering a single oral dose of warfarin 25 mg with a single oral dose of nilotinib 800 mg or matched placebo 30 minutes after a high-fat meal in 24 healthy volunteers (extensive CYP2C9 metabolizer, n =16; intermediate CYP2C9 metabolizer, n = 8). No significant difference occurred in warfarin Cmax or AUC values and PT and INR values in subjects who received warfarin plus nilotinib compared with subjects who received warfarin plus placebo. If nilotinib and warfarin are used together, monitor INR and PT values and for symptoms of warfarin toxicity; adjust the warfarin dose as necessary.
    Zafirlukast: (Major) The concomitant use of nilotinib, a substrate and inhibitor of CYP3A4, and zafirlukast, a CYP3A4 inhibitor, may result in increased nilotinib levels. Monitor patients for nilotinib toxicity (e.g., QT interval prolongation) if these drugs are used together.
    Ziprasidone: (Severe) According to the manufacturer, ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsades de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation. In one study, ziprasidone increased the QT interval 10 msec more than placebo at the maximum recommended dosage. Comparative data with other antipsychotics have shown that the mean QTc interval prolongation occurring with ziprasidone exceeds that of haloperidol, quetiapine, olanzapine, and risperidone, but is less than that which occurs with thioridazine. Given the potential for QT prolongation, ziprasidone is contraindicated for use with drugs that are known to cause QT prolongation with potential for torsades de pointes including nilotinib.
    Zolpidem: (Moderate) It is advisable to closely monitor zolpidem tolerability and safety during concurrent use of nilotinib, a moderate CYP3A4 inhibitor, since CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism. There is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem when the drug is co-administered with some potent inhibitors of CYP3A4, such as azole antifungals. Concurrent administration of nilotinib and midazolam, a CYP3A4 substrate, increased midazolam exposure by 30%.

    PREGNANCY AND LACTATION

    Pregnancy

    Nilotinib may cause fetal harm when administered during pregnancy, based on its mechanism of action and animal studies. Females of reproductive potential should avoid pregnancy during and after treatment. Discuss the potential hazard to the fetus if nilotinib is used during pregnancy or if a patient becomes pregnant while taking this drug. In animals studies, embryo-fetal toxicities including skeletal variations (e.g., incomplete ossification, fused sternebra), cleft palate, and dilated ureters and small renal papilla were observed following nilotinib administration during organogenesis at doses that resulted in drug exposures approximately 0.5-times (rabbits) and 2-times (rats) the exposures achieved at the highest recommended human dose.

    It is not known if nilotinib or its metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in nursing infants, women should discontinue breast-feeding during nilotinib therapy and for 14 days after the last dose.

    MECHANISM OF ACTION

    Mechanism of Action: Chronic myelogenous leukemia is a myeloproliferative disorder caused by the reciprocal translocation of chromosomes 9 and 22 (t 9,22), which is also known as the Philadelphia Chromosome. The Philadelphia Chromosome combines the breakpoint cluster region (BCR) of chromosome 22 and the active tyrosine kinase portion of the Abelson murine leukemia (ABL) gene from chromosome 9. Nilotinib is an oral tyrosine kinase inhibitor designed to selectively inhibit the BCR-ABL tyrosine kinase. Nilotinib is a competitive inhibitor at the ATP-binding site of BCR-ABL and prevents tyrosine phosphorylation of downstream intracellular signal transduction proteins. Like imatinib and dasatinib, nilotinib binds to an inactive portion of the ABL kinase domain and prevents the enzyme from converting to its catalytically active conformation. Blocking the tyrosine kinase prevents proliferation of BCR-ABL cells and induces apoptosis.Changes in the BCR-ABL protein such as point mutations and binding site conformation changes are a source of drug resistant disease. Nilotinib is active in 32 of 33 imatinib-resistant BCR-ABL mutant cell lines; the exception is the T315I mutation. Unlike imatinib and dasatinib, nilotinib is selective for ABL kinase over KIT and PDGF receptor kinases and the Src-family of kinases. In addition, nilotinib enhances binding site affinity by offering alternate binding groups while continuing to bind the inactive conformation binding site of the ABL tyrosine kinase. The increased kinase selectivity and binding site affinity make nilotinib 30 times more potent than imatinib in imatinib-sensitive CML cell lines and 3—7 times more potent in imatinib-resistant CML cell lines.

    PHARMACOKINETICS

    Nilotinib is administered orally. It is approximately 98% protein bound in serum; the blood to serum ratio is 0.68. Nilotinib is metabolized via oxidation by CYP3A4 (major) and CYP2C8 (minor) isoenzymes in the liver; no active metabolites have been identified. The elimination half-life of nilotinib is approximately 17 hours (coefficient of variation (CV), 69%) and the mean apparent clearance is about 29 L/hour (CV, 61%). Following a single radiolabeled nilotinib dose, 93% of the dose was eliminated mainly in the feces within 7 days, and parent drug accounted for 69% of the dose.
     
    Affected cytochrome P450 isoenzymes and transporters: CYP3A4, CYP2C8, P-gp
    Nilotinib is a moderately sensitive substrate of CYP3A4 and a moderate CYP3A4 inhibitor. Concomitant administration with strong CYP3A4 inhibitors or inducers may increase or decrease nilotinib concentrations significantly. In vitro, nilotinib is an inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, P-glycoprotein (P-gp) and UGT1A1 and induces CYP2B6 and CYP2C8. Additionally, nilotinib is a substrate and P-gp in vitro. Coadministration of nilotinib and warfarin, a CYP2C9 substrate, did not alter the pharmacokinetic parameters of warfarin in a single-dose drug interaction study.

    Oral Route

    The relative bioavailability of nilotinib capsules is approximately 50% compared with an oral drink solution. However, a single dose of two 200-mg nilotinib capsules (each dispersed in 1 teaspoon of applesauce and administered within 15 minutes) was bioequivalent to a single dose of two 200-mg intact capsules. The steady-state nilotinib exposure is dose-dependent and exhibits less than dose-proportional increases in systemic exposure at dosages higher than 400 mg once or twice daily. The increase in nilotinib exposure between the first dose and steady state is about 2-fold for daily dosing and 3.8-fold for twice daily dosing. The Tmax is reached at 3 hours after oral administration. Following the administration of nilotinib 400 mg PO twice daily, the steady-state mean Cmax and AUC(0-12 hr) values were 2,260 ng/mL (coefficient of variation (CV), 35%) and 18,000 ng X hour/mL (CV, 33%), respectively, in adults with resistant or intolerant chronic myelogenous leukemia (CML). Following the administration of nilotinib 300 mg PO twice daily, the steady-state mean Cmax and AUC(0-12 hr values were 1,540 ng/mL (CV, 48%) and 13,337 ng X hour/mL (CV, 46%), respectively, in adults with newly diagnosed CML. Steady-state concentrations are achieved by day 8.
     
    Effect of Food: The bioavailability of nilotinib is significantly increased by food. The AUC value was increased 82% when nilotinib was taken 30 minutes prior to a high-fat meal (800 to 1,000 calories with 50% of total caloric content as fat) compared with the fasted state.