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  • CLASSES

    Small Molecule Antineoplastic Multikinase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Oral kinase inhibitor against multiple targets, including vascular endothelial growth factor receptors
    Used for advanced endometrial cancer, radioactive iodine refractory differentiated thyroid cancer, advanced renal cell carcinoma, and unresectable hepatocellular carcinoma
    May cause QT prolongation; avoid other drugs that cause QT prolongation

    COMMON BRAND NAMES

    LENVIMA

    HOW SUPPLIED

    LENVIMA Oral Cap: 4mg, 10mg, 4-10mg

    DOSAGE & INDICATIONS

    For the treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).
    Oral dosage
    Adults

    24 mg orally once daily with or without food until disease progression or unacceptable toxicity. In a multicenter, randomized, double-blind, placebo-controlled clinical trial, treatment with lenvatinib (n = 261) significantly improved progression free survival (18.3 months vs. 3.6 months) and objective response rate (65% vs. 2%) compared with placebo (n = 131) in patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer. Overall survival was not estimable in either group, with a hazard ratio of 0.73. Of note, 83% of patients randomly assigned to placebo crossed over to receive open-label lenvatinib upon progression, which may have affected overall survival.

    For the treatment of advanced renal cell cancer (RCC) in combination with everolimus, following one prior anti-angiogenic therapy.
    Oral dosage
    Adults

    18 mg orally once daily, in combination with everolimus 5 mg orally once daily. Continue until disease progression or unacceptable toxicity. In a multicenter, open-label, phase 2 clinical trial, patients with advanced or metastatic renal cell carcinoma (RCC) who had received prior anti-angiogenic therapy were randomized to treatment with lenvatinib plus everolimus (combination therapy, n = 51), or everolimus monotherapy (10 mg per day, n = 50). The primary outcome of investigator-assessed median progression-free survival (PFS) was significantly improved in patients receiving combination therapy compared with everolimus monotherapy (14.6 months vs. 5.5 months); this was supported by a retrospective independent review of radiographs with an observed hazard ratio of 0.43 (95% CI, 0.24 to 0.75). Additionally, the median overall survival was 25.5 months with combination therapy compared with 15.4 months in patients treated with everolimus monotherapy (HR 0.67; 95% CI, 0.42 to 1.08) and the objective response rate was 37% versus 6%, respectively; all but one response (in a patient who received combination therapy) were partial responses.

    For the first-line treatment of unresectable hepatocellular cancer (HCC).
    Oral dosage
    Adults weighing 60 kg or more (actual body weight)

    12 mg PO once daily until disease progression or unacceptable toxicity. In a multicenter, randomized, open-label clinical trial of patients with previously untreated unresectable hepatocellular carcinoma (HCC), treatment with lenvatinib was noninferior to sorafenib therapy for overall survival (13.6 months vs. 12.3 months). Median progression-free survival (7.3 months vs. 3.6 months) and objective response rate (ORR) were significantly improved in the lenvatinib arm. The ORR was 41% in the lenvatinib arm compared with 12% in those treated with sorafenib using modified RECIST criteria (complete response (CR), 2.1% vs. 0.8%; partial response (PR), 38.5% vs. 11.6%). Using RECIST 1.1 criteria, the ORR was 19% versus 7%, respectively (CR, 0.4% vs. 0.2%; PR, 18.4% vs. 6.3%).

    Adults weighing less than 60 kg (actual body weight)

    8 mg PO once daily until disease progression or unacceptable toxicity. In a multicenter, randomized, open-label clinical trial of patients with previously untreated unresectable hepatocellular carcinoma (HCC), treatment with lenvatinib was noninferior to sorafenib therapy for overall survival (13.6 months vs. 12.3 months). Median progression-free survival (7.3 months vs. 3.6 months) and objective response rate (ORR) were significantly improved in the lenvatinib arm. The ORR was 41% in the lenvatinib arm compared with 12% in those treated with sorafenib using modified RECIST criteria (complete response (CR), 2.1% vs. 0.8%; partial response (PR), 38.5% vs. 11.6%). Using RECIST 1.1 criteria, the ORR was 19% versus 7%, respectively (CR, 0.4% vs. 0.2%; PR, 18.4% vs. 6.3%).

    For the treatment of endometrial cancer.
    For the treatment of advanced endometrial cancer that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) in patients who are not candidates for curative surgery or radiation, with disease progression following prior systemic therapy, in combination with pembrolizumab.
    Oral dosage
    Adults

    20 mg PO once daily until disease progression, in combination with pembrolizumab (200 mg IV every 3 weeks OR 400 mg IV every 6 weeks until disease progression or for up to 24 months in patients without disease progression). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Pembrolizumab therapy may need to be temporarily withheld or permanently discontinued in patients who develop immune-related reactions. In a multicenter, noncomparative, multi-cohort trial, the objective response rate was 38.3% (complete response, 10.6%) in patients with metastatic endometrial cancer that had progressed after at least one prior systemic therapy in any setting (n = 108); of these patients, 87% had tumors that were not MSI-H or dMMR. The median duration of response was not reached (range, 1.2 to 33.1 months), and 69% of patients had a response duration of 6 months or longer.

    MAXIMUM DOSAGE

    Adults

    Differentiated Thyroid Cancer (DTC), 24 mg per day PO.
    Renal Cell Carcinoma (RCC), 18 mg per day PO.
    Hepatocellular Carcinoma (HCC), 12 mg per day PO.

    Geriatric

    Differentiated Thyroid Cancer (DTC), 24 mg per day PO.
    Renal Cell Carcinoma (RCC), 18 mg per day PO.
    Hepatocellular Carcinoma (HCC), 12 mg per day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment
    Mild-to-moderate hepatic impairment (Child-Pugh Class A or B): no dosage adjustment needed for patients with DTC or RCC. There is no recommended dose for patients with HCC who have moderate hepatic impairment.
    Severe hepatic impairment (Child-Pugh Class C): Reduce the starting dose for DTC to 14 mg PO once daily; reduce the starting dose for endometrial cancer and RCC to 10 mg PO once daily. There is no recommended dose for patients with HCC who have severe hepatic impairment.
     
    Treatment-Related Hepatotoxicity
    Grade 3 or 4 hepatotoxicity: Hold lenvatinib therapy. When hepatic function improves to grade 0, 1, or baseline, either resume lenvatinib therapy at a reduced dose per the above recommendations, or discontinue therapy depending on severity and persistence of hepatotoxicity. For RCC patients receiving combination therapy with everolimus, adjust or discontinue only the everolimus therapy if the toxicity is thought to be solely due to everolimus. If the toxicity is likely related to both lenvatinib and everolimus, first reduce lenvatinib and then everolimus.
    Hepatic failure: Permanently discontinue lenvatinib.[58782]

    Renal Impairment

    Baseline Renal Impairment
    CrCL greater than or equal to 30 mL/min: no dosage adjustment needed.
    CrCL less than 30 mL/min: Reduce the starting dose for DTC to 14 mg PO once daily; reduce the starting dose for endometrial cancer and RCC to 10 mg PO once daily. There is no recommended dose of lenvatinib for patients with HCC and severe renal impairment.
    End-stage renal disease: Recommendations not available; patients with end-stage renal disease were not studied.
     
    Treatment-Related Nephrotoxicity
    Grade 3 or 4 renal impairment, or renal failure: Hold lenvatinib therapy. When renal function improves to grade 0, 1, or baseline, either resume lenvatinib therapy at a reduced dose per the above recommendations or discontinue therapy depending on the severity and persistence of renal impairment. For RCC patients receiving combination therapy with everolimus, adjust or discontinue only the everolimus therapy if the toxicity is thought to be solely due to everolimus. If the toxicity is likely related to both lenvatinib and everolimus, first reduce lenvatinib and then everolimus.
    Proteinuria (2g or greater in 24 hours): Hold lenvatinib therapy. When there is less than or equal to 2 g of proteinuria per 24 hours, resume lenvatinib therapy at a reduced dose per the recommendations above.
    Nephrotic syndrome: Permanently discontinue lenvatinib therapy.[58782]

    ADMINISTRATION

    Oral Administration

    Lenvatinib may be taken with or without food. Take at the same time each day.
    If a dose is missed, take it as soon as possible. If it cannot be taken within 12 hours, skip that dose and take the next dose at the usual time; do not take a double dose.
    Capsules should be swallowed whole. Alternatively, whole capsules may be placed in 1 tablespoon of water or apple juice (do not break or crush capsules). After 10 minutes, stir for at least 3 minutes and then drink the mixture. After drinking, add the same amount (1 tablespoon) of water or apple juice to the glass, swirl, and drink.

    STORAGE

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

    CONTRAINDICATIONS / PRECAUTIONS

    Bleeding, thyroid cancer

    Bleeding events, including fatal intracranial hemorrhages, have been reported in patients treated with lenvatinib, either as monotherapy or in combination with everolimus. Serious tumor-related bleeds, including fatalities, have also occurred. In post-marketing experience, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid cancer (ATC) than in other tumor types; the safety and effectiveness of lenvatinib therapy in patients with ATC has not been demonstrated in clinical trials. Hold lenvatinib therapy and resume treatment at a reduced dose upon recovery, or permanently discontinue lenvatinib therapy based on the severity of the bleed. Consider the risk of severe or fatal hemorrhage associated with lenvatinib therapy if there is tumor invasion/infiltration of major blood vessels (e.g., carotid artery).[58782]

    Hypertension

    Use caution when treating patients with preexisting hypertension with lenvatinib. Lenvatinib may increase blood pressure in both hypertensive and non-hypertensive patients. Blood pressure should be controlled before starting lenvatinib therapy, and monitored 1 week after initiation of therapy, every 2 weeks for 2 months, and then at least monthly after that. Patients who develop hypertension may require blood pressure monitoring at more frequent intervals and medical management of hypertension. Lenvatinib therapy should be permanently discontinued in patients with life-threatening hypertension; temporary suspension of therapy is recommended in patients with grade 3 or higher hypertension not controlled with medical management. The median time to onset of new or worsening hypertension was 16 to 26 days in patients with differentiated thyroid cancer (DTC) or hepatocellular carcinoma (HCC) receiving monotherapy, and 35 days in renal cell carcinoma (RCC) patients treated with the combination of lenvatinib plus everolimus.[58782]

    Cardiomyopathy, heart failure

    Use lenvatinib with caution in patients with a history of heart failure. Serious and sometimes fatal cardiac dysfunction (e.g., cardiomyopathy, left or right ventricular dysfunction, decreased ejection fraction, cardiac failure, ventricular hypokinesia) has been reported with lenvatinib therapy. Monitor patients for signs and symptoms of cardiac decompensation; treatment interruption, dose reduction, or permanent discontinuation may be necessary. Additionally, heart failure or cardiomyopathy may increase the risk of prolonging the QT interval when using lenvatinib.[28432] [28457] [56592] [58782]

    Cardiac disease, coronary artery disease, myocardial infarction, stroke, thromboembolic disease

    Use lenvatinib with caution in patients with a history of cardiac disease, coronary artery disease, myocardial infarction, stroke, or thromboembolic disease. Arterial thromboembolic events have been reported with lenvatinib therapy; if this occurs, permanently discontinue lenvatinib treatment. The safety of resuming lenvatinib after an arterial thromboembolic event has not been established. Lenvatinib has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months. Additionally, myocardial infarction or stroke may increase the risk of prolonging the QT interval when using lenvatinib.[28432] [28457] [56592] [58782]

    Hepatic disease, hepatotoxicity

    Hepatotoxicity, including hepatic failure, has been reported with lenvatinib therapy. Use lenvatinib with caution in patients with hepatic disease; an initial dosage adjustment may be necessary. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary in patients who develop grade 3 or higher hepatotoxicity. Obtain liver function tests before starting treatment, every 2 weeks for the first 2 months, and at least monthly thereafter during treatment.

    Dehydration, hypovolemia, renal disease, renal failure, renal impairment

    Use lenvatinib with caution in patients with a history of renal disease, renal impairment, or renal failure; a dose reduction may be necessary in patients with a baseline creatinine clearance (CrCl) less than 30 mL/minute. Renal impairment and renal failure have been reported in patients treated with lenvatinib. One risk factor for severe renal impairment was dehydration or hypovolemia due to diarrhea and vomiting; diarrhea is also commonly reported with lenvatinib therapy. Initiate prompt medical management in patients who develop diarrhea and monitor for dehydration. Treatment interruption, dose reduction, or discontinuation of therapy may be necessary for patients who develop severe diarrhea or renal dysfunction.[58782]

    Fistula, GI perforation

    GI perforation and fistula formation have been reported in patients treated with lenvatinib. Discontinue lenvatinib therapy in patients who develop GI perforation or life-threatening fistula.

    Apheresis, AV block, bradycardia, celiac disease, electrolyte imbalance, females, fever, geriatric, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, long QT syndrome, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, systemic lupus erythematosus (SLE)

    Prolongation of the QT interval has been reported with lenvatinib treatment. Evaluate electrolytes at baseline and monitor periodically during therapy in all patients; correct any electrolyte imbalance as necessary. Additionally, serum calcium levels should be monitored at least monthly and replaced as needed. Use with caution and monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradycardia, or who are receiving medications known to prolong the QT interval (including Class Ia and III antiarrhythmics). Treatment interruption, dose reduction, or discontinuation may be necessary. Use lenvatinib with caution in patients with conditions that may increase the risk of QT prolongation including AV block, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.[28432] [28457] [56592] [58782]

    Hypothyroidism, thyroid disease

    Use lenvatinib with caution in patients with a history of thyroid disease, as lenvatinib impairs exogenous thyroid suppression. Hypothyroidism has been reported with lenvatinib therapy. Monitor thyroid function before initiation of lenvatinib therapy and at least monthly during treatment; treat hypothyroidism according to standard medical practice. Hypothyroidism may increase the risk of prolonging the QT interval when using lenvatinib.[28432] [28457] [56592] [58782]

    Proteinuria

    Proteinuria has been reported in patients treated with lenvatinib. Patients who develop 2 grams or more of proteinuria in 24 hours may require an interruption of therapy, dose reduction, or discontinuation of therapy. Permanently discontinue lenvatinib in patients with nephrotic syndrome. Monitor patients for the development of proteinuria with urinalysis before starting treatment and periodically throughout treatment. Patients with a 2+ protein or greater urine dipstick reading should undergo further assessment (e.g., a 24-hour urine collection).

    Impaired wound healing, surgery

    Impaired wound healing has been reported in patients treated with lenvatinib. Therefore, temporarily hold lenvatinib therapy for at least 1 week before elective surgery; do not administer lenvatinib for at least 2 weeks following major surgery and until adequate wound healing. The safety of resuming lenvatinib after the resolution of wound healing complications has not been established.

    Encephalopathy

    Reversible Posterior Leukoencephalopathy Syndrome (RPLS), also known as Posterior Reversible Encephalopathy Syndrome (PRES), has been reported with lenvatinib use. Symptoms of RPLS include seizures, headache, visual disturbances, confusion, and altered mental status; this syndrome may be confirmed on magnetic resonance imaging. Hold lenvatinib therapy if RPLS is suspected. Upon complete resolution, resume treatment at a reduced dose or discontinue therapy, depending on the severity and persistence of neurologic symptoms.[58782]

    Pregnancy

    Fetal harm may occur if lenvatinib is administered during pregnancy, based on animal studies. The use of effective contraception is recommended to avoid pregnancy during treatment and for 30 days following the last dose. No human data are available regarding teratogenic risk. Women who become pregnant while receiving lenvatinib should be apprised of the potential hazard to the fetus. During the period of organogenesis, exposures of 0.14 and 0.03 times the human exposure at the recommended dose resulted in reduced fetal body weights and an increased incidence of external, visceral, and skeletal variations in rats and rabbits, respectively. Post-implantation loss occurred in more than 80% of rats at approximately 0.5 times the recommended human dose based on BSA; increased post-implantation loss, including 1 fetal death, occurred at exposures of 0.03 times the recommended human dose based on BSA in rabbits. Additionally, late abortions occurred in approximately one-third of rabbits at approximately 0.5 times the recommended human dose based on BSA.[58782]

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during lenvatinib treatment. Lenvatinib can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 30 days after treatment with lenvatinib. Females of reproductive potential should undergo pregnancy testing prior to initiation of lenvatinib. Women who become pregnant while receiving lenvatinib should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of lenvatinib on human fertility, male and female infertility has been observed in animal studies.[58782]

    Breast-feeding

    Due to the potential for serious adverse reactions in nursing infants from lenvatinib, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. It is not known whether lenvatinib is present in human milk, although many drugs are excreted in human milk.[58782]

    ADVERSE REACTIONS

    Severe

    hypertension / Early / 13.0-45.0
    diarrhea / Early / 4.0-19.0
    fatigue / Early / 7.0-18.0
    elevated hepatic enzymes / Delayed / 3.0-17.0
    weight loss / Delayed / 3.0-13.0
    QT prolongation / Rapid / 2.0-11.0
    hyponatremia / Delayed / 0-11.0
    hypophosphatemia / Delayed / 0-11.0
    hypercholesterolemia / Delayed / 0-11.0
    proteinuria / Delayed / 6.0-11.0
    dehydration / Delayed / 2.0-10.0
    renal failure (unspecified) / Delayed / 2.0-10.0
    thrombocytopenia / Delayed / 2.0-10.0
    hypocalcemia / Delayed / 0.8-9.0
    bleeding / Early / 2.0-8.0
    vomiting / Early / 0-7.0
    anorexia / Delayed / 0-7.0
    abdominal pain / Early / 2.0-6.0
    hyperkalemia / Delayed / 0-6.0
    hypokalemia / Delayed / 0-6.0
    nausea / Early / 1.0-5.0
    stomatitis / Delayed / 0-5.0
    arthralgia / Delayed / 1.0-5.0
    myalgia / Early / 1.0-5.0
    hepatic encephalopathy / Delayed / 0-5.0
    dyspnea / Early / 0-5.0
    stroke / Early / 0-5.0
    myocardial infarction / Delayed / 0-5.0
    ascites / Delayed / 0-4.0
    pleural effusion / Delayed / 0-4.0
    palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / 3.0-3.0
    prolonged bleeding time / Delayed / 0-3.0
    hepatic failure / Delayed / 0-3.0
    hypoalbuminemia / Delayed / 0-3.0
    heart failure / Delayed / 3.0-3.0
    cardiomyopathy / Delayed / 3.0-3.0
    pulmonary embolism / Delayed / 0-3.0
    hyperglycemia / Delayed / 0-3.0
    headache / Early / 0-3.0
    hypotension / Rapid / 0-2.0
    GI perforation / Delayed / 2.0-2.0
    fever / Early / 0-2.0
    infection / Delayed / 0-2.0
    insomnia / Early / 0-2.0
    peripheral edema / Delayed / 0.4-2.0
    constipation / Delayed / 0-1.0
    intracranial bleeding / Delayed / 0-1.0
    dysphonia / Delayed / 0-1.0
    xerostomia / Early / 0-0.4
    dyspepsia / Early / 0-0.4
    rash / Early / 0-0.4
    dizziness / Early / 0-0.4
    leukoencephalopathy / Delayed / 0.3-0.3
    hypertensive crisis / Early / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    hematemesis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    coma / Early / Incidence not known
    cholecystitis / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    thromboembolism / Delayed / Incidence not known
    nephrotic syndrome / Delayed / Incidence not known
    wound dehiscence / Delayed / Incidence not known

    Moderate

    hypothyroidism / Delayed / 21.0-70.0
    hypertriglyceridemia / Delayed / 0-18.0
    hyperbilirubinemia / Delayed / 5.0-13.0
    lymphopenia / Delayed / 8.0-10.0
    anemia / Delayed / 4.0-8.0
    neutropenia / Delayed / 0-7.0
    confusion / Early / 0-4.0
    adrenocortical insufficiency / Delayed / 0-3.0
    hypercalcemia / Delayed / 5.0
    hypomagnesemia / Delayed / 5.0
    hyperamylasemia / Delayed / 5.0
    hypoglycemia / Early / 5.0
    oral ulceration / Delayed / Incidence not known
    glossitis / Early / Incidence not known
    erythema / Early / Incidence not known
    hematoma / Early / Incidence not known
    hematuria / Delayed / Incidence not known
    hemoptysis / Delayed / Incidence not known
    hypermagnesemia / Delayed / Incidence not known
    encephalopathy / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    parotitis / Delayed / Incidence not known
    cystitis / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    impaired wound healing / Delayed / Incidence not known

    Mild

    cough / Delayed / 24.0-37.0
    gastroesophageal reflux / Delayed / 0-21.0
    dysgeusia / Early / 0-18.0
    epistaxis / Delayed / 0-12.0
    alopecia / Delayed / 0-12.0
    hyperkeratosis / Delayed / 0-7.0
    musculoskeletal pain / Early / Incidence not known
    back pain / Delayed / Incidence not known
    asthenia / Delayed / Incidence not known
    malaise / Early / Incidence not known
    lethargy / Early / Incidence not known
    maculopapular rash / Early / Incidence not known
    gingivitis / Delayed / Incidence not known
    weakness / Early / Incidence not known

    DRUG INTERACTIONS

    Aclidinium; Formoterol: (Moderate) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. Prolongation of the QT interval has been reported with lenvatinib therapy. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia; the risk may be more clinically significant with long-acting beta-agonists. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Albuterol: (Minor) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Albuterol; Ipratropium: (Minor) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Alfuzosin: (Major) Avoid coadministration of lenvatinib with alfuzosin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Based on electrophysiology studies performed by the manufacturer, alfuzosin may also prolong the QT interval in a dose-dependent manner.
    Amiodarone: (Major) Avoid coadministration of lenvatinib with amiodarone due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Amiodarone, a Class III antiarrhythmic agent, is also associated with a well-established risk of QT prolongation; although the frequency of torsade de pointes (TdP) is less with amiodarone than with other Class III agents, amiodarone is still also associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amitriptyline: (Major) Avoid coadministration of lenvatinib with tricyclic antidepressants due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amitriptyline; Chlordiazepoxide: (Major) Avoid coadministration of lenvatinib with tricyclic antidepressants due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of lenvatinib with clarithromycin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Clarithromycin is also associated with an established risk for QT prolongation and torsade de pointes (TdP).
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of lenvatinib with clarithromycin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Clarithromycin is also associated with an established risk for QT prolongation and torsade de pointes (TdP).
    Anagrelide: (Major) Do not use anagrelide with lenvatinib due to the risk of QT prolongation. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. Prolongation of the QT interval has been reported with lenvatinib therapy.
    Apomorphine: (Major) Avoid coadministration of lenvatinib with apomorphine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
    Arformoterol: (Moderate) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. Prolongation of the QT interval has been reported with lenvatinib therapy. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia; the risk may be more clinically significant with long-acting beta-agonists. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Aripiprazole: (Major) Avoid coadministration of lenvatinib with aripiprazole due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. QT prolongation has also occurred during therapeutic use of aripiprazole and following overdose.
    Arsenic Trioxide: (Major) Avoid coadministration of lenvatinib with arsenic trioxide due to the risk of QT prolongation. Torsade de pointes (TdP), QT interval prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. Prolongation of the QT interval has also been reported with lenvatinib therapy.
    Artemether; Lumefantrine: (Major) Avoid coadministration of lenvatinib with artemether due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Artemether; lumefantrine is also associated with prolongation of the QT interval and should be avoided in combination with other QT prolonging drugs. (Major) Avoid coadministration of lenvatinib with lumefantrine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Artemether; lumefantrine is also associated with prolongation of the QT interval and should be avoided in combination with other QT prolonging drugs.
    Asenapine: (Major) Avoid coadministration of lenvatinib with asenapine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Asenapine has also been associated with QT prolongation.
    Atomoxetine: (Major) Avoid coadministration of lenvatinib with atomoxetine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. QT prolongation has also occurred during therapeutic use of atomoxetine and following overdose.
    Azithromycin: (Major) Avoid coadministration of azithromycin with lenvatinib due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Prolongation of the QT interval has been reported with lenvatinib therapy.
    Bedaquiline: (Major) Avoid coadministration of lenvatinib with bedaquiline due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Bedaquiline has also been reported to prolong the QT interval. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Avoid coadministration of lenvatinib with metronidazole due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Avoid coadministration of lenvatinib with metronidazole due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Budesonide; Formoterol: (Moderate) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. Prolongation of the QT interval has been reported with lenvatinib therapy. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia; the risk may be more clinically significant with long-acting beta-agonists. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. Prolongation of the QT interval has been reported with lenvatinib therapy. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia; the risk may be more clinically significant with long-acting beta-agonists. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Buprenorphine: (Major) Avoid coadministration of lenvatinib with buprenorphine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
    Buprenorphine; Naloxone: (Major) Avoid coadministration of lenvatinib with buprenorphine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP).
    Ceritinib: (Major) Avoid coadministration of lenvatinib with ceritinib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Ceritinib causes concentration-dependent QT prolongation.
    Chloroquine: (Major) Avoid coadministration of chloroquine with lenvatinib due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Prolongation of the QT interval has been reported with lenvatinib therapy.
    Chlorpromazine: (Major) Avoid coadministration of lenvatinib with chlorpromazine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Chlorpromazine, a phenothiazine, is also associated with an established risk of QT prolongation and torsade de pointes (TdP).
    Ciprofloxacin: (Major) Avoid coadministration of lenvatinib with ciprofloxacin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Rare cases of QT prolongation and torsade de pointes (TdP) have been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Severe) Because of the potential for torsades de pointes (TdP), use of cisapride with lenvatinib is contraindicated. QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. Prolongation of the QT interval has also been reported with lenvatinib therapy.
    Citalopram: (Major) Avoid coadministration of lenvatinib with citalopram due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Citalopram causes dose-dependent QT interval prolongation.
    Clarithromycin: (Major) Avoid coadministration of lenvatinib with clarithromycin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Clarithromycin is also associated with an established risk for QT prolongation and torsade de pointes (TdP).
    Clofazimine: (Major) Avoid coadministration of lenvatinib with clofazimine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. QT prolongation and torsade de pointes have been reported in patients receiving clofazimine in combination with QT prolonging medications.
    Clomipramine: (Major) Avoid coadministration of lenvatinib with tricyclic antidepressants due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Clozapine: (Major) Avoid coadministration of lenvatinib with clozapine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Treatment with clozapine has also been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
    Codeine; Phenylephrine; Promethazine: (Major) Avoid coadministration of lenvatinib with promethazine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Codeine; Promethazine: (Major) Avoid coadministration of lenvatinib with promethazine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Crizotinib: (Major) Avoid coadministration of lenvatinib with crizotinib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Crizotinib has been associated with concentration-dependent QT prolongation.
    Dasatinib: (Major) Avoid coadministration of lenvatinib with dasatinib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. In vitro studies have shown that dasatinib also has the potential to prolong the QT interval.
    Degarelix: (Major) Avoid coadministration of lenvatinib with degarelix due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval.
    Desipramine: (Major) Avoid coadministration of lenvatinib with tricyclic antidepressants due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Deutetrabenazine: (Major) Avoid coadministration of lenvatinib with deutetrabenazine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Clinically relevant QTc prolongation may also occur with deutetrabenazine.
    Dextromethorphan; Promethazine: (Major) Avoid coadministration of lenvatinib with promethazine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Dextromethorphan; Quinidine: (Major) Avoid coadministration of lenvatinib with quinidine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Quinidine administration is also associated with QT prolongation as well as torsade de pointes (TdP).
    Disopyramide: (Major) Avoid coadministration of lenvatinib with disopyramide due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Disopyramide administration is also associated with QT prolongation and torsade de pointes (TdP).
    Dofetilide: (Major) Coadministration of dofetilide and lenvatinib is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Prolongation of the QT interval has been reported with lenvatinib therapy.
    Dolasetron: (Major) Avoid coadministration of lenvatinib with dolasetron due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir; Rilpivirine: (Major) Avoid coadministration of lenvatinib with rilpivirine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Donepezil: (Major) Avoid coadministration of lenvatinib with donepezil due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Case reports indicate that QT prolongation and torsade de pointes (TdP) can also occur during donepezil therapy.
    Donepezil; Memantine: (Major) Avoid coadministration of lenvatinib with donepezil due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Case reports indicate that QT prolongation and torsade de pointes (TdP) can also occur during donepezil therapy.
    Doxepin: (Major) Avoid coadministration of lenvatinib with tricyclic antidepressants due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Dronedarone: (Severe) Because of the potential for torsades de pointes (TdP), use of dronedarone with lenvatinib is contraindicated. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Prolongation of the QT interval has also been reported with lenvatinib therapy.
    Droperidol: (Major) Avoid coadministration of lenvatinib with droperidol due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes (TdP). Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal.
    Efavirenz: (Major) Avoid coadministration of lenvatinib with efavirenz due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Prolongation of the QTc interval has also been observed with the use of efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Avoid coadministration of lenvatinib with efavirenz due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Prolongation of the QTc interval has also been observed with the use of efavirenz.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of lenvatinib with efavirenz due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Prolongation of the QTc interval has also been observed with the use of efavirenz.
    Eliglustat: (Major) Avoid coadministration of lenvatinib with eliglustat due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid coadministration of lenvatinib with rilpivirine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Avoid coadministration of lenvatinib with rilpivirine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Encorafenib: (Major) Avoid coadministration of encorafenib and lenvatinib due to QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. QT prolongation was reported during clinical trials of lenvatinib.
    Entrectinib: (Major) Avoid coadministration of entrectinib with lenvatinib due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Prolongation of the QT interval has also been reported with lenvatinib therapy.
    Eribulin: (Major) Avoid coadministration of lenvatinib with eribulin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Eribulin has also been associated with QT prolongation.
    Erythromycin: (Major) Avoid coadministration of lenvatinib with erythromycin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Erythromycin is also associated with QT prolongation and torsade de pointes (TdP).
    Erythromycin; Sulfisoxazole: (Major) Avoid coadministration of lenvatinib with erythromycin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Erythromycin is also associated with QT prolongation and torsade de pointes (TdP).
    Escitalopram: (Major) Avoid coadministration of lenvatinib with escitalopram due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Escitalopram has also been associated with a risk of QT prolongation and torsade de pointes (TdP).
    Ezogabine: (Major) Avoid coadministration of lenvatinib with ezogabine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Ezogabine has also been associated with QT prolongation.
    Fingolimod: (Major) Avoid coadministration of lenvatinib with fingolimod due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Although fingolimod has not been studied in patients treated with drugs that prolong the QT interval, drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
    Flecainide: (Major) Avoid coadministration of lenvatinib with flecainide due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsade de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Fluconazole: (Major) Avoid coadministration of lenvatinib with fluconazole due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Fluconazole has also been associated with QT prolongation and rare cases of torsade de pointes (TdP).
    Fluoxetine: (Major) Avoid coadministration of lenvatinib with fluoxetine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. QT prolongation and torsade de pointes (TdP) have also been reported in patients treated with fluoxetine
    Fluoxetine; Olanzapine: (Major) Avoid coadministration of lenvatinib with fluoxetine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. QT prolongation and torsade de pointes (TdP) have also been reported in patients treated with fluoxetine (Major) Avoid coadministration of lenvatinib with olanzapine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Fluphenazine: (Minor) Use caution if coadministration of fluphenazine with lenvatinib is necessary. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation such as lenvatinib.
    Fluticasone; Salmeterol: (Moderate) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. Prolongation of the QT interval has been reported with lenvatinib therapy. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia; the risk may be more clinically significant with long-acting beta-agonists. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. Prolongation of the QT interval has been reported with lenvatinib therapy. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia; the risk may be more clinically significant with long-acting beta-agonists. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Fluticasone; Vilanterol: (Moderate) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. Prolongation of the QT interval has been reported with lenvatinib therapy. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia; the risk may be more clinically significant with long-acting beta-agonists. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Fluvoxamine: (Major) Avoid coadministration of lenvatinib with fluvoxamine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. QT prolongation and torsade de pointes (TdP) have also been reported during fluvoxamine in postmarketing experience.
    Formoterol: (Moderate) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. Prolongation of the QT interval has been reported with lenvatinib therapy. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia; the risk may be more clinically significant with long-acting beta-agonists. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Formoterol; Mometasone: (Moderate) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. Prolongation of the QT interval has been reported with lenvatinib therapy. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia; the risk may be more clinically significant with long-acting beta-agonists. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Foscarnet: (Major) Avoid coadministration of lenvatinib with foscarnet due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Both QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of foscarnet.
    Fostemsavir: (Major) Avoid coadministration of lenvatinib with fostemsavir due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
    Gemifloxacin: (Major) Avoid coadministration of lenvatinib with gemifloxacin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Major) Avoid coadministration of lenvatinib with gemtuzumab due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.
    Gilteritinib: (Major) Avoid coadministration of lenvatinib with gilteritinib due to the potential for additive QT prolongation. Both drugs have been associated with QT prolongation.
    Glasdegib: (Major) Avoid coadministration of lenvatinib with glasdegib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia.
    Glycopyrrolate; Formoterol: (Moderate) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. Prolongation of the QT interval has been reported with lenvatinib therapy. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia; the risk may be more clinically significant with long-acting beta-agonists. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Goserelin: (Major) Avoid coadministration of lenvatinib with goserelin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Androgen deprivation therapy (i.e., goserelin) may prolong the QT/QTc interval.
    Granisetron: (Major) Avoid coadministration of lenvatinib with granisetron due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Granisetron has also been associated with QT prolongation.
    Halogenated Anesthetics: (Major) Avoid coadministration of lenvatinib with halogenated anesthetics due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Halogenated anesthetics can also prolong the QT interval.
    Haloperidol: (Major) Avoid coadministration of lenvatinib with haloperidol due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. QT prolongation and torsade de pointes (TdP) have also been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
    Histrelin: (Major) Avoid coadministration of lenvatinib with histrelin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Hydroxychloroquine: (Major) Avoid coadministration of lenvatinib and hydroxychloroquine due to an increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Hydroxychloroquine and lenvatinib are both associated with QT prolongation.
    Hydroxyzine: (Major) Avoid coadministration of lenvatinib with hydroxyzine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Postmarketing data indicate that hydroxyzine causes QT prolongation and torsade de pointes (TdP).
    Ibutilide: (Major) Avoid coadministration of lenvatinib with ibutilide due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Ibutilide administration can also cause QT prolongation and torsade de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
    Iloperidone: (Major) Avoid coadministration of lenvatinib with iloperidone due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Iloperidone has also been associated with QT prolongation.
    Imipramine: (Major) Avoid coadministration of lenvatinib with tricyclic antidepressants due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Indacaterol: (Moderate) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. Prolongation of the QT interval has been reported with lenvatinib therapy. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia; the risk may be more clinically significant with long-acting beta-agonists. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Indacaterol; Glycopyrrolate: (Moderate) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. Prolongation of the QT interval has been reported with lenvatinib therapy. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia; the risk may be more clinically significant with long-acting beta-agonists. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of lenvatinib with inotuzumab due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Inotuzumab has also been associated with QT interval prolongation.
    Itraconazole: (Major) Avoid coadministration of lenvatinib with itraconazole due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Itraconazole has also been associated with prolongation of the QT interval.
    Ivosidenib: (Major) Avoid coadministration of lenvatinib with ivosidenib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Prolongation of the QTc interval and ventricular arrhythmias have also been reported in patients treated with ivosidenib.
    Ketoconazole: (Major) Avoid coadministration of lenvatinib with ketoconazole due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Ketoconazole has also been associated with prolongation of the QT interval.
    Lapatinib: (Major) Avoid coadministration of lenvatinib with lapatinib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Lefamulin: (Major) Avoid coadministration of lefamulin with lenvatinib as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Prolongation of the QT interval has been reported with lenvatinib therapy.
    Leuprolide: (Major) Avoid coadministration of lenvatinib with leuprolide due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Major) Avoid coadministration of lenvatinib with leuprolide due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
    Levalbuterol: (Minor) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Levofloxacin: (Major) Avoid coadministration of lenvatinib with levofloxacin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Levofloxacin has also been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, torsade de pointes has been reported during postmarketing surveillance of levofloxacin.
    Lithium: (Major) Avoid coadministration of lenvatinib with lithium due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Lithium has also been associated with QT prolongation.
    Lofexidine: (Major) Avoid coadministration of lenvatinib with lofexidine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Lofexidine also prolongs the QT interval.
    Long-acting beta-agonists: (Moderate) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. Prolongation of the QT interval has been reported with lenvatinib therapy. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia; the risk may be more clinically significant with long-acting beta-agonists. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Loperamide: (Major) Avoid coadministration of lenvatinib with loperamide due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Loperamide; Simethicone: (Major) Avoid coadministration of lenvatinib with loperamide due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with lenvatinib due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Prolongation of the QT interval has also been reported with lenvatinib therapy.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as lenvatinib. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. QT prolongation was also reported during clinical trials of lenvatinib.
    Maprotiline: (Major) Avoid coadministration of lenvatinib with maprotiline due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Mefloquine: (Major) Avoid coadministration of lenvatinib with mefloquine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation.
    Meperidine; Promethazine: (Major) Avoid coadministration of lenvatinib with promethazine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Metaproterenol: (Minor) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Methadone: (Major) Avoid coadministration of lenvatinib with methadone due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Methadone is also considered to be associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (greater than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Metronidazole: (Major) Avoid coadministration of lenvatinib with metronidazole due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Potential QT prolongation has also been reported in limited case reports with metronidazole.
    Midostaurin: (Major) Avoid coadministration of lenvatinib with midostaurin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Prolongation of the QT interval was also reported in patients who received midostaurin in clinical trials.
    Mifepristone: (Major) Avoid coadministration of lenvatinib with mifepristone due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Mifepristone has been associated with dose-dependent prolongation of the QT interval.
    Mirtazapine: (Major) Avoid coadministration of lenvatinib with mirtazapine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has also been reported in postmarketing experience with mirtazapine, primarily in overdose or in patients with other risk factors for QT prolongation.
    Moxifloxacin: (Major) Avoid coadministration of lenvatinib with moxifloxacin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Quinolones have also been associated with a risk of QT prolongation; although extremely rare, torsade de pointes (TdP) has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nilotinib: (Major) Avoid coadministration of lenvatinib with nilotinib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy.
    Norfloxacin: (Major) Avoid coadministration of lenvatinib with norfloxacin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Quinolones have also been associated with a risk of QT prolongation; although extremely rare, torsade de pointes (Tdp) has been reported during postmarketing surveillance of norfloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nortriptyline: (Major) Avoid coadministration of lenvatinib with tricyclic antidepressants due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Octreotide: (Major) Avoid coadministration of lenvatinib with octreotide due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes (TdP), the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Major) Avoid coadministration of lenvatinib with ofloxacin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Quinolones have also been associated with a risk of QT prolongation; although extremely rare, torsade de pointes (TdP) has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Major) Avoid coadministration of lenvatinib with olanzapine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Olodaterol: (Moderate) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. Prolongation of the QT interval has been reported with lenvatinib therapy. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia; the risk may be more clinically significant with long-acting beta-agonists. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Ondansetron: (Major) Avoid coadministration of lenvatinib with ondansetron due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP).
    Osilodrostat: (Major) Avoid coadministration of lenvatinib with osilodrostat due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Osilodrostat is associated with dose-dependent QT prolongation.
    Osimertinib: (Major) Avoid coadministration of lenvatinib with osimertinib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib.
    Oxaliplatin: (Major) Avoid coadministration of lenvatinib with oxaliplatin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have been reported with oxaliplatin use in postmarketing experience.
    Ozanimod: (Major) In general, do not initiate ozanimod in patients taking lenvatinib due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Prolongation of the QT interval has been reported with lenvatinib therapy.
    Paliperidone: (Major) Avoid coadministration of lenvatinib with paliperidone due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of paliperidone overdose.
    Panobinostat: (Major) Avoid coadministration of lenvatinib with panobinostat due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. QT prolongation has also been reported with panobinostat.
    Pasireotide: (Major) Avoid coadministration of lenvatinib with pasireotide due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Prolongation of the QT interval has occurred with pasireotide at therapeutic and supra-therapeutic doses.
    Pazopanib: (Major) Avoid coadministration of lenvatinib with pazopanib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Pazopanib has also been reported to prolong the QT interval.
    Pentamidine: (Major) Avoid coadministration of lenvatinib with pentamidine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Systemic pentamidine has also been associated with QT prolongation.
    Perphenazine: (Minor) Use caution if coadministration of perphenazine with lenvatinib is necessary. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation such as lenvatinib.
    Perphenazine; Amitriptyline: (Major) Avoid coadministration of lenvatinib with tricyclic antidepressants due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). (Minor) Use caution if coadministration of perphenazine with lenvatinib is necessary. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation such as lenvatinib.
    Phenylephrine; Promethazine: (Major) Avoid coadministration of lenvatinib with promethazine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Pimavanserin: (Major) Avoid coadministration of lenvatinib with pimavanserin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Pimavanserin may also cause QT prolongation.
    Pimozide: (Severe) Because of the potential for torsades de pointes (TdP), use of pimozide with lenvatinib is contraindicated. Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Prolongation of the QT interval has been reported with lenvatinib therapy.
    Pirbuterol: (Minor) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Pitolisant: (Major) Avoid coadministration of pitolisant with lenvatinib as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Prolongation of the QT interval has also been reported with lenvatinib therapy.
    Posaconazole: (Major) Avoid coadministration of lenvatinib with posaconazole due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes.
    Primaquine: (Major) Avoid coadministration of lenvatinib with primaquine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Primaquine also prolongs the QT interval.
    Procainamide: (Major) Avoid coadministration of lenvatinib with procainamide due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Procainamide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP).
    Prochlorperazine: (Minor) Use caution if coadministration of prochlorperazine with lenvatinib is necessary. Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation such as lenvatinib.
    Promethazine: (Major) Avoid coadministration of lenvatinib with promethazine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Propafenone: (Major) Avoid coadministration of lenvatinib with propafenone due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Propafenone is a Class IC antiarrhythmic which increases the QT interval, largely due to prolongation of the QRS interval.
    Protriptyline: (Major) Avoid coadministration of lenvatinib with tricyclic antidepressants due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Quetiapine: (Major) Avoid coadministration of lenvatinib with quetiapine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Limited data, including some case reports, suggest that quetiapine may also be associated with a significant prolongation of the QTc interval in rare instances.
    Quinidine: (Major) Avoid coadministration of lenvatinib with quinidine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Quinidine administration is also associated with QT prolongation as well as torsade de pointes (TdP).
    Quinine: (Major) Avoid coadministration of lenvatinib with quinine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Quinine has also been associated with QT prolongation and rare cases of torsade de pointes (TdP).
    Ranolazine: (Major) Avoid coadministration of lenvatinib with ranolazine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Ribociclib: (Major) Avoid coadministration of ribociclib with lenvatinib due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; QT prolongation was also reported during clinical trials of lenvatinib. Concomitant use may increase the risk for QT prolongation.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with lenvatinib due to an increased risk for QT prolongation. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; QT prolongation was also reported during clinical trials of lenvatinib. Concomitant use may increase the risk for QT prolongation.
    Rilpivirine: (Major) Avoid coadministration of lenvatinib with rilpivirine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
    Risperidone: (Major) Avoid coadministration of lenvatinib with risperidone due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Risperidone has also been associated with a possible risk for QT prolongation and/or torsade de pointes (TdP), primarily in the overdose setting.
    Romidepsin: (Major) Avoid coadministration of lenvatinib with romidepsin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Romidepsin has also been reported to prolong the QT interval.
    Salmeterol: (Moderate) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. Prolongation of the QT interval has been reported with lenvatinib therapy. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia; the risk may be more clinically significant with long-acting beta-agonists. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Saquinavir: (Major) Avoid coadministration of lenvatinib with saquinavir due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsade de pointes (TdP).
    Selpercatinib: (Major) Avoid coadministration of lenvatinib with selpercatinib due to the risk of QT prolongation. Monitor ECGs more frequently for QT prolongation if coadministration is necessary. Prolongation of the QT interval has been reported with lenvatinib therapy. Concentration-dependent QT prolongation has been observed with selpercatinib therapy.
    Sertraline: (Major) Avoid coadministration of lenvatinib with sertraline due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. QTc prolongation and TdP have been reported during postmarketing use of sertraline; most cases had confounding risk factors. The risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure).
    Short-acting beta-agonists: (Minor) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Siponimod: (Major) Avoid coadministration of siponimod and lenvatinib due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Prolongation of the QT interval has been reported with lenvatinib therapy.
    Solifenacin: (Major) Avoid coadministration of lenvatinib with solifenacin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Solifenacin has also been associated with dose-dependent prolongation of the QT interval; torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined.
    Sorafenib: (Major) Avoid coadministration of lenvatinib with sorafenib due to the risk of additive QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Sorafenib is also associated with QTc prolongation.
    Sotalol: (Major) Avoid coadministration of lenvatinib with sotalol due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Sotalol administration is also associated with QT prolongation and torsade de pointes (TdP). Proarrhythmic events should be anticipated after initiation of sotalol therapy and after each upward dosage adjustment.
    Sunitinib: (Major) Avoid coadministration of lenvatinib with sunitinib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Sunitinib can also prolong the QT interval.
    Tacrolimus: (Major) Avoid coadministration of lenvatinib with tacrolimus due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tacrolimus also causes QT prolongation.
    Tamoxifen: (Major) Avoid coadministration of lenvatinib with tamoxifen due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses.
    Telavancin: (Major) Avoid coadministration of lenvatinib with telavancin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Telavancin also has been associated with QT prolongation.
    Telithromycin: (Major) Avoid coadministration of lenvatinib with telithromycin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Telithromycin is also associated with QT prolongation and torsade de pointes (TdP).
    Terbutaline: (Minor) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Tetrabenazine: (Major) Avoid coadministration of lenvatinib with tetrabenazine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tetrabenazine also causes a small increase in the corrected QT interval (QTc).
    Thioridazine: (Severe) Because of the potential for torsades de pointes (TdP), use of thioridazine with lenvatinib is contraindicated. Thioridazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP) and is contraindicated for use with other drugs that are known to prolong the QT interval. Prolongation of the QT interval has also been reported with lenvatinib therapy.
    Tiotropium; Olodaterol: (Moderate) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. Prolongation of the QT interval has been reported with lenvatinib therapy. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia; the risk may be more clinically significant with long-acting beta-agonists. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Tolterodine: (Major) Avoid coadministration of lenvatinib with tolterodine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
    Toremifene: (Major) Avoid coadministration of lenvatinib with toremifene due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner.
    Trazodone: (Major) Avoid coadministration of lenvatinib with trazodone due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Trazodone can also prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of torsade de pointes (TdP).
    Triclabendazole: (Major) Avoid coadministration of lenvatinib with triclabendazole due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Transient prolongation of the mean QTc interval was noted on the ECG recordings in dogs administered triclabendazole.
    Tricyclic antidepressants: (Major) Avoid coadministration of lenvatinib with tricyclic antidepressants due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Trifluoperazine: (Minor) Use caution if coadministration of trifluoperazine with lenvatinib is necessary. Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation such as lenvatinib.
    Trimipramine: (Major) Avoid coadministration of lenvatinib with tricyclic antidepressants due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Triptorelin: (Major) Avoid coadministration of lenvatinib with triptorelin due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval.
    Umeclidinium; Vilanterol: (Moderate) Beta-agonists should be used cautiously and with close monitoring with lenvatinib. Prolongation of the QT interval has been reported with lenvatinib therapy. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia; the risk may be more clinically significant with long-acting beta-agonists. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated.
    Vandetanib: (Major) Avoid coadministration of lenvatinib with vandetanib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib.
    Vardenafil: (Major) Avoid coadministration of lenvatinib with vardenafil due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Vardenafil is associated with QT prolongation at both therapeutic and supratherapeutic doses.
    Vemurafenib: (Major) Avoid coadministration of lenvatinib with vemurafenib due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Vemurafenib has also been associated with QT prolongation.
    Venlafaxine: (Major) Avoid coadministration of lenvatinib with venlafaxine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Voriconazole: (Major) Avoid coadministration of lenvatinib with voriconazole due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Voriconazole has also been associated with QT prolongation and rare cases of torsade de pointes.
    Vorinostat: (Major) Avoid coadministration of lenvatinib with vorinostat due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Vorinostat therapy is also associated with a risk of QT prolongation.
    Ziprasidone: (Major) Avoid coadministration of lenvatinib with ziprasidone due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors.

    PREGNANCY AND LACTATION

    Pregnancy

    Fetal harm may occur if lenvatinib is administered during pregnancy, based on animal studies. The use of effective contraception is recommended to avoid pregnancy during treatment and for 30 days following the last dose. No human data are available regarding teratogenic risk. Women who become pregnant while receiving lenvatinib should be apprised of the potential hazard to the fetus. During the period of organogenesis, exposures of 0.14 and 0.03 times the human exposure at the recommended dose resulted in reduced fetal body weights and an increased incidence of external, visceral, and skeletal variations in rats and rabbits, respectively. Post-implantation loss occurred in more than 80% of rats at approximately 0.5 times the recommended human dose based on BSA; increased post-implantation loss, including 1 fetal death, occurred at exposures of 0.03 times the recommended human dose based on BSA in rabbits. Additionally, late abortions occurred in approximately one-third of rabbits at approximately 0.5 times the recommended human dose based on BSA.[58782]

    Due to the potential for serious adverse reactions in nursing infants from lenvatinib, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. It is not known whether lenvatinib is present in human milk, although many drugs are excreted in human milk.[58782]

    MECHANISM OF ACTION

    Lenvatinib is a kinase inhibitor, inhibiting the kinase activities of vascular endothelial growth factor receptor 1 (VEGFR1; FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib also inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression including fibroblast growth factor receptors 1 (FGFR1), FGFR2, FGFR3, and FGFR4, platelet-derived growth factor receptor alpha (PDGFR-alpha), KIT, and RET. It also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2 alpha (FRS2 alpha) phosphorylation. The combination of lenvatinib and everolimus showed increased anti-angiogenic and anti-tumor activity (decreased endothelial cell proliferation, tube formation, and VEGF signaling, as well as tumor volume) in mouse xenograft models of human renal cell carcinoma, greater than each drug alone.[58782]

    PHARMACOKINETICS

    Lenvatinib is administered orally. Lenvatinib is 98% to 99% bound in vitro to human plasma proteins at concentrations of 0.3 to 30 mcg/mL; in vitro, the blood-to-plasma concentration ratio was 0.589 to 0.608 (0.1 to 10 mcg/mL). The terminal elimination half-life was approximately 28 hours, although patients with hepatocellular carcinoma (HCC) had a 13% lower lenvatinib clearance (CL/F) than patients with other cancer types. The main metabolic pathways are enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic. Radiolabeled lenvatinib was administered to 6 patients with solid tumors; after 10 days, approximately 64% and 25% of the dose were eliminated in the feces and urine, respectively.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)
    CYP3A is one of the main metabolic pathways for lenvatinib; in vitro, lenvatinib is also a P-gp and BCRP substrate. When administered with ketoconazole (a CYP3A, P-gp, and BCRP inhibitor) in a dedicated clinical trial, the AUC and Cmax of lenvatinib increased by 15% and 19%, respectively. Administration with rifampin as a single dose increased the AUC (31%) and Cmax (33%) of lenvatinib, but reduced the AUC by 18% when administered daily for 21 days (no change to the Cmax). Lenvatinib inhibits CYP2C8, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A in vitro; lenvatinib also induces CYP3A. Lenvatinib inhibits UGT1A1, UGT1A4, and UGT1A9 in vitro, but likely only inhibits UGT1A1 in vivo in the gastrointestinal tract based on the expression of the enzyme in tissues.[58782]

    Oral Route

    Peak plasma concentrations of lenvatinib (Tmax) are observed 1 to 4 hours after oral administration. Administration with a high-fat meal (approximately 900 calories; fat, 55%; protein, 15%; carbohydrates, 30%) does not affect the extent of absorption but decreases the rate of absorption and delays the median Tmax from 2 to 4 hours. Cmax and AUC increased proportionally over the dose range of 3.2 to 32 mg, with a median accumulation index of 0.96 (20 mg) to 1.54 (6.4 mg).[58782]