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  • CLASSES

    Protein Kinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Nilotinib is a selective oral tyrosine kinase inhibitor, FDA-approved for Ph+ CML.

    COMMON BRAND NAMES

    Tasigna

    HOW SUPPLIED

    Tasigna Oral Cap: 150mg, 200mg

    DOSAGE & INDICATIONS

    For the treatment of Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML).
    NOTE: If clinically indicated, nilotinib may be given with hydroxyurea, anagrelide, or hematopoietic growth factors.
    Obtain an electrocardiogram at baseline, 7 days after initiation, and periodically thereafter including approximately 7 days after any dose adjustment.
    For the treatment of chronic phase and 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. Continue treatment until disease progression or unacceptable toxicity occurs. Avoid the concomitant use of strong CYP3A4 inhibitors or inducers. 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 major cytogenic response rate (primary end point) of 59% in patients with Philadelphia chromosome–positive chronic phase chronic myelogenous leukemia (CP-CML; n = 321) and a hematologic response rate (primary end point) of 55% in patients with Ph+ accelerated phase CML (AP-CML; n = 137) in a multicenter, single-arm trial.

    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. Continue treatment until disease progression or unacceptable toxicity occurs. Avoid the concomitant use of strong CYP3A4 inhibitors or inducers. Temporary interruption of therapy and/or a dosage reduction may be necessary in patients who develop toxicity or intolerable side effects. 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. Additionally, the MMR rate continued to be higher in patients who received nilotinib therapy (77% vs. 60%).

    MAXIMUM DOSAGE

    Adults

    800 mg/day PO given as 400 mg PO every 12 hours.

    Elderly

    800 mg/day PO given as 400 mg PO every 12 hours.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline hepatic impairment:
    NOTE: Consider alternative therapies in patients with hepatic impairment. If nilotinib treatment is warranted, a lower starting dose is recommended and the QT interval should be monitored closely.
    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 hepatotoxicity in patients with newly diagnosed or resistant/intolerant Ph+ CML:
    Grade 3 or higher bilirubin or transaminase level elevations during therapy: Hold nilotinib. Once toxicity is resolved to grade 1 or less, resume nilotinib at 400 mg PO once daily. Monitor liver function tests monthly or as clinically indicated.

    Renal Impairment

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

    ADMINISTRATION

    Oral Administration

    Administer 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. Separate doses by approximately 12 hours.

    Oral Solid Formulations

    Capsules should be swallowed intact and whole. If the whole capsule cannot be swallowed, the capsule contents may be dispersed in 1 teaspoon of applesauce. The mixture must be consumed 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, QT prolongation, thyroid disease

    Concentration-dependent QT prolongation and prolonged cardiac ventricular repolarization possibly leading to sudden cardiac death 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 co-administration 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 > 480 milliseconds; additionally, a nilotinib dosage adjustment and/or therapy discontinuation may be necessary.

    Hepatic disease

    Hepatotoxicity (e.g., elevated hepatic enzymes (AST/ALT), hyperbilirubinemia, and increased alkaline phosphatase levels) has been reported with nilotinib therapy. 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.

    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.

    Females, pregnancy

    Nilotinib is classified as FDA pregnancy risk category D. Fetal harm may occur if nilotinib is administered to pregnant women, based on animal studies. Females of reproductive potential should avoid becoming pregnant and should be instructed to utilize effective contraceptive methods during nilotinib therapy. Woman who become pregnant while receiving nilotinib should be apprised of the potential hazard to the fetus. Embryo-fetal toxicity reported in pregnant rats at nilotinib doses that achieved higher exposure (AUC) observed with recommended human doses of 400 mg twice daily included increased resorption and post-implantation loss (at doses of >= 30 mg/kg/day; AUC about 2X higher than human dosage) and decrease in viable fetuses (at doses of 100 mg/kg/day; AUC about 5.7X higher than human dosage). In pregnant rabbits, increased resorption and minor skeletal abnormalities were observed with nilotinib doses of 300 mg/kg/day (AUC about on half of the human dosage).

    Breast-feeding

    According to the manufacturer, nilotinib or breast-feeding should be discontinued because of the potential for serious adverse reactions in nursing infants from nilotinib. It is not known if nilotinib is excreted into human milk. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    The safety and efficacy of nilotinib in neonates, infants, children, and adolescents has not been established.

    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.

    ADVERSE REACTIONS

    Severe

    thrombocytopenia / Delayed / 10.0-42.0
    neutropenia / Delayed / 12.0-42.0
    anemia / Delayed / 4.0-27.0
    hypophosphatemia / Delayed / 8.0-17.0
    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
    hyperbilirubinemia / Delayed / 4.0-9.0
    hypokalemia / Delayed / 0-9.0
    hyponatremia / Delayed / 0-7.0
    hypocalcemia / Delayed / 0-5.0
    hypoalbuminemia / Delayed / 3.0-4.0
    elevated hepatic enzymes / Delayed / 1.0-4.0
    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
    GI bleeding / Delayed / 0.1-2.9
    nausea / Early / 0-2.0
    hypertension / Early / 0-2.0
    dyspnea / Early / 2.0-2.0
    rash (unspecified) / 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 / 0-1.1
    constipation / Delayed / 0-1.0
    dyspepsia / Early / 0-1.0
    anorexia / Delayed / 0-1.0
    vomiting / Early / 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
    infection / Delayed / 0-1.0
    pharyngitis / Delayed / 0-1.0
    musculoskeletal pain / Early / 0-1.0
    dizziness / Early / 0-1.0
    stroke / Early / 0.1-1.0
    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
    GI perforation / Delayed / 0-0.1
    peptic ulcer / 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
    erythema nodosum / Delayed / 0-0.1
    skin atrophy / Delayed / 0-0.1
    erythema multiforme / Delayed / 0-0.1
    cerebral edema / Early / 0-0.1
    optic neuritis / Delayed / 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

    hypercholesterolemia / Delayed / 1.0-28.0
    hypertriglyceridemia / Delayed / 1.0-12.0
    lymphopenia / Delayed / 1.0-10.0
    leukopenia / Delayed / 1.0-10.0
    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
    stomatitis / Delayed / 0.1-1.0
    oral ulceration / Delayed / 0.1-1.0
    melena / Delayed / 0.1-1.0
    gastritis / Delayed / 0.1-1.0
    hypothyroidism / Delayed / 0.1-1.0
    hyperthyroidism / Delayed / 0.1-1.0
    jaundice / Delayed / 0.1-1.0
    hepatitis / 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
    psoriasis / Delayed / 0-0.1
    skin ulcer / Delayed / 0-0.1
    cholestasis / Delayed / 0-0.1
    hepatomegaly / 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
    flatulence / Early / 1.0-10.0
    dysgeusia / 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
    urticaria / Rapid / 1.0-10.0
    hyperhidrosis / Delayed / 1.0-10.0
    flushing / Rapid / 1.0-10.0
    acne vulgaris / Delayed / 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
    xerostomia / Early / 0.1-1.0
    gastroesophageal reflux / Delayed / 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
    petechiae / Delayed / 0-0.1
    skin hyperpigmentation / Delayed / 0-0.1
    hyperkeratosis / Delayed / 0-0.1
    photosensitivity / 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

    Abciximab: (Moderate) Nilotinib can cause thrombocytopenia. Cautious use of nilotinib is warranted in patients receiving concomitant platelet inhibitors.
    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) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of codeine. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as codeine.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Nilotinib is an inhibitor of CYP3A4 and 2D6. Dextromethorphan is a CYP2D6 and CYP3A4 substrate. Administering these drugs together may result in increased dextromethorphan levels. A dextromethorphan dose reduction may be necessary if these drugs are used together.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Nilotinib is an inhibitor of CYP3A4 and 2D6. Dextromethorphan is a CYP2D6 and CYP3A4 substrate. Administering these drugs together may result in increased dextromethorphan levels. A dextromethorphan dose reduction may be necessary if these drugs are used together.
    Acetaminophen; Codeine: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of codeine. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as codeine.
    Acetaminophen; Dextromethorphan: (Moderate) Nilotinib is an inhibitor of CYP3A4 and 2D6. Dextromethorphan is a CYP2D6 and CYP3A4 substrate. Administering these drugs together may result in increased dextromethorphan levels. A dextromethorphan dose reduction may be necessary if these drugs are used together.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Nilotinib is an inhibitor of CYP3A4 and 2D6. Dextromethorphan is a CYP2D6 and CYP3A4 substrate. Administering these drugs together may result in increased dextromethorphan levels. A dextromethorphan dose reduction may be necessary if these drugs are used together.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Nilotinib is an inhibitor of CYP3A4 and 2D6. Dextromethorphan is a CYP2D6 and CYP3A4 substrate. Administering these drugs together may result in increased dextromethorphan levels. A dextromethorphan dose reduction may be necessary if these drugs are used together.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Nilotinib is an inhibitor of CYP3A4 and 2D6. Dextromethorphan is a CYP2D6 and CYP3A4 substrate. Administering these drugs together may result in increased dextromethorphan levels. A dextromethorphan dose reduction may be necessary if these drugs are used together.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Nilotinib is an inhibitor of CYP3A4 and 2D6. Dextromethorphan is a CYP2D6 and CYP3A4 substrate. Administering these drugs together may result in increased dextromethorphan levels. A dextromethorphan dose reduction may be necessary if these drugs are used together.
    Acetaminophen; Hydrocodone: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of hydrocodone. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as hydrocodone.
    Acetaminophen; Oxycodone: (Major) Concomitant use of nilotinib, a CYP3A4 and CYP2D6 inhibitor, and oxycodone, a CYP3A4 and CYP2D6 substrate, may result in increased oxycodone levels. If these drugs are used together, consider an oxycodone dose reduction and monitor patients for toxicity (e.g., sedation, respiratory depression).
    Acetaminophen; Propoxyphene: (Moderate) Propoxyphene is a substrate of CYP2D6. Nilotinib is an inhibitor of CYP2D6. Increased propoxyphene concentrations may occur if nilotinib and propoxyphene are concurrently used; exercise caution.
    Acetaminophen; Tramadol: (Moderate) Tramadol is a substrate of CYP2D6 and CYP3A4. Nilotinib is a competitive inhibitor of CYP3A4 and CYP2D6. As the analgesic activity of tramadol is due to both the parent drug and O-desmethyltramadol (M1), inhibition of CYP2D6 may affect analgesic effects; reduced analgesic effects are possible. Increased serum concentrations of tramadol and reduced serum concentrations of M1 would be expected from concurrent use of tramadol and a CYP2D6 inhibitor and/or CYP3A4 inhibitor. The risk for serious adverse effects such as seizures and serotonin syndrome may be increased. Caution should be exercised when coadministering nilotinib with CYP3A4 and CYP2D6 substrates; a tramadol dose reduction may be necessary. Monitor patients closely for tramadol toxicity and efficacy if these drugs are used together.
    Afatinib: (Major) If the concomitant use of nilotinib and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of nilotinib. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and nilotinib is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of another P-gp inhibitor, ritonavir (200 mg twice daily for 3 days), 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise.
    Albuterol: (Minor) 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. Additionally, indacaterol is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate, and nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp. Increased concentrations of indacaterol are likely if it is coadministered with nilotinib.
    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. Additionally, indacaterol is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate, and nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp. Increased concentrations of indacaterol are likely if it is coadministered with nilotinib.
    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.
    Alosetron: (Moderate) Concomitant use of nilotinib, a CYP3A4 inhibitor and a CYP2C9 inhibitor and inducer, and alosetron, a CYP2C9 and CYP3A4 substrate, may result in altered levels of alosetron. Monitor patients closely for alosetron toxicity and efficacy if these drugs are used together.
    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) Coadministration of nilotinib with amiodarone should be avoided. First, amiodarone is established to have a causal association with QT prolongation and torsade de pointes (TdP). Coadministration of nilotinib and a drug that prolongs the QT interval is not advised as 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. Additionally, amiodarone is an inhibitor and a substrate of CYP3A4 and a substrate of P-glycoprotein (P-gp). Nilotinib is a substrate and an inhibitor of CYP3A4 and a substrate of P-gp. Altered nilotinib serum concentrations may occur leading to either an increased risk of nilotinib-related adverse reactions (including QT interval prolongation) or a risk of decreased nilotinib efficacy. Additionally, increased amiodarone concentrations may occur, which could result in a potential for serious or life-threatening reactions, including cardiac arrhythmias.
    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 other agents that prolong the QT interval. Clarithromycin has a causal association with QT prolongation and torsade de pointes. Additionally, nilotinib is a substrate and inhibitor of CYP3A4 and a substrate and inhibitor of P-glycoprotein (P-gp) and clarithromycin is a substrate and a strong inhibitor of CYP3A4 and an inhibitor of P-gp; nilotinib and/or clarithromycin levels may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and clarithromycin 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.
    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 other agents that prolong the QT interval. Clarithromycin has a causal association with QT prolongation and torsade de pointes. Additionally, nilotinib is a substrate and inhibitor of CYP3A4 and a substrate and inhibitor of P-glycoprotein (P-gp) and clarithromycin is a substrate and a strong inhibitor of CYP3A4 and an inhibitor of P-gp; nilotinib and/or clarithromycin levels may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and clarithromycin 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.
    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.
    Amprenavir: (Major) Avoid the concomitant use of nilotinib (a substrate and inhibitor of CYP3A4 and P-glycoprotein or 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 amprenavir 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.
    Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. In addition, drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include nilotinib. In addition, nilotinib can cause thrombocytopenia. Cautious use of nilotinib is warranted in patients receiving concomitant platelet inhibitors.
    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.
    Antithrombin III: (Moderate) Nilotinib can cause thrombocytopenia. Cautious use of nilotinib is warranted in patients receiving concomitant anticoagulants.
    Apixaban: (Moderate) Use apixaban and nilotinib together with caution, especially in patients with significant renal dysfunction, as risk of bleeding may be increased. Nilotinib is a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor. Apixaban is a substrate of CYP3A4 and P-gp. In a pharmacokinetic study, apixaban Cmax and AUC increased by 31% and 40%, respectively, when given with another moderate CYP3A4 and P-gp inhibitor. Although serum concentrations of non-vitamin K oral anticoagulants have been increased in the presence of moderate inhibitors, one cohort study found that the risk of bleeding was not increased.
    Apomorphine: (Major) Concurrent use of nilotinib and apomorphine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). 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 prolongs the QT interval. Limited data indicate that QT prolongation is also possible with apomorphine administration. The change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines; however, large increases (> 60 msecs from pre-dose) have occurred in two patients receiving 6 mg doses. Doses <= 6 mg SC are associated with minimal increases in QTc; doses > 6 mg SC do not provide additional clinical benefit and are not recommended.
    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: (Moderate) 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. Nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp; the AUC and concentrations of indacaterol are likely to increase if it is coadministered with nilotinib.
    Argatroban: (Moderate) Nilotinib can cause thrombocytopenia. Cautious use of nilotinib is warranted in patients receiving concomitant anticoagulants.
    Aripiprazole: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval such as aripiprazole. Additionally, nilotinib is an inhibitor of CYP3A4 and CYP2D6 and aripiprazole is a CYP3A4 and CYP2D6 substrate; administering these drugs together may result in increased aripiprazole levels. If the use of nilotinib and aripiprazole cannot be avoided, reduce the oral aripiprazole dose to one-quarter (25%) of the usual dose. In patients receiving Abilify Maintena and nilotinib for more than 14 days, the Abilify Maintena dose should be reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada during use of a mild to moderate CYP3A4 and CYP2D6 inhibitor.
    Arsenic Trioxide: (Major) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with arsenic trioxide include nilotinib. If nilotinib must be continued, closely monitor the patient for QT interval prolongation.
    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) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of codeine. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as codeine.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of codeine. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as codeine.
    Aspirin, ASA; Dipyridamole: (Moderate) Concurrent use of dipyridamole and antineoplastic agents may lead to an increased risk of bleeding. Cautious use of nilotinib is warranted in patients receiving concomitant platelet inhibitors.
    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: (Major) Concomitant use of nilotinib, a CYP3A4 and CYP2D6 inhibitor, and oxycodone, a CYP3A4 and CYP2D6 substrate, may result in increased oxycodone levels. If these drugs are used together, consider an oxycodone dose reduction and monitor patients for toxicity (e.g., sedation, respiratory depression).
    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, 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. (Major) When possible, avoid concurrent use of cobicistat with nilotinib as there is a potential for elevated concentrations of both drugs. If the use of cobicistat 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 cobicistat is discontinued, titrate the nilotinib dosage upward to the recommended dosage following a washout period. Both nilotinib and cobicistat are a CYP3A4 inhibitor/substrate. In addition, nilotinib is an substrate of P-glycoprotein (P-gp) and an inhibitor of CYP2D6; cobicistat is a CYP2D6 substrate and a P-gp inhibitor.
    Atomoxetine: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Both atomoxetine and nilotinib are considered drugs with a possible risk of torsade de pointes (TdP); therefore, the combination should be used cautiously and with close monitoring. In addition, because atomoxetine is primarily metabolized by CYP2D6, concurrent use of CYP2D6 inhibitors such as nilotinib may theoretically increase the risk of atomoxetine-induced adverse effects. Monitor for adverse effects, such as dizziness, drowsiness, nervousness, insomnia, and cardiac effects (e.g., hypertension, increased pulse rate, QT prolongation).
    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.
    Axitinib: (Moderate) Use caution if coadministration of axitinib with nilotinib is necessary, due to the risk of increased axitinib-related adverse reactions. Axitinib is a CYP3A4 substrate and nilotinib is a moderate CYP3A4 inhibitor. Coadministration with a strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers. The manufacturer of axitinib recommends a dose reduction in patients receiving strong CYP3A4 inhibitors, but recommendations are not available for moderate or weak CYP3A4 inhibitors.
    Azithromycin: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. There have been case reports of QT prolongation and torsade de pointes (TdP) with the use of azithromycin in post-marketing reports. Nilotinib is a substrate and inhibitor of P-glycoprotein (P-gp) and azithromycin is also a substrate and inhibitor of P-gp; therefore, levels of nilotinib and/or azithromycin may increase. If the use of azithromycin is required, hold nilotinib therapy. If the use of nilotinib and azithromycin cannot be avoided, exercise caution; close monitoring of the QT interval is recommended.
    Barbiturates: (Moderate) Avoid the concurrent use of nilotinib and a strong CYP3A4 inducer (e.g., barbiturates), as decreased nilotinib plasma concentrations may be seen. If these drugs must be coadministered, consider an increased dose of nilotinib. If the nilotinib dose is increased, carefully monitor the patient for nilotinib-related toxicity. Also, reduce the nilotinib dose to the indicated dose if the strong CYP3A4 inducer is discontinued.
    Bedaquiline: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as nilotinib, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, nilotinib may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions. Furthermore, since both drugs are associated with QT prolongation, coadministration may result in additive prolongation of the QT. 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. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Avoid administration of nilotinib with other drugs that may prolong QT interval, such as metronidazole. Both nilotinib and metronidazole have been associated with QT prolongation. 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.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Avoid administration of nilotinib with other drugs that may prolong QT interval, such as metronidazole. Both nilotinib and metronidazole have been associated with QT prolongation. 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.
    Bivalirudin: (Moderate) Nilotinib can cause thrombocytopenia. Cautious use of nilotinib is warranted in patients receiving concomitant anticoagulants.
    Bosentan: (Major) Nilotinib is metabolized by CYP3A4. Concurrent use of nilotinib and a strong CYP3A4 inducer (e.g., bosentan) may decrease nilotinib plasma concentrations. Coadministration should be avoided. If nilotinib must be administered with a strong CYP3A4 inducer, consider an increased dose of nilotinib. If the nilotinib dose is increased, carefully monitor the patient for nilotinib-related toxicity. Reduce the nilotinib dose to the indicated dose if the strong CYP3A4 inducer is discontinued. Also, increased bosentan concentrations may also occur, as nilotinib is a competitive inhibitor of CYP3A4, and bosentan is a CYP3A4 substrate.
    Brexpiprazole: (Major) 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 both CYP3A4 and CYP2D6. If these agents are used in combination, 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.
    Brigatinib: (Moderate) Monitor for decreased efficacy of nilotinib if coadministration is necessary. Nilotinib is a CYP3A substrate and brigatinib induces CYP3A in vitro. In healthy subjects, coadministration with a strong CYP3A4 inducer decreased the AUC of nilotinib by approximately 80%. Brigatinib may also decrease nilotinib exposure.
    Brimonidine; Timolol: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of timolol. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as timolol.
    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; Dextromethorphan; Guaifenesin: (Moderate) Nilotinib is an inhibitor of CYP3A4 and 2D6. Dextromethorphan is a CYP2D6 and CYP3A4 substrate. Administering these drugs together may result in increased dextromethorphan levels. A dextromethorphan dose reduction may be necessary if these drugs are used together.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of hydrocodone. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as hydrocodone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of hydrocodone. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as hydrocodone.
    Budesonide; Formoterol: (Moderate) 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. Nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp; the AUC and concentrations of indacaterol are likely to increase if it is coadministered with nilotinib.
    Bupivacaine Liposomal: (Moderate) Nilotinib is a time-dependent inhibitor of CYP3A4, and cautious use of nilotinib with a CYP3A4 substrate such as bupivacaine is recommended. For example, single-dose coadministration of nilotinib with midazolam, a CYP3A4 substrate, increased midazolam exposure by 30%.
    Bupivacaine: (Moderate) Nilotinib is a time-dependent inhibitor of CYP3A4, and cautious use of nilotinib with a CYP3A4 substrate such as bupivacaine is recommended. For example, single-dose coadministration of nilotinib with midazolam, a CYP3A4 substrate, increased midazolam exposure by 30%.
    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. (Moderate) Nilotinib is a time-dependent inhibitor of CYP3A4, and cautious use of nilotinib with a CYP3A4 substrate such as bupivacaine is recommended. For example, single-dose coadministration of nilotinib with midazolam, a CYP3A4 substrate, increased midazolam exposure by 30%.
    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.
    Bupropion; Naltrexone: (Moderate) Nilotinib is a competitive inhibitor of UGT1A1, and cautious coadministration with UGT1A1 substrates (e.g., naltrexone) is recommended. Increased naltrexone concentrations are likely.
    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.
    Cabozantinib: (Moderate) Monitor for an increase in cabozantinib- and nilotinib-related adverse events if concomitant use of cabozantinib and nilotinib is necessary. Cabozantinib is primarily metabolized by CYP3A4 and nilotinib is a CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. The manufacturer of cabozantinib recommends a dose reduction when used with strong CYP3A4 inhibitors; however, recommendations are not available for concomitant use with a moderate inhibitor of CYP3A4. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and nilotinib is a substrate of P-gp; plasma concentrations of nilotinib may be increased. However, the clinical relevance of this finding is unknown.
    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: (Moderate) Avoid the concurrent use of nilotinib, a substrate and moderate inhibitor of CYP3A4 and a P-glycoprotein (P-gp) substrate, and carbamazepine, a substrate and strong inducer of CYP3A4 and a P-gp inducer; decreased nilotinib concentrations are likely. Additionally, increased carbamazepine 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.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Nilotinib is an inhibitor of CYP3A4 and 2D6. Dextromethorphan is a CYP2D6 and CYP3A4 substrate. Administering these drugs together may result in increased dextromethorphan levels. A dextromethorphan dose reduction may be necessary if these drugs are used together.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of hydrocodone. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as hydrocodone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of hydrocodone. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as hydrocodone.
    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.
    Carvedilol: (Moderate) Nilotinib is an inhibitor of the efflux transporter P-glycoprotein and of CYP2D6. Carvedilol is a P-glycoprotein and CYP2D6 substrate. Increased concentrations of carvedilol are likely if it is coadministered with nilotinib; exercise caution.
    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.
    Cetirizine: (Minor) Nilotinib is an inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). Cetirizine is a P-glycoprotein substrate. Increased concentrations of cetirizine are likely if it is coadministered with nilotinib; exercise caution.
    Cetirizine; Pseudoephedrine: (Minor) Nilotinib is an inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). Cetirizine is a P-glycoprotein substrate. Increased concentrations of cetirizine are likely if it is coadministered with nilotinib; exercise caution.
    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 administration of nilotinib with other drugs that may prolong QT interval, such as chloroquine. 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. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses.
    Chlorpheniramine; Codeine: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of codeine. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as codeine.
    Chlorpheniramine; Dextromethorphan: (Moderate) Nilotinib is an inhibitor of CYP3A4 and 2D6. Dextromethorphan is a CYP2D6 and CYP3A4 substrate. Administering these drugs together may result in increased dextromethorphan levels. A dextromethorphan dose reduction may be necessary if these drugs are used together.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Nilotinib is an inhibitor of CYP3A4 and 2D6. Dextromethorphan is a CYP2D6 and CYP3A4 substrate. Administering these drugs together may result in increased dextromethorphan levels. A dextromethorphan dose reduction may be necessary if these drugs are used together.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of hydrocodone. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as hydrocodone.
    Chlorpheniramine; Hydrocodone: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of hydrocodone. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as hydrocodone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of hydrocodone. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as hydrocodone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of hydrocodone. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as hydrocodone.
    Chlorpromazine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Chlorpromazine is associated with an established risk of QT prolongation and torsade de pointes. Additionally, nilotinib is a CYP2D6 inhibitor and chlorpromazine is a substrate of CYP2D6; administering these drugs together may result in increased chlorpromazine levels. If the use of chlorpromazine is necessary, hold nilotinib therapy. Use caution and monitor patients for toxicity (e.g., QT interval prolongation) if these drugs are used together.
    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) Concurrent use of nilotinib and ciprofloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Nilotinib prolongs the QT interval, and ciprofloxacin is associated with a possible risk for QT prolongation and TdP. 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.
    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 other agents that prolong the QT interval. Clarithromycin has a causal association with QT prolongation and torsade de pointes. Additionally, nilotinib is a substrate and inhibitor of CYP3A4 and a substrate and inhibitor of P-glycoprotein (P-gp) and clarithromycin is a substrate and a strong inhibitor of CYP3A4 and an inhibitor of P-gp; nilotinib and/or clarithromycin levels may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and clarithromycin 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.
    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) When possible, avoid concurrent use of cobicistat with nilotinib as there is a potential for elevated concentrations of both drugs. If the use of cobicistat 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 cobicistat is discontinued, titrate the nilotinib dosage upward to the recommended dosage following a washout period. Both nilotinib and cobicistat are a CYP3A4 inhibitor/substrate. In addition, nilotinib is an substrate of P-glycoprotein (P-gp) and an inhibitor of CYP2D6; cobicistat is a CYP2D6 substrate and a P-gp inhibitor.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) When possible, avoid concurrent use of cobicistat with nilotinib as there is a potential for elevated concentrations of both drugs. If the use of cobicistat 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 cobicistat is discontinued, titrate the nilotinib dosage upward to the recommended dosage following a washout period. Both nilotinib and cobicistat are a CYP3A4 inhibitor/substrate. In addition, nilotinib is an substrate of P-glycoprotein (P-gp) and an inhibitor of CYP2D6; cobicistat is a CYP2D6 substrate and a P-gp inhibitor.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) When possible, avoid concurrent use of cobicistat with nilotinib as there is a potential for elevated concentrations of both drugs. If the use of cobicistat 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 cobicistat is discontinued, titrate the nilotinib dosage upward to the recommended dosage following a washout period. Both nilotinib and cobicistat are a CYP3A4 inhibitor/substrate. In addition, nilotinib is an substrate of P-glycoprotein (P-gp) and an inhibitor of CYP2D6; cobicistat is a CYP2D6 substrate and a P-gp inhibitor.
    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) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of codeine. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as codeine.
    Codeine; Guaifenesin: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of codeine. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as codeine.
    Codeine; Phenylephrine; Promethazine: (Major) Avoid administration of nilotinib with promethazine. If treatment with promethazine is necessary, interrupt nilotinib therapy. If interruption of treatment with nilotinib is not possible, closely monitor for evidence of QT prolongation during concurrent use. Nilotinib prolongs the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of codeine. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as codeine.
    Codeine; Promethazine: (Major) Avoid administration of nilotinib with promethazine. If treatment with promethazine is necessary, interrupt nilotinib therapy. If interruption of treatment with nilotinib is not possible, closely monitor for evidence of QT prolongation during concurrent use. Nilotinib prolongs the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of codeine. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as codeine.
    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) Concomitant use of nilotinib, a CYP3A4/P-glycoprotein (P-gp) substrate and CYP3A4 inhibitor, and conivaptan, a CYP3A4 substrate/inhibitor and P-gp inhibitor, may result in increased concentrations of both agents. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Treatment with nilotinib may be initiated no sooner than 1 week after completion of conivaptan therapy. According to the manufacturer of nilotinib, concomitant use of nilotinib and a strong CYP3A4 inhibitor should be avoided. If a strong CYP3A4 inhibitor cannot be avoided, interruption of nilotinib treatment is advised. If nilotinib must be continued, 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.
    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.
    Dalteparin: (Moderate) Nilotinib can cause thrombocytopenia. Cautious use of nilotinib is warranted in patients receiving concomitant anticoagulants.
    Danaparoid: (Moderate) Nilotinib can cause thrombocytopenia. Cautious use of nilotinib is warranted in patients receiving concomitant anticoagulants.
    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) When possible, avoid concurrent use of cobicistat with nilotinib as there is a potential for elevated concentrations of both drugs. If the use of cobicistat 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 cobicistat is discontinued, titrate the nilotinib dosage upward to the recommended dosage following a washout period. Both nilotinib and cobicistat are a CYP3A4 inhibitor/substrate. In addition, nilotinib is an substrate of P-glycoprotein (P-gp) and an inhibitor of CYP2D6; cobicistat is a CYP2D6 substrate and a P-gp inhibitor. (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.
    Dasatinib: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. In vitro studies have shown that dasatinib has the potential to prolong cardiac ventricular repolarization (prolong QT interval). Additionally, both nilotinib and dasatinib are substrates and inhibitors of CYP3A4; administering these drugs together may result in increased nilotinib and/or dasatinib levels. If the use of dasatinib is necessary, hold nilotinib therapy. If these drugs are used together, consider a dasatinib dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Daunorubicin: (Major) Coadministration of nilotinib with daunorubicin should be avoided. Acute cardiotoxicity can occur during the administration of daunorubicin; 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 is not advised as 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). Daunorubicin is a P-glycoprotein substrate. Increased concentrations of daunorubicin are likely if it is coadministered with nilotinib; exercise caution.
    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) Coadministration of nilotinib and a drug that prolongs the QT interval 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. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be avoided in combination with nilotinib include degarelix.
    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) Coadministration of nilotinib and a drug that prolongs the QT interval 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. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be avoided in combination with nilotinib include halogenated anesthetics.
    Desirudin: (Moderate) Nilotinib can cause thrombocytopenia. Cautious use of nilotinib is warranted in patients receiving concomitant anticoagulants.
    Desloratadine: (Minor) Nilotinib is an inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). Desloratadine is a P-glycoprotein substrate. Increased concentrations of desloratadine are likely if it is coadministered with nilotinib; exercise caution.
    Desloratadine; Pseudoephedrine: (Minor) Nilotinib is an inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). Desloratadine is a P-glycoprotein substrate. Increased concentrations of desloratadine are likely if it is coadministered with nilotinib; exercise caution.
    Deutetrabenazine: (Major) Avoid coadministration of deutetrabenazine with nilotinib. 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. 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. Nilotinib prolongs the QT interval.
    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.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Nilotinib is an inhibitor of CYP3A4 and 2D6. Dextromethorphan is a CYP2D6 and CYP3A4 substrate. Administering these drugs together may result in increased dextromethorphan levels. A dextromethorphan dose reduction may be necessary if these drugs are used together.
    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: (Moderate) Nilotinib is an inhibitor of CYP3A4 and 2D6. Dextromethorphan is a CYP2D6 and CYP3A4 substrate. Administering these drugs together may result in increased dextromethorphan levels. A dextromethorphan dose reduction may be necessary if these drugs are used together.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Nilotinib is an inhibitor of CYP3A4 and 2D6. Dextromethorphan is a CYP2D6 and CYP3A4 substrate. Administering these drugs together may result in increased dextromethorphan levels. A dextromethorphan dose reduction may be necessary if these drugs are used together.
    Dextromethorphan; Guaifenesin: (Moderate) Nilotinib is an inhibitor of CYP3A4 and 2D6. Dextromethorphan is a CYP2D6 and CYP3A4 substrate. Administering these drugs together may result in increased dextromethorphan levels. A dextromethorphan dose reduction may be necessary if these drugs are used together.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Nilotinib is an inhibitor of CYP3A4 and 2D6. Dextromethorphan is a CYP2D6 and CYP3A4 substrate. Administering these drugs together may result in increased dextromethorphan levels. A dextromethorphan dose reduction may be necessary if these drugs are used together.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Nilotinib is an inhibitor of CYP3A4 and 2D6. Dextromethorphan is a CYP2D6 and CYP3A4 substrate. Administering these drugs together may result in increased dextromethorphan levels. A dextromethorphan dose reduction may be necessary if these drugs are used together.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Nilotinib is an inhibitor of CYP3A4 and 2D6. Dextromethorphan is a CYP2D6 and CYP3A4 substrate. Administering these drugs together may result in increased dextromethorphan levels. A dextromethorphan dose reduction may be necessary if these drugs are used together.
    Dextromethorphan; Promethazine: (Major) Avoid administration of nilotinib with promethazine. If treatment with promethazine is necessary, interrupt nilotinib therapy. If interruption of treatment with nilotinib is not possible, closely monitor for evidence of QT prolongation during concurrent use. Nilotinib prolongs the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. (Moderate) Nilotinib is an inhibitor of CYP3A4 and 2D6. Dextromethorphan is a CYP2D6 and CYP3A4 substrate. Administering these drugs together may result in increased dextromethorphan levels. A dextromethorphan dose reduction may be necessary if these drugs are used together.
    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. (Moderate) Nilotinib is an inhibitor of CYP3A4 and 2D6. Dextromethorphan is a CYP2D6 and CYP3A4 substrate. Administering these drugs together may result in increased dextromethorphan levels. A dextromethorphan dose reduction may be necessary if these drugs are used together.
    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.
    Digoxin: (Major) Nilotinib is an inhibitor of the efflux transporter P-glycoprotein. Digoxin is a P-glycoprotein substrate. Increased concentrations of digoxin are likely if it is coadministered with nilotinib; exercise caution.
    Diltiazem: (Major) The concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), and diltiazem, a substrate and inhibitor of CYP3A4 and a P-gp inhibitor, may result in increased nilotinib and/or diltiazem levels. 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.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of hydrocodone. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as hydrocodone.
    Dipyridamole: (Moderate) Concurrent use of dipyridamole and antineoplastic agents may lead to an increased risk of bleeding. Cautious use of nilotinib is warranted in patients receiving concomitant platelet inhibitors.
    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.
    Dorzolamide; Timolol: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of timolol. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as timolol.
    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, THC: (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.
    Edoxaban: (Moderate) Coadministration of edoxaban and nilotinib may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and nilotinib is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of nilotinib; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    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.
    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) Concomitant use of nilotinib, a CYP3A4 and P-glycoprotein (P-gp) inhibitor, and eletriptan, a CYP3A4 and P-gp substrate, may result in increased eletriptan levels. An eletriptan dose reduction may be necessary if these drugs are used together.
    Eliglustat: (Major) Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with eliglustat include nilotinib.
    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).
    Encainide: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of encainide. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as encainide.
    Enflurane: (Major) Coadministration of nilotinib and a drug that prolongs the QT interval 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. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be avoided in combination with nilotinib include halogenated anesthetics.
    Enoxaparin: (Moderate) Nilotinib can cause thrombocytopenia. Cautious use of nilotinib is warranted in patients receiving concomitant anticoagulants.
    Enzalutamide: (Major) Avoid coadministration of nilotinib with enzalutamide due to decreased plasma concentrations of nilotinib. Nilotinib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%. Based on the nonlinear pharmacokinetic profile of nilotinib, increasing the dose when coadministered with strong CYP3A4 inducers is unlikely to compensate for the loss of exposure.
    Epirubicin: (Major) Acute cardiotoxicity can occur during the administration of epirubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with epirubicin include nilotinib.
    Eplerenone: (Major) Eplerenone is metabolized by the CYP3A4 pathway. Nilotinib inhibits the hepatic CYP3A4 isoenzyme and therefore may increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension. If these medications are given concurrently in post-myocardial infarction patients with heart failure, do not exceed an eplerenone dose of 25 mg PO once daily. If these medications are given concurrently, and eplerenone is used for hypertension, 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.
    Eptifibatide: (Moderate) An increased risk of bleeding may occur when eptifibatide is used concomitantly with agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    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) Coadministration of nilotinib and a drug that prolongs the QT interval 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, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be avoided in combination with nilotinib include eribulin.
    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 the concomitant use of nilotinib with other agents that prolong the QT interval. Erythromycin has 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 erythromycin is an inhibitor and a substrate of CYP3A4 and P-gp; nilotinib and/or erythromycin levels may increase. If the use of erythromycin is necessary, hold nilotinib therapy. Monitor patients for toxicity (e.g., QT interval prolongation) if these drugs are used together.
    Erythromycin; Sulfisoxazole: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Erythromycin has 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 erythromycin is an inhibitor and a substrate of CYP3A4 and P-gp; nilotinib and/or erythromycin levels may increase. If the use of erythromycin is necessary, hold nilotinib therapy. Monitor patients for toxicity (e.g., QT interval prolongation) if these drugs are used together.
    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.
    Ester local anesthetics: (Major) Nilotinib prolongs the QT interval; coadministration with a drug that prolongs the QT interval (e.g., local anesthetics) is not advised. If concurrent administration is unavoidable, consider interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation.
    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; 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) Coadministration of nilotinib and a drug that prolongs the QT interval 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. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be avoided in combination with nilotinib include ezogabine.
    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.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    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.
    Fexofenadine: (Minor) Nilotinib is an inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). Fexofenadine is a P-glycoprotein substrate. Increased concentrations of fexofenadine are likely if it is coadministered with nilotinib; exercise caution.
    Fexofenadine; Pseudoephedrine: (Minor) Nilotinib is an inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). Fexofenadine is a P-glycoprotein substrate. Increased concentrations of fexofenadine are likely if it is coadministered with nilotinib; exercise caution.
    Fingolimod: (Major) Avoid coadministration of nilotinib with other drugs that may prolong the QT interval, such as fingolimod. 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. 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 with other agents that prolong the QT interval. Flecainide is associated with a possible risk for QT prolongation and torsade de pointes. Additionally, nilotinib is a CYP2D6 inhibitor and flecainide is a substrate of CYP2D6; administering these drugs together may result in increased flecainide levels. If the use of flecainide is necessary, hold nilotinib therapy. Use caution and monitor patients for toxicity (e.g., QT interval prolongation) if these drugs are used together.
    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) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including nilotinib. In addition, nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of fluoxetine. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as fluoxetine.
    Fluoxetine; Olanzapine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Olanzapine may be associated with a significant prolongation of the QT interval in rare instances. Additionally, nilotinib is a CYP2D6 inhibitor and olanzapine is a substrate of CYP2D6; administering these drugs together may result in increased olanzapine levels. If the use of olanzapine is necessary, hold nilotinib therapy. Use caution and monitor patients for toxicity (e.g., QT interval prolongation) if these drugs are used together. (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including nilotinib. In addition, nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of fluoxetine. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as fluoxetine.
    Fluphenazine: (Minor) Coadministration of nilotinib and a drug that prolongs the QT interval 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. Drugs with a possible risk for QT prolongation that should be avoided in combination with nilotinib include fluphenazine.
    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: (Moderate) 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. Nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp; the AUC and concentrations of indacaterol are likely to increase if it is coadministered with nilotinib.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) 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. Nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp; the AUC and concentrations of indacaterol are likely to increase if it is coadministered with nilotinib.
    Fluticasone; Vilanterol: (Moderate) 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. Nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp; the AUC and concentrations of indacaterol are likely to increase if it is coadministered with nilotinib.
    Fluvastatin: (Moderate) The concomitant use of nilotinib, a CYP2C9 inhibitor and inducer, and fluvastatin, a CYP2C9 substrate, may result in altered levels of fluvastatin. Monitor patients closely for fluvastatin toxicity and efficacy if these drugs are used together.
    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).
    Fondaparinux: (Moderate) Nilotinib can cause thrombocytopenia. Cautious use of nilotinib is warranted in patients receiving concomitant anticoagulants.
    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: (Moderate) 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. Nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp; the AUC and concentrations of indacaterol are likely to increase if it is coadministered with nilotinib.
    Formoterol; Mometasone: (Moderate) 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. Nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp; the AUC and concentrations of indacaterol are likely to increase if it is coadministered with nilotinib.
    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) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as nilotinib. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Nilotinib also 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 these drugs must be administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Fosphenytoin: (Major) Avoid concomitant use of nilotinib, a CYP3A4 substrate, and strong CYP3A4 inducers such as phenytoin or fosphenytoin, because decreased nilotinib plasma concentrations are likely. Selecting an alternate agent with less potential for CYP3A4 induction is recommended. If use of nilotinib and phenytoin or fosphenytoin is required, increasing the nilotinib dosage will most likely not account for the loss of exposure based on the nonlinear pharmacokinetics of nilotinib. Additionally, nilotinib is a CYP2C9 inducer and phenytoin and fosphenytoin are CYP29C substrates with a narrow therapeutic range; decreased phenytoin or fosphenytoin levels and reduced efficacy may occur. Monitor patients closely if these drugs are used together.
    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) Concurrent use of nilotinib and gemifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). 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 prolongs the QT interval. 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 coadministration of gemtuzumab ozogamicin with nilotinib due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab ozogamicin, it has been reported with other drugs that contain calicheamicin. Concentration-dependent QT prolongation and prolonged cardiac ventricular repolarization possibly leading to sudden cardiac death have been reported with nilotinib use.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and nilotinib as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Glecaprevir and nilotinib are both substrates and inhibitors of P-glycoprotein (P-gp). (Moderate) Caution is advised with the coadministration of pibrentasvir and nilotinib as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Both pibrentasvir and nilotinib are substrates and inhibitors of P-glycoprotein (P-gp).
    Glycopyrrolate; Formoterol: (Moderate) 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. Nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp; the AUC and concentrations of indacaterol are likely to increase if it is coadministered with nilotinib.
    Goserelin: (Major) Coadministration of nilotinib and a drug that prolongs the QT interval 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. Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Granisetron: (Major) 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.
    Griseofulvin: (Major) Avoid concomitant use of nilotinib, a CYP3A4 substrate, and griseofulvin, a strong CYP3A4 inducer, because decreased nilotinib plasma concentrations are likely; 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.
    Guaifenesin; Hydrocodone: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of hydrocodone. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as hydrocodone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of hydrocodone. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as hydrocodone.
    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) Coadministration of nilotinib and a drug that prolongs the QT interval 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. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be avoided in combination with nilotinib include halogenated anesthetics.
    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) Coadministration of nilotinib and a drug that prolongs the QT interval 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. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be avoided in combination with nilotinib include halogenated anesthetics.
    Heparin: (Moderate) Nilotinib can cause thrombocytopenia. Cautious use of nilotinib is warranted in patients receiving concomitant anticoagulants.
    Homatropine; Hydrocodone: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of hydrocodone. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as hydrocodone.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of metoprolol. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as metoprolol.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of propranolol. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as propranolol.
    Hydrocodone: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of hydrocodone. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as hydrocodone.
    Hydrocodone; Ibuprofen: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of hydrocodone. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as hydrocodone.
    Hydrocodone; Phenylephrine: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of hydrocodone. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of hydrocodone. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of hydrocodone. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as hydrocodone.
    Hydrocodone; Pseudoephedrine: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of hydrocodone. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as hydrocodone.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and nilotinib. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes have been reported with the use of hydroxychloroquine. 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.
    Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include nilotinib.
    Ibrutinib: (Major) If coadministered with nilotinib, initiate ibrutinib therapy at a reduced dose of 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; monitor patients more frequently for ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). 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: (Major) Concomitant use of nilotinib, a CYP3A4 and CYP2D6 inhibitor, and oxycodone, a CYP3A4 and CYP2D6 substrate, may result in increased oxycodone levels. If these drugs are used together, consider an oxycodone dose reduction and monitor patients for toxicity (e.g., sedation, respiratory depression).
    Ibutilide: (Major) Coadministration of nilotinib and a drug that prolongs the QT interval, such as ibutilide is not advised; nilotinib prolongs the QT interval. Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of 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.
    Idarubicin: (Major) Acute cardiotoxicity can occur during the administration of idarubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with idarubicin include nilotinib.
    Iloperidone: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as iloperidone. Nilotinib is a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp) and iloperidone is a substrate of CYP3A4 and an inhibitor of P-gp; administering these drugs together may result in increased nilotinib and/or iloperidone levels. If the use of iloperidone is necessary, hold nilotinib therapy. If these drugs are used together, consider an iloperidone dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    Imatinib: (Major) The concomitant use of nilotinib (a substrate and moderate inhibitor of CYP3A4, a P-glycoprotein (P-gp) substrate and inhibitor, and a CYP2C9 inducer and inhibitor), with imatinib, STI-571 (a substrate and inhibitor of CYP3A4 and a P-gp and CYP2C9 substrate), resulted in increased levels of both drugs. 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: (Moderate) 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. Nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp; the AUC and concentrations of indacaterol are likely to increase if it is coadministered with nilotinib.
    Indacaterol; Glycopyrrolate: (Moderate) 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. Nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp; the AUC and concentrations of indacaterol are likely to increase if it is coadministered with nilotinib.
    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 (TdP). 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. Nilotinib also prolongs the QT interval.
    Irinotecan Liposomal: (Moderate) Use caution if irinotecan liposomal is coadministered with nilotinib, a CYP3A4 inhibitor, due to increased risk of irinotecan-related toxicity. The metabolism of liposomal irinotecan has not been evaluated; however, coadministration of ketoconazole, a strong CYP3A4 and UGT1A1 inhibitor, with non-liposomal irinotecan HCl resulted in increased exposure to both irinotecan and its active metabolite, SN-38.
    Irinotecan: (Major) Concomitant use of nilotinib, a CYP3A4 and P-glycoprotein (P-gp) inhibitor, and irinotecan, a CYP3A4 and P-gp substrate with a narrow therapeutic range, may result in increased irinotecan levels. An irinotecan dose reduction may be necessary if these drugs are used together.
    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) Coadministration of nilotinib and a drug that prolongs the QT interval 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. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be avoided in combination with nilotinib include halogenated anesthetics.
    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 concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), and rifampin, a strong CYP3A4 inducer and a substrate and inducer of P-gp. In healthy subjects, the AUC value of nilotinib was decreased by about 80% following the addition of rifampicin/rifampin 600 mg once daily for 12 days. Additionally, increased rifampin 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. (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 concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), and rifampin, a strong CYP3A4 inducer and a substrate and inducer of P-gp. In healthy subjects, the AUC value of nilotinib was decreased by about 80% following the addition of rifampicin/rifampin 600 mg once daily for 12 days. Additionally, increased rifampin 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. (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.
    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.
    Ledipasvir; Sofosbuvir: (Moderate) Caution and close monitoring of adverse reactions is advised with concomitant administration of nilotinib and ledipasvir; sofosbuvir. Both ledipasvir and nilotinib are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp); sofosbuvir is a P-gp substrate. Taking these drugs together may increase plasma concentrations of all three drugs. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors.
    Lenvatinib: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval such as lenvatinib. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects.
    Lepirudin: (Moderate) Nilotinib can cause thrombocytopenia. Cautious use of nilotinib is warranted in patients receiving concomitant anticoagulants.
    Lesinurad: (Moderate) Use lesinurad and nilotinib together with caution; nilotinib may increase or decrease the systemic exposure of lesinurad. Monitor for potential reduction in efficacy or increased side effects of lesinurad. Nilotinib is a CYP2C9 inducer, and a mild inhibitor of CYP2C9 in vitro, and lesinurad is a CYP2C9 substrate. Nilotinib is an inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate.
    Lesinurad; Allopurinol: (Moderate) Use lesinurad and nilotinib together with caution; nilotinib may increase or decrease the systemic exposure of lesinurad. Monitor for potential reduction in efficacy or increased side effects of lesinurad. Nilotinib is a CYP2C9 inducer, and a mild inhibitor of CYP2C9 in vitro, and lesinurad is a CYP2C9 substrate. Nilotinib is an inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate.
    Leuprolide: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include nilotinib.
    Leuprolide; Norethindrone: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include nilotinib.
    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. Additionally, indacaterol is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate, and nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp. Increased concentrations of indacaterol are likely if it is coadministered with nilotinib.
    Levocetirizine: (Minor) Nilotinib is an inhibitor of the efflux transporter P-glycoprotein (Pgp, ABCB1). Cetirizine is a P-glycoprotein substrate. Increased concentrations of cetirizine are likely if it is coadministered with nilotinib; exercise caution.
    Levofloxacin: (Major) Concurrent use of nilotinib and levofloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). 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. Levofloxacin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Additionally, rare cases of TdP have been spontaneously reported during postmarketing surveillance in patients receiving levofloxacin. Nilotinib also prolongs the QT interval.
    Levomethadyl: (Major) Nilotinib prolongs the QT interval; coadministration with other drugs that also prolong the QT interval (e.g., levomethadyl) is not advised. If concurrent administration is unavoidable, consider interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation.
    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) Lithium should be avoided in combination with nilotinib. Lithium has been associated with QT prolongation. Coadministration of nilotinib and a drug that prolongs the QT interval 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.
    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.
    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: (Moderate) 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. Nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp; the AUC and concentrations of indacaterol are likely to increase if it is coadministered with nilotinib.
    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.
    Loratadine: (Moderate) Concomitant use of nilotinib, an inhibitor of CYP3A4, CYP2D6, and P-glycoprotein (P-gp) and loratadine, a substrate for CYP3A4, CYP2D6, and P-gp, may result in increased loratadine levels. A loratadine dose reduction may be necessary if these drugs are used together.
    Loratadine; Pseudoephedrine: (Moderate) Concomitant use of nilotinib, an inhibitor of CYP3A4, CYP2D6, and P-glycoprotein (P-gp) and loratadine, a substrate for CYP3A4, CYP2D6, and P-gp, may result in increased loratadine levels. A loratadine dose reduction may be necessary if these drugs are used together.
    Lovastatin: (Moderate) Concomitant use of nilotinib, a CYP3A4 and P-glycoprotein (P-gp) inhibitor, and lovastatin, a CYP3A4 and P-gp substrate, may result in increased lovastatin levels. An lovastatin dose reduction may be necessary if these drugs are used together. Be alert for symptoms of statin-induced myopathy.
    Lovastatin; Niacin: (Moderate) Concomitant use of nilotinib, a CYP3A4 and P-glycoprotein (P-gp) inhibitor, and lovastatin, a CYP3A4 and P-gp substrate, may result in increased lovastatin levels. An lovastatin dose reduction may be necessary if these drugs are used together. Be alert for symptoms of statin-induced myopathy.
    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.
    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 with other agents that prolong the QT interval. Maprotiline is associated with a possible risk for QT prolongation and torsade de pointes. Additionally, nilotinib is a CYP2D6 inhibitor and maprotiline is a substrate of CYP2D6; administering these drugs together may result in increased maprotiline levels. If the use of maprotiline is necessary, hold nilotinib therapy. Use caution and monitor patients for toxicity (e.g., QT interval prolongation) if these drugs are used together.
    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: (Major) Avoid administration of nilotinib with promethazine. If treatment with promethazine is necessary, interrupt nilotinib therapy. If interruption of treatment with nilotinib is not possible, closely monitor for evidence of QT prolongation during concurrent use. Nilotinib prolongs the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Mesoridazine: (Major) Nilotinib prolongs the QT interval; coadministration with drugs that prolong the QT interval (e.g., mesoridazine) is not advised. 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.
    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. Additionally, indacaterol is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate, and nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp. Increased concentrations of indacaterol are likely if it is coadministered with nilotinib.
    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.
    Methamphetamine: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of methamphetamine. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as methamphetamine.
    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.
    Metoprolol: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of metoprolol. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as metoprolol.
    Metronidazole: (Major) Avoid administration of nilotinib with other drugs that may prolong QT interval, such as metronidazole. Both nilotinib and metronidazole have been associated with QT prolongation. 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.
    Mexiletine: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of mexiletine. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as mexiletine.
    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 midostaurin and nilotinib; both drugs have been reported to increase the QT interval. If possible, interrupt nilotinib therapy if treatment with midostaurin is required. If concomitant use is necessary, closely monitor for evidence of QT prolongation (e.g., electrocardiograms (ECG)) during concurrent use. Evaluate electrolytes at baseline and monitor periodically during nilotinib therapy. Correct electrolyte abnormalities prior to starting nilotinib. Obtain an ECG at baseline, after 7 days on therapy, after dose adjustments, and periodically as clinically indicated. Hold nilotinib therapy in patients who develop a QTc greater than 480 milliseconds; additionally, a nilotinib dosage adjustment and/or therapy discontinuation may be necessary. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation and sudden cardiac death (possibly related to prolonged cardiac ventricular repolarization) occurred in patients who received nilotinib in clinical trials.
    Mifepristone, RU-486: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Mifepristone, RU-486 has been associated with dose-dependent prolongation of the QT interval. There is no experience with high exposure or concomitant use with other QT prolonging drugs. 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; nilotinib and/or mifepristone levels may increase. If the use of mifepristone is necessary, hold nilotinib therapy. To minimize the risk of QT prolongation, the lowest effective mifepristone dose should always be used. Monitor patients for toxicity (e.g., QT interval prolongation, adrenal insufficiency) if these drugs are used together.
    Mirtazapine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and nilotinib. 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. Cases of QT prolongation, TdP, 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.
    Mitomycin: (Major) Nilotinib is an inhibitor of the efflux transporter P-glycoprotein. Mitomycin is a P-glycoprotein substrate. Increased concentrations of mitomycin are likely if it is coadministered with nilotinib; exercise caution.
    Mitotane: (Major) Avoid the concomitant use of mitotane with nilotinib; if coadministration cannot be avoided, monitor for decreased efficacy of nilotinib. 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. Mitotane is a strong CYP3A4 inducer and nilotinib is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of nilotinib. In healthy subjects, the AUC value of nilotinib was decreased by about 80% following the addition of another strong CYP3A inducer (rifampicin/rifampin).
    Modafinil: (Moderate) Avoid the concomitant use of nilotinib, a substrate and an inhibitor of CYP3A4, and modafinil, a CYP3A4 substrate and strong inducer; decreased nilotinib plasma concentrations are likely. Increased modafinil concentrations may also occur. Selecting an alternate agent with less potential for CYP3A4 induction is recommended. 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.
    Morphine: (Major) Nilotinib is a competitive inhibitor of UGT1A1, and cautious coadministration with UGT1A1 substrates (e.g., morphine), especially substrates with a narrow therapeutic index, is recommended. Morphine is also a substrate for P-glycoprotein (P-gp) and nilotinib is an inhibitor of the efflux transporter P-gp. Increased concentrations of morphine are likely, and caution should be exercised.
    Morphine; Naltrexone: (Major) Nilotinib is a competitive inhibitor of UGT1A1, and cautious coadministration with UGT1A1 substrates (e.g., morphine), especially substrates with a narrow therapeutic index, is recommended. Morphine is also a substrate for P-glycoprotein (P-gp) and nilotinib is an inhibitor of the efflux transporter P-gp. Increased concentrations of morphine are likely, and caution should be exercised.
    Moxifloxacin: (Major) Concurrent use of nilotinib and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). 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 prolongs the QT interval. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, 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.
    Naltrexone: (Moderate) Nilotinib is a competitive inhibitor of UGT1A1, and cautious coadministration with UGT1A1 substrates (e.g., naltrexone) is recommended. Increased naltrexone concentrations are likely.
    Nebivolol: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with nilotinib. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as nilotinib, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Nebivolol; Valsartan: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with nilotinib. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as nilotinib, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    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; 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.
    Nicardipine: (Major) The concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), and nicardipine, a substrate and inhibitor of CYP3A4 and a P-gp inhibitor, may result in increased nilotinib and/or nicardipine levels. A nilotinib and/or nicardipine dose reduction may be necessary if these drugs are used together. Monitor patients for nilotinib and/or nicardipine toxicity (e.g., QT interval prolongation, hypotension) if these drugs are used together.
    Nintedanib: (Moderate) Nilotinib is a moderate inhibitor of both P-glycoprotein (P-gp) and CYP3A4; nintedanib is a P-gp substrate as well as a minor substrate of CYP3A4. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of nilotinib and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of therapy may be necessary.
    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) Concurrent use of nilotinib and norfloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). 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 prolongs the QT interval. Quinolones have also been associated with QT prolongation and 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) Due to a possible risk for QT prolongation and torsade de pointes (TdP), octreotide and nilotinib should be used together cautiously. 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 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. 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.
    Ofloxacin: (Major) Concurrent use of nilotinib and ofloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). 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 prolongs the QT interval. Some quinolones, including ofloxacin, have also been associated with QT prolongation. Additionally, post-marketing surveillance for ofloxacin has identified very rare cases of TdP.
    Olanzapine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Olanzapine may be associated with a significant prolongation of the QT interval in rare instances. Additionally, nilotinib is a CYP2D6 inhibitor and olanzapine is a substrate of CYP2D6; administering these drugs together may result in increased olanzapine levels. If the use of olanzapine is necessary, hold nilotinib therapy. Use caution and monitor patients for toxicity (e.g., QT interval prolongation) if these drugs are used together.
    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: (Moderate) 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. Nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp; the AUC and concentrations of indacaterol are likely to increase if it is coadministered with nilotinib.
    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 coadministration of nilotinib with osimertinib due to the risk of QT prolongation. 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. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib; nilotinib has also been associated with QT prolongation.
    Oxaliplatin: (Major) Avoid coadministration of nilotinib with oxaliplatin due to the potential for QT prolongation. If concomitant use is unavoidable, closely monitor electrolytes and ECGs for QT prolongationy; correct electrolyte abnormalities prior to administration of oxaliplatin. Nilotinib prolongs the QT interval; QT prolongation and ventricular arrhythmias including fatal torsade de pointes (TdP) have been reported with oxaliplatin use in post-marketing experience.
    Oxcarbazepine: (Major) Avoid concomitant use of nilotinib, a CYP3A4 substrate, and oxcarbazepine, a strong CYP3A4 inducer, because decreased nilotinib plasma concentrations are likely; 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.
    Oxycodone: (Major) Concomitant use of nilotinib, a CYP3A4 and CYP2D6 inhibitor, and oxycodone, a CYP3A4 and CYP2D6 substrate, may result in increased oxycodone levels. If these drugs are used together, consider an oxycodone dose reduction and monitor patients for toxicity (e.g., sedation, respiratory depression).
    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.
    Paliperidone: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval such as paliperidone. Nilotinib is a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp) and paliperidone is a CYP3A4 substrate and an inhibitor and substrate of P-gp; nilotinib and/or paliperidone levels may increase. If the use of paliperidone is necessary, hold nilotinib therapy. Monitor patients for toxicity (e.g., QT interval prolongation) if these drugs are used together.
    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.
    Paroxetine: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of paroxetine. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as paroxetine.
    Pasireotide: (Major) Coadministration of nilotinib and a drug that prolongs the QT interval, such as pasireotide is not advised, as coadministration may have additive effects on the prolongation of 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.
    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 with other agents that prolong the QT interval. Systemic pentamidine has been associated with QT prolongation. Additionally, nilotinib is a CYP2D6 inhibitor and pentamidine is a substrate of CYP2D6; administering these drugs together may result in increased pentamidine levels. If the use of pentamidine is necessary, hold nilotinib therapy. Use caution and monitor patients for toxicity (e.g., QT interval prolongation) if these drugs are used together.
    Pentosan: (Moderate) Nilotinib can cause thrombocytopenia. Cautious use of nilotinib is warranted in patients receiving concomitant anticoagulants.
    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: (Moderate) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Perphenazine is associated with a possible risk for QT prolongation and torsade de pointes. Additionally, nilotinib is a CYP2D6 inhibitor and perphenazine is a substrate of CYP2D6; administering these drugs together may result in increased perphenazine levels. If the use of perphenazine is necessary, hold nilotinib therapy. Use caution and monitor patients for toxicity (e.g., QT interval prolongation) if these drugs are used together.
    Perphenazine; Amitriptyline: (Moderate) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Perphenazine is associated with a possible risk for QT prolongation and torsade de pointes. Additionally, nilotinib is a CYP2D6 inhibitor and perphenazine is a substrate of CYP2D6; administering these drugs together may result in increased perphenazine levels. If the use of perphenazine is necessary, hold nilotinib therapy. Use caution and monitor patients for toxicity (e.g., QT interval prolongation) if these drugs are used together.
    Phenylephrine; Promethazine: (Major) Avoid administration of nilotinib with promethazine. If treatment with promethazine is necessary, interrupt nilotinib therapy. If interruption of treatment with nilotinib is not possible, closely monitor for evidence of QT prolongation during concurrent use. Nilotinib prolongs the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Phenytoin: (Moderate) Avoid concomitant use of nilotinib, a CYP3A4 substrate, and strong CYP3A4 inducers such as phenytoin or fosphenytoin, because decreased nilotinib plasma concentrations are likely. Selecting an alternate agent with less potential for CYP3A4 induction is recommended. If use of nilotinib and phenytoin or fosphenytoin is required, increasing the nilotinib dosage will most likely not account for the loss of exposure based on the nonlinear pharmacokinetics of nilotinib. Additionally, nilotinib is a CYP2C9 inducer and phenytoin and fosphenytoin are CYP29C substrates with a narrow therapeutic range; decreased phenytoin or fosphenytoin levels and reduced efficacy may occur. Monitor patients closely if these drugs are used together.
    Pimavanserin: (Major) Coadministration of nilotinib and a drug that prolongs the QT interval is not advised; nilotinib prolongs the QT interval. Pimavanserin may cause QT prolongation. 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.
    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. Additionally, indacaterol is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate, and nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp. Increased concentrations of indacaterol are likely if it is coadministered with nilotinib.
    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) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include nilotinib.
    Procainamide: (Major) Coadministration of nilotinib and a drug that prolongs the QT interval 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. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be avoided in combination with nilotinib include procainamide.
    Prochlorperazine: (Minor) Coadministration of nilotinib and a drug that prolongs the QT interval 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. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be avoided in combination with nilotinib include prochlorperazine.
    Promethazine: (Major) Avoid administration of nilotinib with promethazine. If treatment with promethazine is necessary, interrupt nilotinib therapy. If interruption of treatment with nilotinib is not possible, closely monitor for evidence of QT prolongation during concurrent use. Nilotinib prolongs the QT interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Propafenone: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval such as propafenone. Nilotinib is a substrate and inhibitor of P-glycoprotein (P-gp) and an inhibitor of CYP2D6 and propafenone is substrate of CYP2D6 and a strong inhibitor of P-gp; administering these drugs together may result in increased nilotinib and/or propafenone levels. If the use of propafenone is necessary, hold nilotinib therapy. Use caution and monitor patients for toxicity (e.g., QT interval prolongation) if these drugs are used together.
    Propoxyphene: (Moderate) Propoxyphene is a substrate of CYP2D6. Nilotinib is an inhibitor of CYP2D6. Increased propoxyphene concentrations may occur if nilotinib and propoxyphene are concurrently used; exercise caution.
    Propranolol: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of propranolol. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as propranolol.
    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) Coadministration of nilotinib and a drug that prolongs the QT interval 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. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be avoided in combination with nilotinib include regadenoson. If coadministration is necessary, use cautiously.
    Ribociclib: (Major) Avoid coadministration of ribociclib with nilotinib due to an increased risk for QT prolongation. Additionally, the systemic exposure of both drugs may be increased resulting in an increase in treatment-related adverse reactions (e.g., neutropenia, QT prolongation). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Nilotinib has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation. Ribociclib is also extensively metabolized by CYP3A4 and is a moderate CYP3A4 inhibitor; nilotinib is a moderate CYP3A4 inhibitor and CYP3A4 substrate.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with nilotinib due to an increased risk for QT prolongation. Additionally, the systemic exposure of both drugs may be increased resulting in an increase in treatment-related adverse reactions (e.g., neutropenia, QT prolongation). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Nilotinib has also been associated with QT prolongation. Concomitant use may increase the risk for QT prolongation. Ribociclib is also extensively metabolized by CYP3A4 and is a moderate CYP3A4 inhibitor; nilotinib is a moderate CYP3A4 inhibitor and CYP3A4 substrate.
    Rifabutin: (Moderate) Avoid the concurrent use of nilotinib, a CYP3A4 substrate and moderate inhibitor, and rifabutin, a CYP3A4 substrate and strong inducer; decreased nilotinib concentrations are likely. Additionally, increased rifabutin 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.
    Rifampin: (Major) Avoid concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), and rifampin, a strong CYP3A4 inducer and a substrate and inducer of P-gp. In healthy subjects, the AUC value of nilotinib was decreased by about 80% following the addition of rifampicin/rifampin 600 mg once daily for 12 days. Additionally, increased rifampin 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.
    Rifapentine: (Major) Avoid concomitant use of nilotinib, a CYP3A4 substrate, and rifapentine, a strong CYP3A4 inducer; decreased nilotinib plasma concentrations are likely. 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.
    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) If possible, avoid the concomitant use of nilotinib with other agents that may cause QT prolongation and torsade de pointes (TdP), such as risperidone. If coadministration is required and the patient has risk factors for cardiac disease or arrhythmias, careful monitoring is recommended.
    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.
    Rolapitant: (Moderate) Use caution if nilotinib and rolapitant are used concurrently, and monitor for nilotinib-related adverse effects. Nilotinib is a P-glycoprotein (P-gp) substrate, where an increase in exposure may significantly increase adverse effects; rolapitant is a P-gp inhibitor. When rolapitant was administered with another P-gp substrate, digoxin, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied. Additionally, nilotinib is an inhibitor of CYP3A4 and rolapitant is a CYP3A4 substrate. Theoretically this could increase rolapitant concentrations, but this effect is not expected to be clinically relevant.
    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).
    Salicylates: (Moderate) Nilotinib can cause thrombocytopenia. Large doses of salicylates (3 to 4 g/day or higher) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Salmeterol: (Moderate) 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. Nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp; the AUC and concentrations of indacaterol are likely to increase if it is coadministered with nilotinib.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and nilotinib as coadministration may result in increased systemic exposure of nilotinib. Nilotinib is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of nilotinib.
    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.
    Selexipag: (Major) Consider a less frequent dosing regimen (e.g., once daily) when initiating selexipag in patients receiving nilotinib. Reduce the selexipag dose when nilotinib is initiated in patients already taking selexipag. Coadministration can be expected to increase exposure to selexipag and its active metabolite. Selexipag is a substrate of CYP2C8; nilotinib is a moderate CYP2C8 inhibitor.
    Sertraline: (Major) Avoid administration of nilotinib with sertraline due to the potential for QT prolongation. 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.
    Sevoflurane: (Major) Coadministration of nilotinib and a drug that prolongs the QT interval 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. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be avoided in combination with nilotinib include halogenated anesthetics.
    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. Additionally, indacaterol is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate, and nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp. Increased concentrations of indacaterol are likely if it is coadministered with nilotinib.
    Sildenafil: (Moderate) Concomitant use of nilotinib, a CYP3A4 inhibitor and a CYP2C9 inhibitor and inducer, and sildenafil, a CYP3A4 and CYP2C9 substrate, may result in altered levels of sildenafil. Monitor patients closely for toxicity and efficacy if these drugs are used together.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    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.
    Solifenacin: (Major) Nilotinib is a competitive inhibitor of CYP3A4. Concurrent administration of midazolam, a CYP3A4 substrate, and nilotinib increased midazolam exposure by 30%. Caution should be exercised when coadministering nilotinib with CYP3A4 substrates, such as solifenacin, especially substrates with a narrow therapeutic index.
    Sorafenib: (Major) Concurrent use of nilotinib and sorafenib should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If concurrent administration is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both sorafenib and nilotinib have been associated with QT prolongation.
    Sotalol: (Major) Coadministration of nilotinib and a drug that prolongs the QT interval, such as sotalol, is not advised; nilotinib prolongs the QT interval. Sotalol administration is associated with QT prolongation and torsades de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment. 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.
    Sparfloxacin: (Major) Nilotinib prolongs the QT interval; coadministration with a drug that prolongs the QT interval (e.g., sparfloxacin) is not advised. If concurrent administration is unavoidable, consider interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation.
    St. John's Wort, Hypericum perforatum: (Major) Avoid the concomitant use of nilotinib, a substrate and an inhibitor of CYP3A4 and a P-glycoprotein (P-gp) substrate, and St. John's wort, Hypericum perforatum, a strong CYP3A4 inducer and a P-gp inducer; decreased nilotinib plasma concentrations are likely. 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.
    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) QT prolongation resulting in ventricular tachycardia and torsade de pointes (TdP) have been reported during post-marketing use of sulfamethoxazole; trimethoprim. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with sulfamethoxazole; trimethoprim include nilotinib.
    Sunitinib: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Sunitinib has been established to have a causal association with QT prolongation and torsade de pointes. Additionally, nilotinib is a moderate inhibitor of CYP3A4 and sunitinib is a substrate of CYP3A4; administering these drugs together may result in increased sunitinib levels. If the use of sunitinib is necessary, hold nilotinib therapy. If these drugs are used together, consider a sunitinib dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
    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) Concurrent use of nilotinib and telavancin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). 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. Both nilotinib and telavancin have 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.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with nilotinib is necessary, and monitor for an increase in both nilotinib- and temsirolimus-related adverse reactions. Temsirolimus is a CYP3A4 substrate, as well as an in vitro substrate / inhibitor of P-glycoprotein (P-gp). Nilotinib is a moderate CYP3A4 inhibitor and a P-gp substrate / inhibitor. The manufacturer of temsirolimus recommends a dose reduction if coadministered with a strong CYP3A4 inhibitor, but recommendations are not available for concomitant use of moderate CYP3A4 or P-gp inhibitors. Coadministration of temsirolimus with ketoconazole, a strong CYP3A4 inhibitor, had no significant effect on the AUC or Cmax of temsirolimus, but increased the sirolimus AUC and Cmax by 3.1-fold and 2.2-fold, respectively. Pharmacokinetic data are not available regarding the magnitude of effect of P-gp inhibition on temsirolimus exposure.
    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. Additionally, indacaterol is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate, and nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp. Increased concentrations of indacaterol are likely if it is coadministered with nilotinib.
    Tetrabenazine: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Tetrabenazine causes a small increase in the corrected QT interval. Additionally, nilotinib is a CYP2D6 inhibitor and tetrabenazine is a substrate of CYP2D6; administering these drugs together may result in increased tetrabenazine levels. If the use of tetrabenazine is necessary, hold nilotinib therapy. Use caution and monitor patients for toxicity (e.g., QT interval prolongation) if these drugs are used together.
    Thioridazine: (Severe) Nilotinib prolongs the QT interval. Because of the potential for torsade de pointes (TdP), use of thioridazine with nilotinib is contraindicated.
    Ticlopidine: (Moderate) Nilotinib can cause thrombocytopenia. Cautious use of nilotinib is warranted in patients receiving concomitant platelet inhibitors.
    Timolol: (Moderate) Nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of timolol. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as timolol.
    Tinzaparin: (Moderate) Nilotinib can cause thrombocytopenia. Cautious use of nilotinib is warranted in patients receiving concomitant anticoagulants.
    Tiotropium; Olodaterol: (Moderate) 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. Nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp; the AUC and concentrations of indacaterol are likely to increase if it is coadministered with nilotinib.
    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.
    Tirofiban: (Moderate) An increased risk of bleeding may occur when tirofiban is used with agents that cause clinically significant thrombocytopenia (e.g., nilotinib). Cautious use of nilotinib is warranted in patients receiving concomitant platelet inhibitors.
    Tizanidine: (Major) Tizanidine administration may result in QT prolongation. Coadministration of nilotinib and a drug that prolongs the QT interval 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.
    Tolbutamide: (Moderate) Concomitant use of nilotinib, a CYP2C9 inhibitor and inducer, and tolbutamide, a CYP2C9 substrate, may result in altered levels of tolbutamide. Monitor patients closely for tolbutamide toxicity and efficacy if these drugs are used together.
    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.
    Topotecan: (Major) Avoid the concomitant use of nilotinib, a P-glycoprotein (P-gp) inhibitor, with oral topotecan, a P-gp substrate; P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. If coadministration of nilotinib and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea. In a pharmacokinetic cohort study, coadministration of oral topotecan with a potent P-gp inhibitor (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant).
    Toremifene: (Major) Coadministration of nilotinib and a drug that prolongs the QT interval, such as toremifene is not advised; nilotinib prolongs the QT interval. If coadministration is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation.
    Torsemide: (Moderate) Concomitant use of nilotinib, a CYP2C9 inhibitor and inducer, and torsemide, a CYP2C9 substrate, may result in altered levels of torsemide. Monitor patients closely for torsemide toxicity and efficacy if these drugs are used together.
    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: (Moderate) Tramadol is a substrate of CYP2D6 and CYP3A4. Nilotinib is a competitive inhibitor of CYP3A4 and CYP2D6. As the analgesic activity of tramadol is due to both the parent drug and O-desmethyltramadol (M1), inhibition of CYP2D6 may affect analgesic effects; reduced analgesic effects are possible. Increased serum concentrations of tramadol and reduced serum concentrations of M1 would be expected from concurrent use of tramadol and a CYP2D6 inhibitor and/or CYP3A4 inhibitor. The risk for serious adverse effects such as seizures and serotonin syndrome may be increased. Caution should be exercised when coadministering nilotinib with CYP3A4 and CYP2D6 substrates; a tramadol dose reduction may be necessary. Monitor patients closely for tramadol toxicity and efficacy if these drugs are used together.
    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) Coadministration of nilotinib and a drug that prolongs the QT interval is not advised; nilotinib prolongs the QT interval. If concurrent administration is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment for drugs with a definitive risk. Drugs with a possible risk for QT prolongation that should be used cautiously in combination with nilotinib include trifluoperazine. If nilotinib must be continued, closely monitor the patient for QT interval prolongation; ECG monitoring may be advised.
    Triptorelin: (Major) Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with triptorelin include nilotinib.
    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: (Moderate) 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. Nilotinib is a competitive inhibitor of CYP3A4, CYP2D6, and P-gp; the AUC and concentrations of indacaterol are likely to increase if it is coadministered with nilotinib.
    Vandetanib: (Major) The manufacturers of nilotinib and vandetanib recommend avoiding coadministration with other drugs that prolong the QT interval due to an increased risk of QT prolongation and torsade de pointes (TdP). Vandetanib can prolong the QT interval in a concentration-dependent manner. TdP and sudden death have been reported in patients receiving vandetanib; nilotinib can also prolong the QT interval. If coadministration is necessary, an ECG is needed, as well as more frequent monitoring of the QT interval. If QTcF is greater than 500 msec, interrupt vandetanib dosing until the QTcF is less than 450 msec; then, vandetanib may be resumed at a reduced dose. Additionally, nilotinib-related side effects may be increased; nilotinib is a substrate of P-glycoprotein (P-gp). Coadministration with vandetanib increased the Cmax and AUC of digoxin, another P-gp substrate by 29% and 23%, respectively.
    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 may be a P-gp inhibitor at therapeutic dose levels in the gut; 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 co-administered 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) Use caution with concurrent use of nilotinib, a CYP3A4 and P-glycoprotein (P-gp) inhibitor, and vinorelbine, a CYP3A4 and P-gp substrate, as the metabolism of vinorelbine may be decreased. Monitor patients for an earlier onset and/or an increased severity of adverse effects including neurotoxicity and myelosuppression.
    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) Coadministration of nilotinib and a drug that prolongs the QT interval, such as vorinostat, 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.
    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%.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and nilotinib is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

    According to the manufacturer, nilotinib or breast-feeding should be discontinued because of the potential for serious adverse reactions in nursing infants from nilotinib. It is not known if nilotinib is excreted into human milk. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    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. Nilotinib is approximately 98% protein bound in serum. In healthy subjects, the primary metabolic pathways were oxidation and hydroxylation; no active metabolites were identified. The elimination half-life of nilotinib is approximately 17 hours. In healthy patients, 93% of a dose was eliminated mainly in the feces within 7 days, and parent drug accounted for 69% of the dose.
     
    Affected cytochrome P450 isoenzymes:
     
    Nilotinib is metabolized in the liver by CYP3A4; concomitant administration of strong CYP3A4 inhibitors or inducers may increase or decrease nilotinib concentrations significantly. Avoid administering nilotinib with strong CYP3A4 inhibitors. If concomitant use cannot be avoided, a nilotinib dose reduction should be considered and the QT interval should be monitored closely. Because potent CYP3A4 inducers may significantly reduce nilotinib exposure, consider alternative therapeutic agents with less potential for CYP3A4 induction. In vitro, nilotinib is a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, and UGT1A1; the concentrations of drugs eliminated by these enzymes may be increased with nilotinib use. Additionally, nilotinib has been shown to induce CYP2B6, CYP2C8, and CYP2C9 in in vitro studies; the concentrations of drugs eliminated by these enzymes may be decreased with nilotinib use. Use nilotinib with caution with agents that are substrates for CYP3A4 or CYP2C9 that also have a narrow therapeutic index. Nilotinib is a substrate and an inhibitor of P-glycoprotein (P-gp); therefore, use nilotinib with caution in patients receiving other agents that inhibit P-gp or are substrates for P-gp.

    Oral Route

    The bioavailability of nilotinib is significantly increased by food. The systemic exposure of nilotinib was increased 82% when taken 30 minutes prior to a high-fat meal as compared to the fasted state. Peak serum concentrations are achieved 3 hours after oral administration, and steady state concentrations are achieved on day 8. Daily serum exposure to nilotinib 400 mg every 12 hours was 35% higher at steady state than with 800 mg once daily. No relevant increase in exposure to nilotinib occurred with a dose of 600 mg twice daily as compared with 400 mg twice daily.