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  • CLASSES

    Small Molecule Antineoplastic Tropomyosin Receptor Kinase (TRK) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Tissue agnostic kinase inhibitor
    Used for the treatment of adult and pediatric patients 28 days and older with solid tumors that have a neurotrophic receptor tyrosine kinase gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment
    Severe adverse events include neurotoxicity and hepatotoxicity

    COMMON BRAND NAMES

    VITRAKVI

    HOW SUPPLIED

    Larotrectinib/VITRAKVI Oral Cap: 25mg, 100mg
    VITRAKVI Oral Sol: 1mL, 20mg

    DOSAGE & INDICATIONS

    For the treatment of neurotrophic receptor tyrosine kinase-positive solid tumors.
    NOTE: Larotrectinib has been designated an orphan drug by the FDA for the treatment of solid tumors with NTRK-fusion proteins.
    NOTE: Verify the presence of a NTRK gene fusion in the tumor specimen; in clinical studies, identification of positive NTRK gene fusion status was prospectively determined using next generation sequencing or fluorescence in situ hybridization.[63780]
    For the treatment of metastatic or surgically unresectable neurotrophic receptor tyrosine kinase (NTRK) gene fusion-positive solid tumors with no known acquired resistance mutation, in patients with no satisfactory alternative treatments or who have progressed following treatment.
    Oral dosage
    Adults, Adolescents, Children, and Infants

    For BSA of 1 m2 or greater, 100 mg orally twice daily; for BSA less than 1 m2, 100 mg/m2 orally twice daily. Continue therapy until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption, dose reduction, or permanent discontinuation may be necessary in patients who develop toxicity.[63780] In pooled results from 3 phase 1 or 2 trials (n = 55), the overall response rate assessed by independent review (primary endpoint) was 75% in patients with tropomyosin receptor kinases fusion-positive cancers who received larotrectinib. The complete response rate was 16%. The median duration of response and the median progression-free survival time had not been reached at median follow-up times of 8.3 months (range, 0.03 to longer than 24.9 months) and 9.9 months (range, 0.7 to longer than 25.9 months), respectively. In this analysis, the median patient age was 45 years (range, 4 months to 76 years) and patients had received 0 to 1 (49%), 2 (16%), or 3 or more (35%) prior systemic chemotherapies. The most common tumor types were salivary gland tumor (22%), soft-tissue sarcoma (20%), infantile fibrosarcoma (13%), and thyroid tumor (9%).[63791]

    MAXIMUM DOSAGE

    Adults

    100 mg PO twice daily.

    Geriatric

    100 mg PO twice daily.

    Adolescents

    100 mg PO twice daily.

    Children

    BSA 1 m2 or greater: 100 mg PO twice daily; BSA less than 1 m2: 100 mg/m2 PO twice daily.

    Infants

    100 mg/m2 PO twice daily.

    Neonates

    Safety and efficacy not established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    A larotrectinib dosage adjustment is not necessary in patients with baseline mild hepatic impairment (Child-Pugh class A). Reduce the initial larotrectinib dose by 50% in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment.[63780]

    Renal Impairment

    A larotrectinib dosage adjustment is not necessary in patients with baseline renal impairment.[63780]

    ADMINISTRATION

    Oral Administration

    The oral capsule and oral solution of larotrectinib may be used interchangeably.
    Do not make up a missed dose within 6 hours of the next scheduled dose.
    If vomiting occurs after taking a dose, take the next dose at the scheduled time.[63780]

    Oral Solid Formulations

    Do not chew or crush the larotrectinib capsules. Swallow capsules whole with water.[63780]

    Oral Liquid Formulations

    Read and become familiar with the manufacturer's complete "Instructions for Use" prior to preparing or administering the larotrectinib oral solution.
    Write the date of opening the bottle on the bottle.
    Each bottle of larotrectinib should be dispensed with 5 measured oral syringes (either 1 mL or 5 mL). Each syringe may be used over a 7-day period only.
    A bottle adaptor should be utilized with the oral syringes per the manufacturer's "Instructions for Use".
    Once the correct dosage is withdrawn per the manufacturer's "Instructions for Use", place the tip of the oral syringe into the patient's mouth against the side of the cheek and slowly squirt the oral solution into the mouth and allow the patient to swallow.
    Keep the patient in an upright position for a few minutes right after giving the dose.
    If the patient spits up the dose or if you are not sure the entire dose was given, do not give another dose and wait until the next scheduled dose.
    Follow the manufacturer's "Instructions for Use" for cleaning the oral syringe.
    Replace the oral syringe after 7 days, or if any of the conditions below apply to to the syringe:
    there is any damage to the barrel, plunger, or tip
    the dosage marking is no longer clearly recognizable
    it becomes difficult to move the plunger
    Storage: Store under refrigeration between 36 degrees F and 46 degrees F (2 degrees C and 8 degrees C). Do not freeze. Discard any unused larotrectinib oral solution remaining after 90 days of first opening the bottle.[63780]

    STORAGE

    VITRAKVI:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Driving or operating machinery

    Neurotoxicity (e.g., delirium, dizziness, gait disturbance, paresthesias) has been reported with larotrectinib therapy. Advise patients against driving or operating machinery if they experience neurologic adverse events. Therapy interruption, dose reduction, or permanent discontinuation may be necessary in patients who develop severe neurotoxicity.[63780]

    Hepatic disease

    Hepatotoxicity (e.g., elevated hepatic enzymes) has been reported with larotrectinib therapy; use with caution in patients with pre-existing hepatic disease. Reduce the initial dose in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. Monitor liver function tests (LFTs) every 2 weeks during the first month of therapy, then monitor LFTs monthly and as clinically indicated. Therapy interruption, dose reduction, or permanent discontinuation may be necessary in patients who develop severe hepatotoxicity.[63780]

    Pregnancy

    Larotrectinib may cause fetal harm when administered during pregnancy, based on literature reports in human subjects with congenital mutations leading to changes in TRK signaling, its mechanism of action, and data from animal studies. Females of reproductive potential should avoid becoming pregnant while taking larotrectinib. Discuss the potential hazard to the fetus if a patient becomes pregnant while taking this drug. Although larotrectinib has not been evaluated in pregnant women, congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are associated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis. Fetal malformations (e.g., anasarca, omphalocele) occurred when pregnant rats and rabbits received a larotrectinib dose resulting in approximately 11- and 0.7-times the exposure that was observed in humans who received the recommended dose.

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

    Counsel patients about the reproductive risk and contraception requirements during larotrectinib treatment. Pregnancy testing should be performed in women of reproductive potential prior to initiating therapy. These women should use effective contraception during therapy and for at least 1 week after the final larotrectinib dose. Due to the risk of male-mediated teratogenicity, male patients should use effective contraception to avoid potential drug exposure in female partners of reproductive potential during therapy and 1 week after the final larotrectinib dose. The risk of infertility with larotrectinib has not been studied in humans, although histopathological findings from a 1-month repeated-dose study suggest that impaired fertility may occur in female patients.[63780]

    Breast-feeding

    It is not known if larotrectinib or its active metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Because there is a potential for adverse reactions in nursing infants from larotrectinib, women should discontinue breast-feeding during larotrectinib therapy and for 1 week after the last dose.[63780]

    ADVERSE REACTIONS

    Severe

    anemia / Delayed / 10.0-10.0
    neutropenia / Delayed / 7.0-7.0
    neurotoxicity / Early / 6.6-6.6
    elevated hepatic enzymes / Delayed / 6.0-6.0
    weight gain / Delayed / 4.0-4.0
    fatigue / Early / 3.0-3.0
    hypoalbuminemia / Delayed / 2.0-2.0
    delirium / Early / 2.0-2.0
    GI obstruction / Delayed / 1.0-2.0
    abdominal pain / Early / 2.0-2.0
    anorexia / Delayed / 2.0-2.0
    diarrhea / Early / 2.0-2.0
    GI perforation / Delayed / 1.0-2.0
    enterocutaneous fistula / Delayed / 1.0-2.0
    dyspnea / Early / 2.0-2.0
    hypertension / Early / 2.0-2.0
    cerebral edema / Early / 1.0-2.0
    pleural effusion / Delayed / 1.0-2.0
    pericardial effusion / Delayed / 1.0-2.0
    leukemia / Delayed / 1.0-2.0
    paresthesias / Delayed / 1.0-1.0
    dysarthria / Delayed / 1.0-1.0
    dizziness / Early / 1.0-1.0
    fever / Early / 1.0-1.0
    constipation / Delayed / 1.0-1.0
    vomiting / Early / 1.0-1.0
    nausea / Early / 1.0-1.0
    myalgia / Early / 1.0-1.0
    back pain / Delayed / 1.0-1.0
    arthralgia / Delayed / 1.0-1.0
    encephalopathy / Delayed / 0.6-0.6
    infection / Delayed / 2.0
    new primary malignancy / Delayed / Incidence not known

    Moderate

    peripheral edema / Delayed / 15.0-15.0
    jaundice / Delayed / 1.0-2.0
    hyperamylasemia / Delayed / 1.0-2.0
    hyponatremia / Delayed / 1.0-2.0
    dehydration / Delayed / 2.0
    memory impairment / Delayed / Incidence not known

    Mild

    cough / Delayed / 26.0-26.0
    headache / Early / 14.0-14.0
    weakness / Early / 13.0-13.0
    nasal congestion / Early / 10.0-10.0
    asthenia / Delayed / 1.0-2.0
    syncope / Early / 1.0-2.0
    tremor / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with larotrectinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of larotrectinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Larotrectinib is a weak inhibitor of CYP3A4.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with larotrectinib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Larotrectinib is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with larotrectinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of larotrectinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Larotrectinib is a weak inhibitor of CYP3A4.
    Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like larotrectinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If larotrectinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Acetaminophen; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with larotrectinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of larotrectinib, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
    Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If larotrectinib is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of larotrectinib with clarithromycin due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If clarithromycin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of clarithromycin. Larotrectinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of larotrectinib with clarithromycin due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If clarithromycin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of clarithromycin. Larotrectinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Apalutamide: (Major) Avoid coadministration of larotrectinib with apalutamide due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If apalutamide is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of apalutamide. Larotrectinib is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
    Aripiprazole: (Moderate) Administering aripiprazole with larotrectinib may result in elevated aripiprazole plasma concentrations. Aripiprazole is a substrate of CYP3A4 and larotrectinib is a weak CYP3A inhibitor. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. In addition, because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada during use of a mild to moderate CYP3A4 inhibitor.
    Artemether; Lumefantrine: (Moderate) Administering artemether with larotrectinib may result in elevated artemether plasma concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation. Artemether is a substrate of CYP3A; larotrectinib is a weak CYP3A inhibitor. (Moderate) Administering lumefantrine with larotrectinib may result in elevated lumefantrine plasma concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation. Lumefantrine is a substrate of CYP3A; larotrectinib is a weak CYP3A inhibitor.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with larotrectinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of larotrectinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Larotrectinib is a weak inhibitor of CYP3A4.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with larotrectinib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Larotrectinib is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with larotrectinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of larotrectinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Larotrectinib is a weak inhibitor of CYP3A4.
    Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like larotrectinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If larotrectinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Atazanavir: (Major) Avoid coadministration of larotrectinib with atazanavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If atazanavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of atazanavir. Larotrectinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of larotrectinib with atazanavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If atazanavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of atazanavir. Larotrectinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study. (Major) Avoid coadministration of larotrectinib with cobicistat due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If cobicistat is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of cobicistat. Larotrectinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid coadministration of larotrectinib with phenobarbital due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If phenobarbital is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of phenobarbital. Larotrectinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of larotrectinib with phenobarbital due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If phenobarbital is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of phenobarbital. Larotrectinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study. (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and larotrectinib together is medically necessary. An ergotamine dose reduction may be necessary if these drugs are used together. Concomitant use of larotrectinib, a weak CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate, may result in increased ergot alkaloid levels.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Caffeine; Ergotamine: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and larotrectinib together is medically necessary. An ergotamine dose reduction may be necessary if these drugs are used together. Concomitant use of larotrectinib, a weak CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate, may result in increased ergot alkaloid levels.
    Carbamazepine: (Major) Avoid coadministration of larotrectinib with carbamazepine due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If carbamazepine is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of carbamazepine. Larotrectinib is a CYP3A4 substrate; carbamazepine is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Ceritinib: (Major) Avoid coadministration of larotrectinib with ceritinib due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If ceritinib is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of ceritinib. Larotrectinib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Chloramphenicol: (Major) Avoid coadministration of larotrectinib with chloramphenicol due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If chloramphenicol is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of chloramphenicol. Larotrectinib is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with larotrectinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of larotrectinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Larotrectinib is a weak inhibitor of CYP3A4.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with larotrectinib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Larotrectinib is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with larotrectinib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Larotrectinib is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Clarithromycin: (Major) Avoid coadministration of larotrectinib with clarithromycin due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If clarithromycin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of clarithromycin. Larotrectinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with larotrectinib and monitor for adverse reactions. If larotrectinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4. larotrectinib is a weak CYP3A4 inhibitor.
    Cobicistat: (Major) Avoid coadministration of larotrectinib with cobicistat due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If cobicistat is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of cobicistat. Larotrectinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Codeine: (Moderate) Concomitant use of codeine with larotrectinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of larotrectinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Larotrectinib is a weak inhibitor of CYP3A4.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with larotrectinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of larotrectinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Larotrectinib is a weak inhibitor of CYP3A4.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with larotrectinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of larotrectinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Larotrectinib is a weak inhibitor of CYP3A4.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with larotrectinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of larotrectinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Larotrectinib is a weak inhibitor of CYP3A4.
    Colchicine: (Moderate) Monitor for an increase in colchicine-related adverse reactions including neuromuscular toxicity and other serious toxicities if coadministration with larotrectinib is necessary, especially in patients with renal or hepatic impairment. Larotrectinib is a weak inhibitor of CYP3A while colchicine is a CYP3A4 substrate with a narrow therapeutic index.
    Colchicine; Probenecid: (Moderate) Monitor for an increase in colchicine-related adverse reactions including neuromuscular toxicity and other serious toxicities if coadministration with larotrectinib is necessary, especially in patients with renal or hepatic impairment. Larotrectinib is a weak inhibitor of CYP3A while colchicine is a CYP3A4 substrate with a narrow therapeutic index.
    Conivaptan: (Major) Avoid coadministration of larotrectinib with conivaptan due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If conivaptan is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of conivaptan. Larotrectinib is a CYP3A4 substrate; conivaptan is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Cyclosporine: (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with larotrectinib. Use of these medications together may result in elevated cyclosporine serum concentrations, causing an increased risk for cyclosporine-related adverse events. Larotrectinib is a weak inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine.
    Darunavir: (Major) Avoid coadministration of larotrectinib with darunavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If darunavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of darunavir. Larotrectinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Darunavir; Cobicistat: (Major) Avoid coadministration of larotrectinib with cobicistat due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If cobicistat is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of cobicistat. Larotrectinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study. (Major) Avoid coadministration of larotrectinib with darunavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If darunavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of darunavir. Larotrectinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of larotrectinib with cobicistat due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If cobicistat is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of cobicistat. Larotrectinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study. (Major) Avoid coadministration of larotrectinib with darunavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If darunavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of darunavir. Larotrectinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of larotrectinib with ritonavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If ritonavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of ritonavir. Larotrectinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Delavirdine: (Major) Avoid coadministration of larotrectinib with delavirdine due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If delavirdine is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of delavirdine. Larotrectinib is a CYP3A4 substrate; delavirdine is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with larotrectinib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Larotrectinib is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Dihydroergotamine: (Moderate) Be alert for symptoms of ergot toxicity if using dihydroergotamine and larotrectinib together is medically necessary. A dihydroergotamine dose reduction may be necessary if these drugs are used together. Concomitant use of larotrectinib, a weak CYP3A4 inhibitor, and dihydroergotamine, a CYP3A4 substrate with a narrow therapeutic range, may result in increased ergot alkaloid levels.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Disopyramide: (Moderate) Caution is warranted during coadministration of disopyramide and larotrectinib due to the potential for elevated disopyramide plasma concentrations and associated adverse events including QT prolongation. Disopyramide is a CYP3A4 substrate; larotrectinib is a weak CYP3A4 inhibitor.
    Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with larotrectinib is necessary. larotrectinib is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
    Doxorubicin: (Major) Avoid coadministration of larotrectinib with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Larotrectinib is a weak CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
    Eliglustat: (Major) In poor CYP2D6 metabolizers (PMs), coadministration of larotrectinib and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Larotrectinib ia a weak CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration of eliglustat with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of larotrectinib with cobicistat due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If cobicistat is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of cobicistat. Larotrectinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of larotrectinib with cobicistat due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If cobicistat is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of cobicistat. Larotrectinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Enalapril; Felodipine: (Moderate) Concurrent use of felodipine and larotrectinib should be approached with caution with conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and larotrectinib is a weak CYP3A4 inhibitor. Concurrent use of another weak CYP3A4 inhibitor increased felodipine AUC and Cmax by approximately 50%.
    Enzalutamide: (Major) Avoid coadministration of larotrectinib with enzalutamide due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If enzalutamide is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of enzalutamide. Larotrectinib is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
    Ergotamine: (Moderate) Be alert for symptoms of ergot toxicity if using ergotamine and larotrectinib together is medically necessary. An ergotamine dose reduction may be necessary if these drugs are used together. Concomitant use of larotrectinib, a weak CYP3A4 inhibitor, and ergotamine, a CYP3A4 substrate, may result in increased ergot alkaloid levels.
    Felodipine: (Moderate) Concurrent use of felodipine and larotrectinib should be approached with caution with conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and larotrectinib is a weak CYP3A4 inhibitor. Concurrent use of another weak CYP3A4 inhibitor increased felodipine AUC and Cmax by approximately 50%.
    Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If larotrectinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
    Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including larotrectinib, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the potential outcomes of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient.
    Fosamprenavir: (Major) Avoid coadministration of larotrectinib with fosamprenavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If fosamprenavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of fosamprenavir. Larotrectinib is a CYP3A4 substrate; fosamprenavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Fosphenytoin: (Major) Avoid coadministration of larotrectinib with fosphenytoin due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If fosphenytoin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of fosphenytoin. Larotrectinib is a CYP3A4 substrate; fosphenytoin is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
    Grapefruit juice: (Major) Advise patients to avoid grapefruit or grapefruit juice while taking larotrectinib. Coadministration may increase larotrectinib exposure resulting in treatment-related adverse effects. Larotrectinib is a CYP3A4 substrate; grapefruit is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like larotrectinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. If larotrectinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like larotrectinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If larotrectinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Idelalisib: (Major) Avoid coadministration of larotrectinib with idelalisib due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If idelalisib is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of idelalisib. Larotrectinib is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Indinavir: (Major) Avoid coadministration of larotrectinib with indinavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If indinavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of indinavir. Larotrectinib is a CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of larotrectinib with rifampin due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If rifampin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of rifampin. Larotrectinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the larotrectinib AUC by 81% in a drug interaction study.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of larotrectinib with rifampin due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If rifampin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of rifampin. Larotrectinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the larotrectinib AUC by 81% in a drug interaction study.
    Itraconazole: (Major) Avoid coadministration of larotrectinib with Itraconazole due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If itraconazole is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of itraconazole. Larotrectinib is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Ixabepilone: (Moderate) Frequently monitor peripheral blood counts between cycles of ixabepilone, and for other acute ixabepilone-related adverse reactions if coadministration with larotrectinib is necessary; consider the use of an alternative agent to larotrectinib that does not inhibit CYP3A4. Ixabepilone is a CYP3A4 substrate and larotrectinib is a weak CYP3A4 inhibitor. The effect of weak CYP3A4 inhibitors on exposure to ixabepilone has not been studied.
    Ketoconazole: (Major) Avoid coadministration of larotrectinib with ketoconazole due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If ketoconazole is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of ketoconazole. Larotrectinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Letermovir: (Moderate) Avoid coadministration of larotrectinib with letermovir if the patient is also receiving cyclosporine due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If both letermovir and cyclosporine are discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of letermovir. Larotrectinib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when administered with cyclosporine the effect may be similar to a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Lomitapide: (Major) Decrease the dose of lomitapide by one-half not to exceed 30 mg/day PO if coadministration with larotrectinib is necessary. Concomitant use may significantly increase the serum concentration of lomitapide. Larotrectinib is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of larotrectinib with lopinavir; ritonavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If lopinavir; ritonavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of lopinavir; ritonavir. Larotrectinib is a CYP3A4 substrate; lopinavir; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study. (Major) Avoid coadministration of larotrectinib with ritonavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If ritonavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of ritonavir. Larotrectinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of larotrectinib with lumacaftor; ivacaftor due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If lumacaftor; ivacaftor is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of lumacaftor; ivacaftor. Larotrectinib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of larotrectinib with lumacaftor; ivacaftor due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If lumacaftor; ivacaftor is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of lumacaftor; ivacaftor. Larotrectinib is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
    Methadone: (Moderate) Concomitant use of methadone with larotrectinib may increase methadone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of methadone until stable drug effects are achieved. Discontinuation of larotrectinib could decrease methadone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to methadone. If larotrectinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Methadone is a substrate for CYP3A4. Larotrectinib is a weak inhibitor of CYP3A4.
    Midazolam: (Moderate) Monitor for more intense and prolonged sedation due to increased midazolam exposure if coadministration with larotrectinib is necessary. Midazolam is a CYP3A4 substrate; larotrectinib is a weak CYP3A4 inhibitor. In a drug interaction study, coadministration with larotrectinib increased the both the midazolam AUC and Cmax by 1.7-fold. The AUC and Cmax of 1-hydroxymidazolam, the main metabolite of midazolam, were both increased 1.4-fold.
    Mifepristone: (Major) Avoid coadministration of larotrectinib with chronic mifepristone use due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If mifepristone is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of mifepristone. Larotrectinib is a CYP3A4 substrate; mifepristone is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
    Mitotane: (Major) Avoid coadministration of larotrectinib with mitotane due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If mitotane is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of mitotane. Larotrectinib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
    Nefazodone: (Major) Avoid coadministration of larotrectinib with nefazodone due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If nefazodone is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of nefazodone. Larotrectinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Nelfinavir: (Major) Avoid coadministration of larotrectinib with nelfinavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If nelfinavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of nelfinavir. Larotrectinib is a CYP3A4 substrate; nelfinavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Nimodipine: (Moderate) Monitor blood pressure and watch for an increase in nimodipine-related adverse reactions if coadministration with larotrectinib is necessary; consider reducing the dose of nimodipine if needed. Nimodipine is a CYP3A4 substrate and larotrectinib is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of nimodipine.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with larotrectinib due to increased plasma concentrations of nisoldipine. Nisoldipine is a CYP3A4 substrate and larotrectinib is a weak CYP3A4 inhibitor.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of larotrectinib with ritonavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If ritonavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of ritonavir. Larotrectinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like larotrectinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If larotrectinib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Phenobarbital: (Major) Avoid coadministration of larotrectinib with phenobarbital due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If phenobarbital is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of phenobarbital. Larotrectinib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
    Phenytoin: (Major) Avoid coadministration of larotrectinib with phenytoin due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If phenytoin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of phenytoin. Larotrectinib is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
    Posaconazole: (Major) Avoid coadministration of larotrectinib with posaconazole due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If posaconazole is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of posaconazole. Larotrectinib is a CYP3A4 substrate; posaconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Primidone: (Major) Avoid coadministration of larotrectinib with primidone due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If primidone is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of primidone. Larotrectinib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
    Ribociclib: (Major) Avoid coadministration of larotrectinib with ribociclib due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If ribociclib is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of ribociclib. Larotrectinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Ribociclib; Letrozole: (Major) Avoid coadministration of larotrectinib with ribociclib due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If ribociclib is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of ribociclib. Larotrectinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Rifampin: (Major) Avoid coadministration of larotrectinib with rifampin due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If rifampin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of rifampin. Larotrectinib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the larotrectinib AUC by 81% in a drug interaction study.
    Ritonavir: (Major) Avoid coadministration of larotrectinib with ritonavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If ritonavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of ritonavir. Larotrectinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Saquinavir: (Major) Avoid coadministration of larotrectinib with saquinavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If saquinavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of saquinavir. Larotrectinib is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Sirolimus: (Moderate) Monitor for increased sirolimus adverse reactions if coadministered with larotrectinib. Taking these drugs together may increase sirolimus plasma concentrations, potentially resulting in adverse events. Larotrectinib is a weak CYP3A4 inhibitor; sirolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of larotrectinib with St. John's wort due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If St. John's wort is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of St. John's wort. Larotrectinib is a CYP3A4 substrate; St. John's wort is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
    Sufentanil: (Moderate) Consider a reduced dose of sufentanil with frequent monitoring for respiratory depression and sedation if concurrent use of larotrectinib is necessary. If larotrectinib is discontinued, consider increasing the sufentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a sensitive CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like larotrectinib can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If larotrectinib is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
    Tacrolimus: (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with larotrectinib. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Larotrectinib is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
    Telithromycin: (Major) Avoid coadministration of larotrectinib with telithromycin due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If telithromycin is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of telithromycin. Larotrectinib is a CYP3A4 substrate; telithromycin is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Tipranavir: (Major) Avoid coadministration of larotrectinib with tipranavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If tipranavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of tipranavir. Larotrectinib is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
    Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with larotrectinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of larotrectinib, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
    Triazolam: (Moderate) Monitor for more intense and prolonged sedation due to increased triazolam exposure if coadministration with larotrectinib is necessary. Triazolam is a sensitive CYP3A4 substrate; larotrectinib is a weak CYP3A4 inhibitor.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with larotrectinib is necessary. Vinorelbine is a CYP3A4 substrate and larotrectinib is a weak CYP3A4 inhibitor.
    Voriconazole: (Major) Avoid coadministration of larotrectinib with voriconazole due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If voriconazole is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of voriconazole. Larotrectinib is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.

    PREGNANCY AND LACTATION

    Pregnancy

    Larotrectinib may cause fetal harm when administered during pregnancy, based on literature reports in human subjects with congenital mutations leading to changes in TRK signaling, its mechanism of action, and data from animal studies. Females of reproductive potential should avoid becoming pregnant while taking larotrectinib. Discuss the potential hazard to the fetus if a patient becomes pregnant while taking this drug. Although larotrectinib has not been evaluated in pregnant women, congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are associated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis. Fetal malformations (e.g., anasarca, omphalocele) occurred when pregnant rats and rabbits received a larotrectinib dose resulting in approximately 11- and 0.7-times the exposure that was observed in humans who received the recommended dose.

    It is not known if larotrectinib or its active metabolites are secreted in human milk or if it has effects on the breast-fed infant or on milk production. Because there is a potential for adverse reactions in nursing infants from larotrectinib, women should discontinue breast-feeding during larotrectinib therapy and for 1 week after the last dose.[63780]

    MECHANISM OF ACTION

    Larotrectinib is an inhibitor of the tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC. In a broad panel of purified enzyme assays, larotrectinib inhibited these kinases with IC50 values between 5 to 11 nM. One other kinase, TNK2, was inhibited at approximately 100-fold higher concentrations. TRKA, B, and C are encoded by the genes NTRK1, NTRK2, and NTRK3. Chromosomal rearrangements involving in-frame fusions of these genes with various partners can result in constitutively-activated cell proliferation and survival in tumor cell lines. In in vitro and in vivo tumor models, larotrectinib demonstrated anti-tumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression. It had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the clinically identified acquired resistance mutation, G595R. Point mutations in the TRKC kinase domain with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L.[63780]

    PHARMACOKINETICS

    Larotrectinib is administered orally. It is 70% bound to human plasma proteins in vitro and binding is independent of drug concentrations. The blood-to-plasma ratio is 0.9. The mean (CV%) volume of distribution (Vss) of larotrectinib is 48 (38%) L after intravenous administration in healthy subjects. Larotrectinib is metabolized predominantly by CYP3A4. After oral administration of a single radiolabeled dose to healthy subjects, unchanged larotrectinib constituted 19% and an O-linked glucuronide constituted 26% of the major circulating radioactive drug components in plasma. Additionally, 58% (5% unchanged) of the administered radioactivity was recovered in the feces and 39% (20% unchanged) was recovered in the urine. The mean (CV%) clearance (CL/F) of larotrectinib is 90 (44%) L/h and the half-life is 2.9 hours after oral administration in healthy subjects.[63780]
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-glycoprotein (P-gp)
    Larotrectinib is a CYP3A4 substrate and a weak inhibitor. Coadministration of a single larotrectinib dose with a strong CYP3A inhibitor increased the AUC of larotrectinib by 4.3-fold and the Cmax by 2.8-fold. Coadministration of a single larotrectinib dose with a strong CYP3A inducer decreased the AUC of larotrectinib by 81% and the Cmax by 71%. The effects of moderate and weak CYP3A inhibitors and inducers on larotrectinib pharmacokinetics have not been studied. Coadministration of larotrectinib with a sensitive CYP3A4 substrate, midazolam, increased both the AUC and the Cmax of midazolam by 1.7-fold. The AUC and Cmax of 1-hydroxymidazolam, the main metabolite of midazolam, were both increased 1.4-fold. Larotrectinib is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations. Larotrectinib is a substrate of P-glycoprotein (P-gp). Coadministration with a P-gp inhibitor increased the AUC of larotrectinib by 1.7-fold and the Cmax by 1.8-fold. Larotrectinib is also a substrate for the breast cancer resistance protein (BCRP), but the clinical significance is not known. Larotrectinib is not a substrate of organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, organic anion transporting polypeptide (OATP) 1B1, or OATP1B3. Larotrectinib is not an inhibitor of BCRP, P-gp, OAT1, OAT3, OCT1, OCT2, OATP1B1, OAT1B3, bile salt export pump (BSEP), multidrug and toxin extrusion (MATE) protein 1, or MATE2-K at clinically relevant concentrations.[63780]

    Oral Route

    The mean absolute bioavailability of larotrectinib capsules is 34%. In healthy subjects, the AUC of larotrectinib oral solution was similar to that of the capsules and the Cmax was 36% higher with the oral solution. Larotrectinib is dose proportional after single-dose studies over the dose range of 100 mg to 400 mg (1 to 4 times the recommended adult dose) and slightly greater than proportional at doses of 600 mg to 900 mg (6 to 9 times the recommended adult dose). In adult patients who received the 100 mg capsules twice daily, peak plasma concentrations (Cmax) were achieved at approximately 1 hour after dosing and steady-state was reached within 3 days. Mean steady-state larotrectinib [coefficient of variation (CV%)] for Cmax was 788 (81%) ng/mL and AUC was 4351 (97%) ng x h/mL.[63780]
     
    Effects of food: The AUC of larotrectinib was similar and the Cmax was reduced by 35% after a single 100 mg capsule to healthy subjects was administered with a high-fat meal (approximately 900 calories, 56 g of fat) compared to the fasted state.[63780]