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  • CLASSES

    Small Molecule Antineoplastic Receptor Tyrosine Kinase ROS1 Inhibitors
    Small Molecule Antineoplastic Tropomyosin Receptor Kinase (TRK) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Tyrosine kinase inhibitor with activity against multiple targets
    Used for ROS1-positive non-small cell lung cancer (NSCLC) and for solid tumors with a neurotrophic tyrosine receptor kinase (NTRK) gene fusion
    May cause QT prolongation, cognitive impairment, mood disorders, dizziness, and sleep disturbances; use with caution in patients at risk for these conditions

    COMMON BRAND NAMES

    ROZLYTREK

    HOW SUPPLIED

    Entrectinib/ROZLYTREK Oral Cap: 100mg, 200mg

    DOSAGE & INDICATIONS

    For the treatment of non-small cell lung cancer (NSCLC).
    For the treatment of metastatic ROS1-positive non-small cell lung cancer (NSCLC).
    NOTE: The FDA has designated entrectinib as an orphan drug for the treatment of ROS1-positive non-small cell lung cancer (NSCLC)
    NOTE: Select patients for treatment based on the presence of ROS1 rearrangement(s) in tumor specimens. An FDA-approved test for detection of ROS1 rearrangement(s) in NSCLC is not available.
    Oral dosage
    Adults

    600 mg PO once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with various doses and schedules of entrectinib (90% received entrectinib 600 mg once daily) resulted in an overall response rate of 78% (complete response, 6%) in a pooled subgroup of patients with ROS1-positive metastatic NSCLC (n = 51) enrolled in one of three multicenter, single-arm, open-label trials (ALKA, STARTRK-1, and STARTRK-2). Seventy percent of patients had a response duration of 9 months or more, while the duration of response lasted for 12 months or more in 55% of patients and for 18 months or more in 30% of patients.

    For the treatment of neurotrophic receptor tyrosine kinase-positive solid tumors.
    NOTE: The FDA has designated entrectinib as an orphan drug for the treatment of neurotrophic tyrosine kinase fusion-positive solid tumors.
    For the treatment of metastatic neurotrophic receptor tyrosine kinase-positive solid tumors that have either progressed following treatment or have no satisfactory alternative therapy, where surgical resection will likely result in severe morbidity.
    NOTE: Select patients for treatment based on the presence of a neurotrophic tyrosine kinase (NTRK) gene fusion. An FDA-approved test for detection of NTRK gene fusion in solid tumors is not available.[64567]
    Oral dosage
    Adults

    600 mg PO once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with entrectinib resulted in an overall response rate (ORR) of 57% (complete response, 7.4%) in a pooled subgroup of adult patients with unresectable or metastatic solid tumors with an NTRK gene fusion (n = 54) enrolled in one of three multicenter, single-arm, open-label clinical trials (ALKA, STARTRK-1, and STARTRK-2); patients were required to have progressed after systemic therapy for their disease, if available, or would have required surgery causing significant morbidity for locally advanced disease. Sixty-eight percent of patients had a response duration of 6 months or more, while 61% had a duration of response of 9 months or more, and 45% had a duration of response of 12 months or more. Response rates by tumor type were salivary tumors with an ORR of 86% (n = 7), breast cancer with an ORR of 83% (n = 6), non-small cell lung cancer with an ORR of 70% (n = 10), sarcoma with an ORR of 46% (n = 13), colorectal cancer with an ORR of 25% (n = 4), and thyroid cancer with an ORR of 20% (n = 5).[64567]

    Children and Adolescents 12 years and older, with BSA greater than 1.5 square meters

    600 mg PO once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with entrectinib resulted in an overall response rate (ORR) of 57% (complete response, 7.4%) in a pooled subgroup of adult patients with unresectable or metastatic solid tumors with an NTRK gene fusion (n = 54) enrolled in one of three multicenter, single-arm, open-label clinical trials (ALKA, STARTRK-1, and STARTRK-2); patients were required to have progressed after systemic therapy for their disease, if available, or would have required surgery causing significant morbidity for locally advanced disease. Sixty-eight percent of patients had a response duration of 6 months or more, while 61% had a duration of response of 9 months or more, and 45% had a duration of response of 12 months or more. Response rates by tumor type were salivary tumors with an ORR of 86% (n = 7), breast cancer with an ORR of 83% (n = 6), non-small cell lung cancer with an ORR of 70% (n = 10), sarcoma with an ORR of 46% (n = 13), colorectal cancer with an ORR of 25% (n = 4), and thyroid cancer with an ORR of 20% (n = 5).[64567]

    Children and Adolescents 12 years and older, with BSA 1.11 to 1.5 square meters

    500 mg PO once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with entrectinib resulted in an overall response rate (ORR) of 57% (complete response, 7.4%) in a pooled subgroup of adult patients with unresectable or metastatic solid tumors with an NTRK gene fusion (n = 54) enrolled in one of three multicenter, single-arm, open-label clinical trials (ALKA, STARTRK-1, and STARTRK-2); patients were required to have progressed after systemic therapy for their disease, if available, or would have required surgery causing significant morbidity for locally advanced disease. Sixty-eight percent of patients had a response duration of 6 months or more, while 61% had a duration of response of 9 months or more, and 45% had a duration of response of 12 months or more. Response rates by tumor type were salivary tumors with an ORR of 86% (n = 7), breast cancer with an ORR of 83% (n = 6), non-small cell lung cancer with an ORR of 70% (n = 10), sarcoma with an ORR of 46% (n = 13), colorectal cancer with an ORR of 25% (n = 4), and thyroid cancer with an ORR of 20% (n = 5).[64567]

    Children and Adolescents 12 years and older, with BSA 0.91 to 1.10 square meters

    400 mg PO once daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with entrectinib resulted in an overall response rate (ORR) of 57% (complete response, 7.4%) in a pooled subgroup of adult patients with unresectable or metastatic solid tumors with an NTRK gene fusion (n = 54) enrolled in one of three multicenter, single-arm, open-label clinical trials (ALKA, STARTRK-1, and STARTRK-2); patients were required to have progressed after systemic therapy for their disease, if available, or would have required surgery causing significant morbidity for locally advanced disease. Sixty-eight percent of patients had a response duration of 6 months or more, while 61% had a duration of response of 9 months or more, and 45% had a duration of response of 12 months or more. Response rates by tumor type were salivary tumors with an ORR of 86% (n = 7), breast cancer with an ORR of 83% (n = 6), non-small cell lung cancer with an ORR of 70% (n = 10), sarcoma with an ORR of 46% (n = 13), colorectal cancer with an ORR of 25% (n = 4), and thyroid cancer with an ORR of 20% (n = 5).[64567]

    MAXIMUM DOSAGE

    Adults

    600 mg PO once daily.

    Geriatric

    600 mg PO once daily.

    Adolescents

    BSA more than 1.5 m2: 600 mg PO once daily.
    BSA 1.11 to 1.5 m2: 500 mg PO once daily.
    BSA 0.91 to 1.10 m2: 400 mg PO once daily.
    BSA 0.9 m2 or less: Safety and efficacy have not been established.

    Children

    12 years and older:
    BSA more than 1.5 m2: 600 mg PO once daily.
    BSA 1.11 to 1.5 m2: 500 mg PO once daily.
    BSA 0.91 to 1.10 m2: 400 mg PO once daily.
    BSA 0.9 m2 or less: Safety and efficacy have not been established.
     
    11 years or less: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment:
    Mild hepatic impairment (total bilirubin 1.5 times the upper limit of normal (ULN) or less): No dosage adjustment is recommended.
    Moderate to severe hepatic impairment (total bilirubin greater than 1.5 times ULN): Dosing recommendations for entrectinib are not available as entrectinib has not been studied in this patient population.[64567]
     
    Treatment-Related Hepatotoxicity:
    Grade 3: Hold entrectinib. If hepatic function recovers to grade 1 or less (or baseline) within 4 weeks, resume entrectinib therapy at the same dose for the first occurrence, and at a reduced dose for recurrent grade 3 hepatotoxicity. Permanently discontinue entrectinib therapy if hepatic function does not recover to grade 1 or less (or baseline within 4 weeks) or for patients who are unable to tolerate a minimum dose of 200 mg PO once daily.
    Grade 4: Hold entrectinib. If hepatic function recovers to grade 1 or less (or baseline) within 4 weeks, resume entrectinib therapy at a reduced dose. Permanently discontinue entrectinib therapy if hepatic function does not recover to grade 1 or less (or baseline within 4 weeks) or for patients who are unable to tolerate a minimum dose of 200 mg PO once daily.
    ALT or AST greater than 3 times ULN with concurrent total bilirubin greater than 1.5 times ULN, in the absence of cholestasis or hemolysis: Permanently discontinue entrectinib therapy.[64567]

    Renal Impairment

    CrCl 30 to 89 mL/minute: No dosage adjustment is recommended.
    CrCl less than 30 mL/minute: Dosing recommendations for entrectinib are not available. Entrectinib has not been studied in this patient population.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    May administer capsules with or without food.
    Swallow whole. Do not open, crush, chew or dissolve the capsule contents.
    Avoid grapefruit juice and other grapefruit products during administration and treatment.
    If a dose is missed, make it up unless the next dose is due within 12 hours. Do not administer 2 doses at the same time.
    If a patient vomits immediately after taking a dose, readminister the dose.

    STORAGE

    ROZLYTREK:
    - Store below 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Angina, cardiac disease, coronary artery bypass graft surgery (CABG), heart failure, myocardial infarction, myocarditis, ventricular dysfunction

    Use entrectinib with caution in patients with a history of heart failure or cardiac disease. Congestive heart failure (CHF) has been reported in patients treated with entrectinib across clinical trials. In these trials, baseline cardiac function and routine cardiac monitoring other than ECGs were not conducted and eligibility criteria excluded patients with symptomatic CHF, myocardial infarction, unstable angina, and coronary artery bypass graft surgery (CABG) within 3 months of study entry. Assess left ventricular ejection fraction (LVEF) prior to initiation of therapy in patients with symptoms or known risk factors for CHF; monitor for signs and symptoms of ventricular dysfunction or CHF including shortness of breath and edema. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for patients who develop heart failure. Myocarditis in the absence of CHF has also been reported. For patients with myocarditis, with or without a decreased ejection fraction, MRI or cardiac biopsy may be required to make the diagnosis.[64567]

    Anxiety, behavioral changes, depression, driving or operating machinery

    Use entrectinib with caution in patients with a history of anxiety, depression, or cognitive or mental status changes. A broad spectrum of central nervous system (CNS) adverse reactions occurred in patients treated with entrectinib across clinical trials, including cognitive impairment, behavioral changes / mood disorders, dizziness, and insomnia or other sleep disturbances. The incidence of CNS adverse reactions, in general, was similar in patients with and without CNS metastases, although the incidence of dizziness, headache, paresthesias, balance disorders, and confusion appeared to be increased in patients with CNS metastases who had received prior CNS irradiation; the median time to onset was 1 month. Advise patient against driving or operating machinery if they are experiencing CNS adverse reactions. An interruption of therapy followed by dose reduction or discontinuation of therapy may be necessary for patients who develop CNS adverse reactions, depending on the severity.[64567]

    Bone fractures

    The risk of skeletal bone fractures is increased with entrectinib therapy. In adults, some fractures occurred after a fall or other trauma to the affected area; in pediatric patients, all fractures occurred in patients with minimal or no trauma. In general, there was an inadequate assessment for tumor involvement at the site of the fracture; however, radiologic abnormalities possibly indicative of tumor involvement were reported in some patients. Promptly evaluate patients with signs or symptoms of fractures (e.g., pain, changes in mobility, deformity). There are no data on the healing of known fractures and the risk of future fractures.[64567]

    Hepatic disease, hepatotoxicity

    Hepatotoxicity has also been reported in patients treated with entrectinib across clinical trials with a median time to onset of 2 weeks. Monitor liver function tests including ALT and AST every 2 weeks for the first month of treatment, then monthly thereafter and as clinically indicated. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary. Use entrectinib with caution in patients with known hepatic disease. No dosage adjustment is recommended for patients with mild hepatic impairment, but entrectinib has not been studied in patients with moderate [total bilirubin more than 1.5 to 3 times the upper level of normal (ULN)] and severe (total bilirubin more than 3 times ULN) hepatic impairment.

    Hyperuricemia, tumor lysis syndrome (TLS)

    Hyperuricemia has been reported in patients treated with entrectinib across clinical trials (n = 355), including one patient who died due to tumor lysis syndrome (TLS). Assess serum uric acid levels prior to initiating entrectinib therapy and periodically during treatment; monitor for signs and symptoms of hyperuricemia. If hyperuricemia occurs, interrupt entrectinib therapy and begin treatment with urate-lowering medications as clinically indicated; a dose reduction may be necessary.

    Alcoholism, bradycardia, cardiac arrhythmias, coronary artery disease, diabetes mellitus, electrolyte imbalance, females, geriatric, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, QT prolongation, thyroid disease

    Use entrectinib with caution in patients with heart disease or other conditions that may increase the risk of QT prolongation including patients with known long QT syndromes, clinically significant bradycardia or bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Of patients receiving entrectinib across the clinical trials, 3.1% of patients with at least one post-baseline ECG assessment experienced QTcF interval prolongation of more than 60 ms after starting the drug and 0.6% had a QTcF interval more than 500 ms. Known risk factors for QT prolongation in the literature include cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalance. Females, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic impairment may also be at increased risk for QT prolongation. Monitor these patients for QT prolongation. Assess the QT interval and electrolytes at baseline and periodically during treatment, adjusting the frequency based on risk factors. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs.[28432] [28457] [56959] [56961] [56592] [56963] [64567]

    Visual impairment

    Use with caution in patients with visual impairment; a variety of vision disorders and changes were reported in patients treated with entrectinib across pre-approval clinical trials. For patients with new visual changes or changes that interfere with activities of daily living, withhold entrectinib until improvement or stabilization and conduct an ophthalmological evaluation as clinically appropriate. Upon improvement or stabilization, resume the drug at same or reduced dose.

    Pregnancy

    Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, animal studies, and its mechanism of action, entrectinib can cause fetal harm or death when administered during pregnancy. Pregnancy should be avoided by females of reproductive potential during entrectinib treatment and for at least 5 weeks after the final dose. Women who are pregnant or who become pregnant while receiving entrectinib should be apprised of the potential hazard to the fetus. There are no available data on the use of entrectinib in pregnant women. Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis. Administration of entrectinib to pregnant rats during organogenesis resulted in body closure defects (e.g., omphalocele and gastroschisis) and malformations of the vertebrae, ribs, and limbs (micromelia and adactyly) at maternal exposures approximately 2.7 times the human exposure at the recommended dose (600 mg); embryolethality did not occur. Lower fetal weight and reduced skeletal ossification occurred at approximately 0.2 and 0.9 times the human exposure at the recommended dose, respectively.

    Contraception requirements, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during entrectinib treatment. Entrectinib can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 5 weeks after the final dose of entrectinib. Females of reproductive potential should undergo pregnancy testing prior to initiation of entrectinib. Women who become pregnant while receiving entrectinib should be apprised of the potential hazard to the fetus. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should use effective contraception during and for at least 3 months after treatment with entrectinib.

    Breast-feeding

    Due to the potential for serious adverse reactions in a nursing infant from entrectinib, advise women to discontinue breast-feeding during treatment and for 7 days after the final dose. It is not known whether entrectinib is present in human milk, although many drugs are excreted in human milk.[64567]

    Children, infants

    There is limited clinical experience with entrectinib in children and infants. The safety and efficacy of entrectinib in pediatric patients less than 12 years of age with solid tumors who have an NTRK gene fusion have not been established. The safety and efficacy of entrectinib in pediatric patients with ROS1-positive NSCLC have also not been established. The safety of entrectinib in pediatric patients 12 years and older was established based on extrapolation of data in adults and 30 pediatric patients (younger than 2 years, n = 2; 2 to 11 years, n = 23; 12 to 17 years, n = 5). Of the studied pediatric patients, 57% had metastatic disease and 44% had locally advanced disease. The most common cancers were neuroblastoma (47%), primary CNS tumors (30%), and sarcoma (10%). In an expanded safety database including 338 adult patients and 30 pediatric patients, neutropenia, bone fractures, weight gain, thrombocytopenia, lymphopenia, increased GGT, and device-related infections were more common in pediatric patients. However, due to the small number of patients, single-arm trial design, and other confounding factors, it is not possible to determine whether the difference in the incidence of adverse reactions to entrectinib is related to patient age or other factors. The efficacy of entrectinib in adolescents is based on extrapolation of data from 3 open-label, single-arm clinical trials in adult patients with solid tumors having an NTRK gene fusion. Also, pharmacokinetic data in adolescents (age 12 and older) based on BSA resulted in similar systemic exposure compared to adults receiving the recommended dose of 600 mg.[64567]

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 2.0-27.0
    bone fractures / Delayed / 5.0-23.0
    weight gain / Delayed / 7.0-20.0
    lymphopenia / Delayed / 1.0-12.0
    hyperuricemia / Delayed / 1.7-10.0
    thrombocytopenia / Delayed / 0.3-10.0
    anemia / Delayed / 9.0-9.0
    elevated hepatic enzymes / Delayed / 0-7.0
    hypophosphatemia / Delayed / 7.0-7.0
    dyspnea / Early / 6.0-6.0
    infection / Delayed / 0-6.0
    hyperamylasemia / Delayed / 5.4-5.4
    fatigue / Early / 5.0-5.0
    pulmonary embolism / Delayed / 3.9-3.9
    hyperglycemia / Delayed / 3.8-3.8
    hypoxia / Early / 3.4-3.4
    QT prolongation / Rapid / 0.6-3.1
    pleural effusion / Delayed / 3.1-3.1
    hypoalbuminemia / Delayed / 2.9-2.9
    hypotension / Rapid / 2.8-2.8
    syncope / Early / 2.5-2.5
    heart failure / Delayed / 2.3-2.3
    dizziness / Early / 2.2-2.2
    renal failure (unspecified) / Delayed / 0-2.1
    visual impairment / Early / 2.0-2.0
    diarrhea / Early / 2.0-2.0
    hypocalcemia / Delayed / 1.8-1.8
    hyperkalemia / Delayed / 1.5-1.5
    edema / Delayed / 1.1-1.1
    peripheral neuropathy / Delayed / 1.1-1.1
    dehydration / Delayed / 1.1-1.1
    myalgia / Early / 1.1-1.1
    back pain / Delayed / 1.0-1.0
    hypernatremia / Delayed / 0.9-0.9
    ataxia / Delayed / 0.8-0.8
    rash / Early / 0.8-0.8
    vomiting / Early / 0.8-0.8
    fever / Early / 0.8-0.8
    myasthenia / Delayed / 0.8-0.8
    abdominal pain / Early / 0.6-0.6
    constipation / Delayed / 0.6-0.6
    arthralgia / Delayed / 0.6-0.6
    myocarditis / Delayed / 0.3-0.3
    headache / Early / 0.3-0.3
    dysesthesia / Delayed / 0.3-0.3
    anorexia / Delayed / 0.3-0.3
    nausea / Early / 0.3-0.3
    dysgeusia / Early / 0.3-0.3
    GI perforation / Delayed / 0.3-0.3
    cough / Delayed / 0.3-0.3
    hepatotoxicity / Delayed / Incidence not known
    retinal hemorrhage / Delayed / Incidence not known
    corneal erosion / Delayed / Incidence not known
    tumor lysis syndrome (TLS) / Delayed / Incidence not known

    Moderate

    confusion / Early / 2.0-11.0
    dysphagia / Delayed / 10.0-10.0
    blurred vision / Early / 8.7-8.7
    photophobia / Early / 5.1-5.1
    memory impairment / Delayed / 3.7-3.7
    depression / Delayed / 2.8-2.8
    amnesia / Delayed / 2.5-2.5
    aphasia / Delayed / 2.3-2.3
    photopsia / Delayed / 1.3-1.3
    hallucinations / Early / 1.1-1.1
    cataracts / Delayed / 1.1-1.1
    peripheral edema / Delayed / Incidence not known
    fluid retention / Delayed / Incidence not known
    euphoria / Early / Incidence not known
    neuropathic pain / Delayed / Incidence not known
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
    hyperesthesia / Delayed / Incidence not known
    orthostatic hypotension / Delayed / Incidence not known

    Mild

    paresthesias / Delayed / 6.0-20.0
    drowsiness / Early / 7.0-7.0
    insomnia / Early / 7.0-7.0
    anxiety / Delayed / 4.8-4.8
    diplopia / Early / 3.1-3.1
    agitation / Early / 2.0-2.0
    emotional lability / Early / Incidence not known
    irritability / Delayed / Incidence not known
    vertigo / Early / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    maculopapular rash / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    musculoskeletal pain / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital: (Major) Avoid coadministration of entrectinib with butalbital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Acetaminophen; Butalbital; Caffeine: (Major) Avoid coadministration of entrectinib with butalbital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration of entrectinib with butalbital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Aclidinium; Formoterol: (Moderate) Coadministration of entrectinib and long-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Albuterol: (Minor) Coadministration of entrectinib and short-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Albuterol; Ipratropium: (Minor) Coadministration of entrectinib and short-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Alfuzosin: (Major) Avoid coadministration of entrectinib with alfuzosin due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Alfuzosin may prolong the QT interval in a dose-dependent manner.
    Amiodarone: (Major) Avoid coadministration of entrectinib with amiodarone due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amitriptyline: (Minor) Coadministration of entrectinib and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amitriptyline; Chlordiazepoxide: (Minor) Coadministration of entrectinib and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amobarbital: (Major) Avoid coadministration of entrectinib with amobarbital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; amobarbital is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of entrectinib with clarithromycin due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If clarithromycin is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of clarithromycin. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of entrectinib with clarithromycin due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If clarithromycin is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of clarithromycin. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Anagrelide: (Major) Avoid coadministration of entrectinib with anagrelide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects.
    Apalutamide: (Major) Avoid coadministration of entrectinib with apalutamide due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
    Apomorphine: (Major) Avoid coadministration of entrectinib with apomorphine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Limited data indicate that QT prolongation is possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines.
    Aprepitant, Fosaprepitant: (Major) Avoid coadministration of entrectinib with aprepitant, fosaprepitant due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If aprepitant, fosaprepitant is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of aprepitant, fosaprepitant. Entrectinib is a CYP3A4 substrate; when administered as a 3 day oral regimen, aprepitant is a moderate inhibitor of CYP3A4. Single oral and IV doses have not been shown to alter concentrations of CYP3A4 substrates. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Arformoterol: (Moderate) Coadministration of entrectinib and long-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Aripiprazole: (Major) Avoid coadministration of entrectinib with aripiprazole due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.
    Arsenic Trioxide: (Major) Avoid coadministration of entrectinib with arsenic trioxide due to the risk of QT prolongation. If concomitant drug use is unavoidable, frequently monitor electrocardiograms. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. Entrectinib has been associated with QT prolongation.
    Artemether; Lumefantrine: (Major) Avoid coadministration of entrectinib with artemether; lumefantrine due to the risk of QT prolongation. Consider ECG monitoring if entrectinib must be used with or after artemether; lumefantrine treatment. Artemether; lumefantrine is associated with prolongation of the QT interval. Entrectinib has been associated with QT prolongation.
    Asenapine: (Major) Avoid coadministration of entrectinib with asenapine due to the risk of QT prolongation. Both entrectinib and asenapine have been associated with QT prolongation.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid coadministration of entrectinib with butalbital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Avoid coadministration of entrectinib with butalbital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; butalbital is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Atazanavir: (Major) Avoid coadministration of entrectinib with atazanavir due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If atazanavir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of atazanavir. Entrectinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of entrectinib with atazanavir due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If atazanavir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of atazanavir. Entrectinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study. (Major) Avoid coadministration of entrectinib with cobicistat due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If cobicistat is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of cobicistat. Entrectinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Atomoxetine: (Major) Avoid coadministration of entrectinib with atomoxetine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of entrectinib with phenobarbital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
    Azithromycin: (Major) Avoid coadministration of entrectinib with aripiprazole due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance.
    Bedaquiline: (Major) Avoid coadministration of entrectinib with bedaquiline due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs. Discontinue bedaquiline if evidence of serious ventricular arrhythmia or QTcF interval greater than 500 milliseconds. Bedaquiline prolongs the QT interval. Entrectinib has been associated with QT prolongation.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of entrectinib with phenobarbital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
    Bexarotene: (Major) Avoid coadministration of entrectinib with bexarotene due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; bexarotene is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Avoid coadministration of entrectinib with metronidazole due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Avoid coadministration of entrectinib with metronidazole due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Bosentan: (Major) Avoid coadministration of entrectinib with bosentan due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; bosentan is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Brigatinib: (Moderate) Monitor for decreased entrectinib efficacy during coadministration of brigatinib as concurrent use may decrease entrectinib exposure; an entrectinib dose increase may be needed. Entrectinib is a CYP3A4 substrate; brigatinib is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Budesonide; Formoterol: (Moderate) Coadministration of entrectinib and long-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Buprenorphine: (Major) Avoid coadministration of entrectinib with buprenorphine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
    Buprenorphine; Naloxone: (Major) Avoid coadministration of entrectinib with buprenorphine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
    Carbamazepine: (Major) Avoid coadministration of entrectinib with carbamazepine due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; carbamazepine is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
    Ceritinib: (Major) Avoid coadministration of entrectinib with ceritinib due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If ceritinib is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of ceritinib. Additionally, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for ceritinib if QT prolongation occurs. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; ceritinib is a strong CYP3A4 inhibitor that is associated with concentration-dependent QT prolongation. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Chloramphenicol: (Major) Avoid coadministration of entrectinib with chloramphenicol due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If chloramphenicol is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of chloramphenicol. Entrectinib is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Chloroquine: (Major) Avoid coadministration of entrectinib with chloroquine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. 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.
    Chlorpromazine: (Major) Avoid coadministration of entrectinib with chlorpromazine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP).
    Ciprofloxacin: (Major) Avoid coadministration of entrectinib with ciprofloxacin due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If ciprofloxacin is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of ciprofloxacin. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; ciprofloxacin is a moderate CYP3A4 inhibitor that has been associated with rare cases of QT prolongation and torsade de pointes (TdP) during postmarketing surveillance. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Cisapride: (Severe) Coadministration of cisapride with entrectinib is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). QT prolongation and ventricular arrhythmias, including TdP and death, have been reported with cisapride. Entrectinib has been associated with QT prolongation.
    Citalopram: (Major) Avoid coadministration of entrectinib with citalopram due to the risk of QT prolongation. If concurrent therapy is considered essential, ECG monitoring is recommended. Entrectinib has been associated with QT prolongation. Citalopram causes dose-dependent QT interval prolongation.
    Clarithromycin: (Major) Avoid coadministration of entrectinib with clarithromycin due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If clarithromycin is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of clarithromycin. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; clarithromycin is a strong CYP3A4 inhibitor that is associated with an established risk for QT prolongation and torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Clofazimine: (Major) Avoid coadministration of entrectinib with clofazimine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs. Entrectinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients receiving clofazimine in combination with QT prolonging medications.
    Clomipramine: (Minor) Coadministration of entrectinib and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Clozapine: (Major) Avoid coadministration of entrectinib with clozapine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
    Cobicistat: (Major) Avoid coadministration of entrectinib with cobicistat due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If cobicistat is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of cobicistat. Entrectinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Codeine; Phenylephrine; Promethazine: (Major) Avoid coadministration of entrectinib with promethazine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Codeine; Promethazine: (Major) Avoid coadministration of entrectinib with promethazine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Conivaptan: (Major) Avoid coadministration of entrectinib with conivaptan due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If conivaptan is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of conivaptan. Entrectinib is a CYP3A4 substrate; conivaptan is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Crizotinib: (Major) Avoid coadministration of entrectinib with crizotinib due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If crizotinib is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of crizotinib. Additionally, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; crizotinib is a moderate CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Cyclosporine: (Major) Avoid coadministration of entrectinib with cyclosporine due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If cyclosporine is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of cyclosporine. Entrectinib is a CYP3A4 substrate; cyclosporine is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Dabrafenib: (Major) Avoid coadministration of entrectinib with dabrafenib due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; dabrafenib is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Danazol: (Major) Avoid coadministration of entrectinib with danazol due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If danazol is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of danazol. Entrectinib is a CYP3A4 substrate; danazol is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Darunavir: (Major) Avoid coadministration of entrectinib with darunavir due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If darunavir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of darunavir. Entrectinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Darunavir; Cobicistat: (Major) Avoid coadministration of entrectinib with cobicistat due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If cobicistat is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of cobicistat. Entrectinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study. (Major) Avoid coadministration of entrectinib with darunavir due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If darunavir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of darunavir. Entrectinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of entrectinib with cobicistat due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If cobicistat is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of cobicistat. Entrectinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study. (Major) Avoid coadministration of entrectinib with darunavir due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If darunavir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of darunavir. Entrectinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of entrectinib with ritonavir due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If ritonavir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of ritonavir. Entrectinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Dasatinib: (Major) Avoid coadministration of entrectinib with dasatinib due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
    Degarelix: (Major) Avoid coadministration of entrectinib with degarelix due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval.
    Delavirdine: (Major) Avoid coadministration of entrectinib with delavirdine due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If delavirdine is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of delavirdine. Entrectinib is a CYP3A4 substrate; delavirdine is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Desflurane: (Major) Avoid coadministration of entrectinib with halogenated anesthetics due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Halogenated anesthetics can prolong the QT interval.
    Desipramine: (Minor) Coadministration of entrectinib and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Deutetrabenazine: (Major) Avoid coadministration of entrectinib with deutetrabenazine due to the risk of QT prolongation. If coadministration is necessary, closely monitor the patient for QT interval prolongation. For patients taking a deutetrabenazine dosage more than 24 mg/day with entrectinib, assess the QTc interval before and after increasing the dosage of either medication. Entrectinib has been associated with QT prolongation. Clinically relevant QTc prolongation may occur with deutetrabenazine.
    Dexamethasone: (Major) Avoid coadministration of entrectinib with dexamethasone due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; dexamethasone is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Dextromethorphan; Promethazine: (Major) Avoid coadministration of entrectinib with promethazine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Dextromethorphan; Quinidine: (Major) Avoid coadministration of entrectinib with quinidine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP).
    Diltiazem: (Major) Avoid coadministration of entrectinib with diltiazem due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If diltiazem is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of diltiazem. Entrectinib is a CYP3A4 substrate; diltiazem is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Disopyramide: (Major) Avoid coadministration of entrectinib with disopyramide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Disopyramide administration is associated with QT prolongation and torsade de pointes (TdP).
    Dofetilide: (Major) Avoid coadministration of entrectinib with dofetilide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Dolasetron: (Major) Avoid coadministration of entrectinib with dolasetron due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir; Rilpivirine: (Major) Avoid coadministration of entrectinib with rilpivirine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Donepezil: (Major) Avoid coadministration of entrectinib with donepezil due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Donepezil; Memantine: (Major) Avoid coadministration of entrectinib with donepezil due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Doxepin: (Minor) Coadministration of entrectinib and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Dronedarone: (Severe) Coadministration of dronedarone with entrectinib is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Entrectinib has been associated with QT prolongation. 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 1,600 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 coadministration of entrectinib with droperidol due to the risk of QT prolongation. If coadministration cannot be avoided, use extreme caution; initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Entrectinib has been associated with QT prolongation. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes (TdP). Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal.
    Duvelisib: (Major) Avoid coadministration of entrectinib with duvelisib due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If duvelisib is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of duvelisib. Entrectinib is a CYP3A4 substrate; duvelisib is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Efavirenz: (Major) Avoid coadministration of entrectinib with efavirenz due to additive risk of QT prolongation and decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; efavirenz is a moderate CYP3A4 inducer that has been associated with QTc prolongation. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid coadministration of entrectinib with efavirenz due to additive risk of QT prolongation and decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; efavirenz is a moderate CYP3A4 inducer that has been associated with QTc prolongation. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of entrectinib with efavirenz due to additive risk of QT prolongation and decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; efavirenz is a moderate CYP3A4 inducer that has been associated with QTc prolongation. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Elagolix: (Major) Avoid coadministration of entrectinib with elagolix due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; elagolix is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Eliglustat: (Major) Avoid coadministration of entrectinib with eliglustat due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of entrectinib with cobicistat due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If cobicistat is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of cobicistat. Entrectinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of entrectinib with cobicistat due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If cobicistat is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of cobicistat. Entrectinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid coadministration of entrectinib with rilpivirine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Avoid coadministration of entrectinib with rilpivirine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Encorafenib: (Major) Avoid coadministration of encorafenib and entrectinib due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib has been associated with dose-dependent QT prolongation. Entrectinib has also been associated with QT prolongation.
    Enflurane: (Major) Avoid coadministration of entrectinib with halogenated anesthetics due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Halogenated anesthetics can prolong the QT interval.
    Enzalutamide: (Major) Avoid coadministration of entrectinib with enzalutamide due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
    Eribulin: (Major) Avoid coadministration of entrectinib with eribulin due to the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended. Both entrectinib and eribulin have been associated with QT prolongation.
    Erythromycin: (Major) Avoid coadministration of entrectinib with erythromycin due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If erythromycin is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of erythromycin. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; erythromycin is a moderate CYP3A4 inhibitor that is associated with QT prolongation and torsade de pointes (TdP). Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Erythromycin; Sulfisoxazole: (Major) Avoid coadministration of entrectinib with erythromycin due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If erythromycin is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of erythromycin. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; erythromycin is a moderate CYP3A4 inhibitor that is associated with QT prolongation and torsade de pointes (TdP). Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Escitalopram: (Major) Avoid coadministration of entrectinib with escitalopram due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Escitalopram has been associated with a risk of QT prolongation and torsade de pointes (TdP).
    Eslicarbazepine: (Major) Avoid coadministration of entrectinib with eslicarbazepine due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; eslicarbazepine is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Etravirine: (Major) Avoid coadministration of entrectinib with etravirine due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; etravirine is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Ezogabine: (Major) Avoid coadministration of entrectinib with ezogabine due to the risk of QT prolongation. Both entrectinib and ezogabine have been associated with QT prolongation.
    Fedratinib: (Major) Avoid coadministration of entrectinib with fedratinib due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If fedratinib is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of fedratinib. Entrectinib is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Fingolimod: (Major) Avoid coadministration of entrectinib with fingolimod due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
    Flecainide: (Major) Avoid coadministration of entrectinib with flecainide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsade de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Fluconazole: (Major) Avoid coadministration of entrectinib with fluconazole due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If fluconazole is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of fluconazole. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; fluconazole is a moderate CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Fluoxetine: (Major) Avoid coadministration of entrectinib with fluoxetine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine.
    Fluoxetine; Olanzapine: (Major) Avoid coadministration of entrectinib with fluoxetine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. (Major) Avoid coadministration of entrectinib with olanzapine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Fluphenazine: (Minor) Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as entrectinib.
    Fluticasone; Salmeterol: (Moderate) Coadministration of entrectinib and long-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Coadministration of entrectinib and long-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Vilanterol: (Moderate) Coadministration of entrectinib and long-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluvoxamine: (Major) Avoid coadministration of entrectinib with fluvoxamine due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If fluvoxamine is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of fluvoxamine. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; fluvoxamine is a moderate CYP3A4 inhibitor that has been associated with QT prolongation and torsade de pointes (TdP) in postmarketing use. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Formoterol: (Moderate) Coadministration of entrectinib and long-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Formoterol; Mometasone: (Moderate) Coadministration of entrectinib and long-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fosamprenavir: (Major) Avoid coadministration of entrectinib with fosamprenavir due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If fosamprenavir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of fosamprenavir. Entrectinib is a CYP3A4 substrate; fosamprenavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Foscarnet: (Major) Avoid coadministration of entrectinib with foscarnet due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of foscarnet.
    Fosphenytoin: (Major) Avoid coadministration of entrectinib with fosphenytoin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; fosphenytoin is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
    Gemifloxacin: (Major) Avoid coadministration of entrectinib with gemifloxacin due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Major) Avoid coadministration of entrectinib with gemtuzumab due to the risk of QT prolongation. If coadministration is necessary, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Entrectinib has been associated with QT prolongation. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.
    Gilteritinib: (Major) Avoid coadministration of entrectinib with gilteritinib due to the risk of QT prolongation. If coadministration is necessary, monitor for evidence of QT prolongation during treatment. Both entrectinib and gilteritinib have been associated with QT prolongation.
    Glasdegib: (Major) Avoid coadministration of glasdegib with entrectinib due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Entrectinib has been associated with QT prolongation.
    Glycopyrrolate; Formoterol: (Moderate) Coadministration of entrectinib and long-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Goserelin: (Major) Avoid coadministration of entrectinib with goserelin due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Androgen deprivation therapy (i.e., goserelin) may prolong the QT/QTc interval.
    Granisetron: (Major) Avoid coadministration of entrectinib with granisetron due to the risk of QT prolongation. Both entrectinib and granisetron have been associated with QT prolongation.
    Grapefruit juice: (Major) Advise patients to avoid grapefruit juice or grapefruit-containing foods while taking entrectinib due to increased entrectinib exposure. Entrectinib is a CYP3A4 substrate; grapefruit juice is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Halogenated Anesthetics: (Major) Avoid coadministration of entrectinib with halogenated anesthetics due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Halogenated anesthetics can prolong the QT interval.
    Haloperidol: (Major) Avoid coadministration of entrectinib with haloperidol due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
    Halothane: (Major) Avoid coadministration of entrectinib with halogenated anesthetics due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Halogenated anesthetics can prolong the QT interval.
    Histrelin: (Major) Avoid coadministration of entrectinib with histrelin due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Hydroxychloroquine: (Major) Avoid coadministration of entrectinib with hydroxychloroquine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Hydroxychloroquine also prolongs the QT interval.
    Hydroxyzine: (Major) Avoid coadministration of entrectinib with hydroxyzine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Postmarketing data indicate that hydroxyzine causes QT prolongation and torsade de pointes (TdP).
    Ibutilide: (Major) Avoid coadministration of entrectinib with ibutilide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Ibutilide administration can cause QT prolongation and torsade 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.
    Idelalisib: (Major) Avoid coadministration of entrectinib with idelalisib due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If idelalisib is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of idelalisib. Entrectinib is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Iloperidone: (Major) Avoid coadministration of entrectinib with iloperidone due to the risk of QT prolongation. Both entrectinib and iloperidone have been associated with QT prolongation.
    Imatinib: (Major) Avoid coadministration of entrectinib with imatinib due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If imatinib is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of imatinib. Entrectinib is a CYP3A4 substrate; imatinib is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Imipramine: (Minor) Coadministration of entrectinib and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Indacaterol: (Moderate) Coadministration of entrectinib and long-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Indacaterol; Glycopyrrolate: (Moderate) Coadministration of entrectinib and long-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Indinavir: (Major) Avoid coadministration of entrectinib with indinavir due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If indinavir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of indinavir. Entrectinib is a CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab with entrectinib due to the potential for additive QT prolongation and torsade de pointes. If coadministration is unavoidable, obtain ECGs and electrolytes prior to the start of treatment and periodically during treatment. Both entrectinib and inotuzumab have been associated with QT prolongation.
    Isavuconazonium: (Major) Avoid coadministration of entrectinib with isavuconazonium due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If isavuconazonium is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of isavuconazonium. Entrectinib is a CYP3A4 substrate; isavuconazonium is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Isoflurane: (Major) Avoid coadministration of entrectinib with halogenated anesthetics due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Halogenated anesthetics can prolong the QT interval.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of entrectinib with rifampin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration of rifampin decreased the entrectinib AUC by 77% in a drug interaction study.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of entrectinib with rifampin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration of rifampin decreased the entrectinib AUC by 77% in a drug interaction study.
    Itraconazole: (Major) Avoid coadministration of entrectinib with itraconazole due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If itraconazole is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of itraconazole. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; itraconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Coadministration of itraconazole increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with entrectinib due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Entrectinib has been associated with QT prolongation.
    Ketoconazole: (Major) Avoid coadministration of entrectinib with ketoconazole due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If ketoconazole is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of ketoconazole. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; ketoconazole is a strong CYP3A4 inhibitor that has been associated with prolongation of the QT interval. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Lapatinib: (Major) Avoid coadministration of entrectinib with lapatinib due to the risk of QT prolongation. If coadministration is necessary, monitor for evidence of QT prolongation during treatment. Entrectinib has been associated with QT prolongation. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Lefamulin: (Major) Coadministration of lefamulin tablets is contraindicated with entrectinib due to increased entrectinib exposure which may result in QT prolongation and torsade de pointes (TdP). Avoid use of lefamulin injection with entrectinib. If coadministration of lefamulin injection cannot be avoided, ECG monitoring is recommended during treatment. Entrectinib is a sensitive CYP3A4 substrate that has been associated with QT prolongation. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown.
    Lenvatinib: (Major) Avoid coadministration of entrectinib with lenvatinib due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Prolongation of the QT interval has also been reported with lenvatinib therapy.
    Letermovir: (Major) Avoid coadministration of entrectinib with letermovir due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If letermovir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of letermovir. Entrectinib is a CYP3A4 substrate; letermovir is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Leuprolide: (Major) Avoid coadministration of entrectinib with leuprolide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Major) Avoid coadministration of entrectinib with leuprolide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
    Levalbuterol: (Minor) Coadministration of entrectinib and short-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Levofloxacin: (Major) Avoid coadministration of entrectinib with levofloxacin due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Levofloxacin has been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare,TdP has been reported during postmarketing surveillance of levofloxacin.
    Lithium: (Major) Avoid coadministration of entrectinib with lithium due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Lithium has been associated with QT prolongation.
    Lofexidine: (Major) Avoid coadministration of entrectinib with lofexidine due to the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended. Entrectinib has been associated with QT prolongation. Lofexidine also prolongs the QT interval.
    Long-acting beta-agonists: (Moderate) Coadministration of entrectinib and long-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Loperamide: (Major) Avoid coadministration of entrectinib with loperamide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Loperamide; Simethicone: (Major) Avoid coadministration of entrectinib with loperamide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of entrectinib with lopinavir; ritonavir due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If lopinavir; ritonavir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of lopinavir; ritonavir. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; lopinavir; ritonavir is a strong CYP3A4 inhibitor that has been associated with QT prolongation. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study. (Major) Avoid coadministration of entrectinib with ritonavir due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If ritonavir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of ritonavir. Entrectinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Lorlatinib: (Major) Avoid coadministration of entrectinib with lorlatinib due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; lorlatinib is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of entrectinib with lumacaftor; ivacaftor due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of entrectinib with lumacaftor; ivacaftor due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
    Macimorelin: (Major) Avoid coadministration of macimorelin with entrectinib as concurrent use may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Entrectinib has been associated with QT prolongation.
    Maprotiline: (Major) Avoid coadministration of entrectinib with maprotiline due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Mefloquine: (Major) Avoid coadministration of entrectinib with mefloquine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation.
    Meperidine; Promethazine: (Major) Avoid coadministration of entrectinib with promethazine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Metaproterenol: (Minor) Coadministration of entrectinib and short-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Methadone: (Major) Avoid coadministration of entrectinib with methadone due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Methadone is considered to be associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Methohexital: (Major) Avoid coadministration of entrectinib with methohexital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; methohexital is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Metronidazole: (Major) Avoid coadministration of entrectinib with metronidazole due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Midostaurin: (Major) Avoid coadministration of entrectinib with midostaurin due to the risk of QT prolongation. If coadministration cannot be avoided, consider interval assessments of QT by EKG. Entrectinib has been associated with QT prolongation. QT prolongation was reported in patients who received midostaurin in clinical trials.
    Mifepristone: (Major) Avoid coadministration of entrectinib with mifepristone due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If mifepristone is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of mifepristone. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; mifepristone is a strong CYP3A4 inhibitor that is associated with dose-related prolongation of the QT interval. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Mirtazapine: (Major) Avoid coadministration of entrectinib with mirtazapine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Mitotane: (Major) Avoid coadministration of entrectinib with mitotane due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
    Modafinil: (Major) Avoid coadministration of entrectinib with modafinil due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; modafinil is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Moxifloxacin: (Major) Avoid coadministration of entrectinib with moxifloxacin due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Quinolones have been associated with a risk of QT prolongation. Although extremely rare, TdP has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nafcillin: (Major) Avoid coadministration of entrectinib with nafcillin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; nafcillin is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Nefazodone: (Major) Avoid coadministration of entrectinib with nefazodone due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If nefazodone is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of nefazodone. Entrectinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Nelfinavir: (Major) Avoid coadministration of entrectinib with nelfinavir due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If nelfinavir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of nelfinavir. Entrectinib is a CYP3A4 substrate; nelfinavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Avoid coadministration of entrectinib with netupitant due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If netupitant is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of netupitant. Entrectinib is a CYP3A4 substrate; netupitant is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Nevirapine: (Major) Avoid coadministration of entrectinib with nevirapine due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; nevirapine is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Nilotinib: (Major) Avoid coadministration of entrectinib with nilotinib due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If nilotinib is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of nilotinib. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; nilotinib is a moderate CYP3A4 inhibitor that has been associated with sudden death and QT interval prolongation. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Nortriptyline: (Minor) Coadministration of entrectinib and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Octreotide: (Major) Avoid coadministration of entrectinib with octreotide due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If octreotide is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of octreotide. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; octreotide is a moderate CYP3A4 inhibitor that has been associated with arrhythmias, sinus bradycardia, and conduction disturbances during therapy. Since bradycardia is a risk factor for development of torsade de pointes (TdP), the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Ofloxacin: (Major) Avoid coadministration of entrectinib with ofloxacin due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Quinolones have been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Major) Avoid coadministration of entrectinib with olanzapine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Olodaterol: (Moderate) Coadministration of entrectinib and long-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of entrectinib with ritonavir due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If ritonavir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of ritonavir. Entrectinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Ondansetron: (Major) Avoid coadministration of entrectinib with ondansetron due to the risk of QT prolongation. If coadministration cannot be avoided, ECG monitoring is recommended. Entrectinib has been associated with QT prolongation. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Osimertinib: (Major) Avoid coadministration of entrectinib with osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Entrectinib has been associated with QT prolongation.
    Oxaliplatin: (Major) Avoid coadministration of entrectinib with oxaliplatin due to the risk of QT prolongation. If coadministration cannot be avoided, monitor ECGs and electrolytes; correct electrolyte abnormalities prior to administration of oxaliplatin. Entrectinib has been associated with QT prolongation. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have been reported with oxaliplatin use in postmarketing experience.
    Paliperidone: (Major) Avoid coadministration of paliperidone with entrectinib due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Paliperidone has been associated with QT prolongation; torsade de pointes and ventricular fibrillation have been reported in the setting of overdose. Entrectinib has been associated with QT prolongation.
    Panobinostat: (Major) Avoid coadministration of entrectinib with panobinostat due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. QT prolongation has also been reported with panobinostat.
    Pasireotide: (Major) Avoid coadministration of entrectinib with pasireotide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
    Pazopanib: (Major) Avoid coadministration of entrectinib with pazopanib due to the risk of QT prolongation. If coadministration cannot be avoided, closely monitor the patient for QT interval prolongation. Entrectinib has been associated with QT prolongation. Pazopanib has also been reported to prolong the QT interval.
    Pentamidine: (Major) Avoid coadministration of entrectinib with pentamidine due to the risk of QT prolongation. Both entrectinib and systemic pentamidine have been associated with QT prolongation.
    Perphenazine: (Minor) Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as entrectinib.
    Perphenazine; Amitriptyline: (Minor) Coadministration of entrectinib and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). (Minor) Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as entrectinib.
    Phenobarbital: (Major) Avoid coadministration of entrectinib with phenobarbital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
    Phenylephrine; Promethazine: (Major) Avoid coadministration of entrectinib with promethazine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Phenytoin: (Major) Avoid coadministration of entrectinib with phenytoin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
    Pimavanserin: (Major) Avoid coadministration of entrectinib with pimavanserin due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Pimavanserin also prolongs the QT interval.
    Pimozide: (Severe) Coadministration of pimozide with entrectinib is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Pimozide is associated with a well-established risk of QT prolongation and TdP. Entrectinib has been associated with QT prolongation.
    Pirbuterol: (Minor) Coadministration of entrectinib and short-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Pitolisant: (Major) Avoid coadministration of pitolisant with entrectinib as concurrent use may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Pitolisant also prolongs the QT interval.
    Posaconazole: (Major) Avoid coadministration of entrectinib with posaconazole due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If posaconazole is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of posaconazole. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; posaconazole is a strong CYP3A4 inhibitor that has been associated with QT prolongation and torsade de pointes. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Primaquine: (Major) Avoid coadministration of entrectinib with primaquine due to the risk of QT prolongation. Both entrectinib and primaquine have been associated with QT prolongation.
    Primidone: (Major) Avoid coadministration of entrectinib with primidone due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
    Procainamide: (Major) Avoid coadministration of entrectinib with procainamide due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Prochlorperazine: (Minor) Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as entrectinib.
    Promethazine: (Major) Avoid coadministration of entrectinib with promethazine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Promethazine, a phenothiazine, is also associated with a possible risk for QT prolongation.
    Propafenone: (Major) Avoid coadministration of entrectinib with propafenone due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval.
    Protriptyline: (Minor) Coadministration of entrectinib and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Quetiapine: (Major) Avoid coadministration of entrectinib with quetiapine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances.
    Quinidine: (Major) Avoid coadministration of entrectinib with quinidine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP).
    Quinine: (Major) Avoid coadministration of entrectinib with quinine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
    Ranolazine: (Major) Avoid coadministration of entrectinib with ranolazine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.
    Ribociclib: (Major) Avoid coadministration of entrectinib with ribociclib due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If ribociclib is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of ribociclib. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; ribociclib is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. The ribociclib ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Ribociclib; Letrozole: (Major) Avoid coadministration of entrectinib with ribociclib due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If ribociclib is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of ribociclib. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; ribociclib is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation. The ribociclib ECG changes occurred within the first four weeks of treatment and were reversible with dose interruption. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Rifabutin: (Major) Avoid coadministration of entrectinib with rifabutin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; rifabutin is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Rifampin: (Major) Avoid coadministration of entrectinib with rifampin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration of rifampin decreased the entrectinib AUC by 77% in a drug interaction study.
    Rifapentine: (Major) Avoid coadministration of entrectinib with rifapentine due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; rifapentine is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Rifaximin: (Major) Avoid coadministration of entrectinib with rifaximin due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; rifaximin is a moderate CYP3A4 inducer. In patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Rilpivirine: (Major) Avoid coadministration of entrectinib with rilpivirine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Risperidone: (Major) Avoid coadministration of entrectinib with risperidone due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting.
    Ritonavir: (Major) Avoid coadministration of entrectinib with ritonavir due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If ritonavir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of ritonavir. Entrectinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Romidepsin: (Major) Avoid coadministration of entrectinib with romidepsin due to the risk of QT prolongation. If coadministration is necessary, consider monitoring electrolytes and ECGs at baseline and periodically during treatment. Entrectinib has been associated with QT prolongation. Romidepsin has been reported to prolong the QT interval.
    Salmeterol: (Moderate) Coadministration of entrectinib and long-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Saquinavir: (Major) Avoid coadministration of entrectinib with saquinavir boosted with ritonavir due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If saquinavir/ritonavir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of saquinavir/ritonavir. Additionally, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; saquinavir/ritonavir is a strong CYP3A4 inhibitor that has been associated with concentration-dependent QT prolongation, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Secobarbital: (Major) Avoid coadministration of entrectinib with secobarbital due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; secobarbital is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Sertraline: (Major) Avoid coadministration of entrectinib with sertraline due to the risk of QT prolongation. If coadministration is necessary, use caution and monitor patients for signs and symptoms of QT prolongation. Entrectinib has been associated with QT prolongation. Sertraline's FDA-approved labeling recommends avoiding concomitant use with drugs known to prolong the QTc interval; however, the risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 milliseconds), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure).
    Sevoflurane: (Major) Avoid coadministration of entrectinib with halogenated anesthetics due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Halogenated anesthetics can prolong the QT interval.
    Short-acting beta-agonists: (Minor) Coadministration of entrectinib and short-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Siponimod: (Major) Avoid coadministration of entrectinib with siponimod due to the risk of QT prolongation. If coadministration cannot be avoided, consult a cardiologist regarding appropriate monitoring. Entrectinib has been associated with QT prolongation. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study.
    Solifenacin: (Major) Avoid coadministration of entrectinib with solifenacin due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Solifenacin has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined.
    Sorafenib: (Major) Avoid coadministration of entrectinib with sorafenib due to the risk of QT prolongation. If coadministration cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct any electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Both entrectinib and sorafenib have been associated with QT prolongation.
    Sotalol: (Major) Avoid coadministration of entrectinib with sotalol due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Sotalol administration is associated with QT prolongation and torsade de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of entrectinib with St. John's Wort due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
    Sunitinib: (Major) Avoid coadministration of entrectinib with sunitinib due to the risk of QT prolongation. If coadministration is necessary, monitor for evidence of QT prolongation. Both entrectinib and sunitinib have been associated with QT prolongation.
    Tacrolimus: (Major) Avoid coadministration of entrectinib with tacrolimus due to the risk of QT prolongation. If coadministration is necessary, consider ECG and electrolyte monitoring periodically during treatment. Entrectinib has been associated with QT prolongation. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP).
    Tamoxifen: (Major) Avoid coadministration of entrectinib with tamoxifen due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Telavancin: (Major) Avoid coadministration of entrectinib with telavancin due to the risk of QT prolongation. Both entrectinib and telavancin have been associated with QT prolongation.
    Telithromycin: (Major) Avoid coadministration of entrectinib with telithromycin due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If telithromycin is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of telithromycin. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; telithromycin is a strong CYP3A4 inhibitor that is associated with QT prolongation and torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Terbutaline: (Minor) Coadministration of entrectinib and short-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tetrabenazine: (Major) Avoid coadministration of entrectinib with tetrabenazine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Tetrabenazine causes a small increase in the corrected QT interval (QTc).
    Thioridazine: (Severe) Coadministration of thioridazine with entrectinib is contraindicated due to the potential for QT prolongation and torsade de pointes (TdP). Thioridazine is associated with a well-established risk of QT prolongation and TdP. Entrectinib has been associated with QT prolongation.
    Tiotropium; Olodaterol: (Moderate) Coadministration of entrectinib and long-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tipranavir: (Major) Avoid coadministration of entrectinib with tipranavir due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If tipranavir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of tipranavir. Entrectinib is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Tolterodine: (Major) Avoid coadministration of entrectinib with tolterodine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
    Toremifene: (Major) Avoid coadministration of entrectinib with toremifene due to the risk of QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes. Entrectinib has been associated with QT prolongation. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Trandolapril; Verapamil: (Major) Avoid coadministration of entrectinib with verapamil due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If verapamil is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of verapamil. Entrectinib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Trazodone: (Major) Avoid coadministration of entrectinib with trazodone due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of torsade de pointes (TdP).
    Tricyclic antidepressants: (Minor) Coadministration of entrectinib and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Trifluoperazine: (Minor) Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as entrectinib.
    Trimipramine: (Minor) Coadministration of entrectinib and tricyclic antidepressants (TCAs) may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. TCAs share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Triptorelin: (Major) Avoid coadministration of entrectinib with triptorelin due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval.
    Umeclidinium; Vilanterol: (Moderate) Coadministration of entrectinib and long-acting beta-agonists may increase the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Vandetanib: (Major) Avoid coadministration of vandetanib with entrectinib due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Entrectinib has been associated with QT prolongation.
    Vardenafil: (Major) Avoid coadministration of entrectinib with vardenafil due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Vemurafenib: (Major) Avoid coadministration of entrectinib with vemurafenib due to the risk of QT prolongation. If concomitant use is unavoidable, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both entrectinib and vemurafenib have been associated with QT prolongation.
    Venlafaxine: (Major) Avoid coadministration of entrectinib with venlafaxine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Verapamil: (Major) Avoid coadministration of entrectinib with verapamil due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 200 mg PO once daily. If verapamil is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of verapamil. Entrectinib is a CYP3A4 substrate; verapamil is a moderate CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor is predicted to increase the AUC of entrectinib by 3-fold.
    Voriconazole: (Major) Avoid coadministration of entrectinib with voriconazole due to additive risk of QT prolongation and increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If voriconazole is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of voriconazole. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; voriconazole is a strong CYP3A4 inhibitor that is associated with QT prolongation and rare cases of torsade de pointes (TdP). Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
    Vorinostat: (Major) Avoid coadministration of entrectinib with vorinostat due to the risk of QT prolongation. Both entrectinib and vorinostat have been associated with QT prolongation.
    Ziprasidone: (Major) Avoid coadministration of entrectinib with ziprasidone due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.

    PREGNANCY AND LACTATION

    Pregnancy

    Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, animal studies, and its mechanism of action, entrectinib can cause fetal harm or death when administered during pregnancy. Pregnancy should be avoided by females of reproductive potential during entrectinib treatment and for at least 5 weeks after the final dose. Women who are pregnant or who become pregnant while receiving entrectinib should be apprised of the potential hazard to the fetus. There are no available data on the use of entrectinib in pregnant women. Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis. Administration of entrectinib to pregnant rats during organogenesis resulted in body closure defects (e.g., omphalocele and gastroschisis) and malformations of the vertebrae, ribs, and limbs (micromelia and adactyly) at maternal exposures approximately 2.7 times the human exposure at the recommended dose (600 mg); embryolethality did not occur. Lower fetal weight and reduced skeletal ossification occurred at approximately 0.2 and 0.9 times the human exposure at the recommended dose, respectively.

    Due to the potential for serious adverse reactions in a nursing infant from entrectinib, advise women to discontinue breast-feeding during treatment and for 7 days after the final dose. It is not known whether entrectinib is present in human milk, although many drugs are excreted in human milk.[64567]

    MECHANISM OF ACTION

    Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB, and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2, and NTRK3, respectively), proto-oncogene tyrosine-protein kinase ROS1 (ROS1), and anaplastic lymphoma kinase (ALK). Entrectinib also inhibits the Janus kinase 2 (JAK2) and Tyrosine Kinase Non Receptor 2 (TNK2). The major active metabolite of entrectinib, M5, showed similar in vitro activity against TRK, ROS1, and ALK. Fusion proteins that include TRK, ROS1, or ALK kinase domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Entrectinib demonstrated in vitro and in vivo inhibition of cancer cell lines derived from multiple tumor types harboring NTRK, ROS1, and ALK fusion genes. Entrectinib demonstrated in vivo antitumor activity in mice with intracranial implantation of TRKA-and ALK-driven tumor cell lines.

    PHARMACOKINETICS

    Entrectinib is administered orally. Both entrectinib and its major active metabolite, M5, are 99% bound to human plasma proteins in vitro. Entrectinib demonstrated steady-state brain-to-plasma concentration ratios of 0.4 to 2.2 in multiple animal species (mice, rats, and dogs). The active metabolite, M5, is the only major active circulating metabolite that has been identified; it has similar pharmacological potency to entrectinib in vitro. Circulating M5 exposures at steady-state in patients were 40% of the corresponding entrectinib exposure. The estimated apparent volume of distribution (Vd) was 551 L for entrectinib and 81.1 L for M5. The estimated apparent clearance was 19.6 L/hour for entrectinib and 52.4 L/hour for M5, with elimination half-lives of 20 hours and 40 hours, respectively. Steady-state is achieved within one week of daily administration for entrectinib and 2 weeks for M5. After oral administration of a single radiolabeled dose, 83% of the radioactivity was excreted in the feces (unchanged entrectinib, 36%; M5, 22%) with minimal excretion in the urine (3%).[64567]
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-glycoprotein (P-gp)
    Entrectinib is primarily metabolized by CYP3A4 (approximately 76%) to the active metabolite, M5. M5 is a substrate of P-glycoprotein (P-gp) and BCRP. Entrectinib increased the AUC of midazolam, a sensitive CYP3A substrate, by 50% but reduced the midazolam Cmax by 21%. Entrectinib increased the Cmax and AUC of digoxin, a sensitive P-gp substrate, by 28% and 18%, respectively.[64567]

    Oral Route

    The pharmacokinetics of entrectinib and M5 are linear and are not dose-dependent or time-dependent. The mean AUC of entrectinib and M5 after the first dose is 31,800 nanoMolar x hour (CV, 48%) and 10,200 nanoMolar x hour (CV, 82%), respectively. The mean Cmax of entrectinib and M5 after the first dose is 2,250 nanoMolar (CV, 58%) and 622 nanoMolar (CV, 79%), respectively. The mean AUC of entrectinib and M5 at steady-state is 48,000 nanoMolar x hour (CV, 77%) and 24,000 nanoMolar x hour (CV, 97%), respectively. The mean Cmax of entrectinib and M5 at steady-state is 3,130 nanoMolar (CV, 80%) and 1,250 nanoMolar (CV, 90%), respectively. The accumulation ratio of entrectinib and M5 is 1.55 (CV, 49%) and 2.84 (CV, 93%), respectively. Maximum entrectinib plasma concentrations are reached 4 to 6 hours after oral administration of a single dose (Tmax). A high-fat, high-calorie meal (approximately 800 to 1,000 calories with 50% fat) did not have a significant effect on entrectinib exposure. Coadministration of a proton pump inhibitor reduced the AUC of entrectinib by 25% and the Cmax by 23%.