lenvatinib (Rx)

Brand and Other Names:Lenvima
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 4mg
  • 10mg

Thyroid Cancer (DTC)

Indicated for locally recurrent or metastatic, progressive, radioactive iodine-refractory DTC

24 mg (two 10 mg capsules and one 4 mg capsule) PO qDay

Renal Cell Carcinoma (RCC)

Indicated in combination with everolimus for advanced RCC following 1 prior anti-angiogenic therapy

18 mg (one 10 mg capsule and two 4 mg capsules) plus everolimus 5 mg PO qDay

Continue until disease progression or until unacceptable toxicity

Dosage Modifications

DTC dose reductions

  • DTC dose reductions
    • Interrupt until resolved to grade 0-1 or baseline
    • Adjusted dose: 20 mg PO qDay
  • Second occurrence
    • Interrupt until resolved to grade 0-1 or baseline
    • Adjusted dose: 14 mg PO qDay
  • Third occurrence
    • Interrupt until resolved to grade 0-1 or baseline
    • Adjusted dose: 10 mg PO qDay

RCC dose reductions

  • First occurrence
    • Interrupt until resolved to grade 0-1 or baseline
    • Adjusted dose: 14 mg PO qDay
  • Second occurrence
    • Interrupt until resolved to grade 0-1 or baseline
    • Adjusted dose: 10 mg PO qDay
  • Third occurrence
    • Interrupt until resolved to grade 0-1 or baseline
    • Adjusted dose: 8 mg PO qDay
  • Dose modification of everolimus in RCC
    • For toxicities thought to be related to everolimus alone, discontinue, interrupt, or use alternate day dosing
    • For toxicities thought to be related to both lenvatinib and everolimus, first reduce lenvatinib and then everolimus
  • Severe renal or hepatic impairment in RCC
    • CrCl <30 mL/min or Child-Pugh C: 10 mg PO qDay

Hypertension or cardiac dysfunction

  • Grade 3: Hold drug; may resume at reduced dose after resolution of adverse effects to grades 0, 1, or 2
  • Grade 4: Discontinue, do not resume

Arterial thrombotic event

  • Any grade: Discontinue, do not resume

Hepatic impairment

  • Hepatotoxicity grade 3 or 4: Hold or discontinue; consider resuming at reduced dose if resolves to grade 0, 1, or baseline
  • Hepatic failure grade 3 or 4: Discontinue, do not resume

Proteinuria

  • ≥2 g/24 hr: Hold dose; may resume at reduced dose after resolution to <2 g/24 hr

Nephrotic syndrome

  • Discontinue; do not resume

GI toxicity

  • Nausea, vomiting, and diarrhea grade 3: Hold; may resume at reduced dose after resolution to grade 0, 1, or baseline
  • Vomiting and diarrhea grade 4: Discontinue, do not resume
  • GI perforation, any grade: Discontinue, do not resume
  • GI fistula grade 3 or 4: Discontinue, do not resume

Renal failure or impairment

  • Grade 3 or 4: Hold or discontinue; consider resuming at reduced dose if resolves to grade 0, 1, or baseline

QTc prolongation

  • >500 ms: Hold; may resume at reduced dose after resolution to <480 ms or baseline

Reversible posterior leukoencephalopathy syndrome (RPLS)

  • Any grade: Hold or discontinue; consider resuming at reduced dose if resolves to grade 0 to 1

Hemorrhage

  • Grade 3: Hold; may resume at reduced dose after resolution to grade 0 to 1
  • Grade 4: Discontinue, do not resume

Safety and efficacy not established

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Interactions

Interaction Checker

and lenvatinib

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    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Percentages are for all grades of adverse effects unless otherwise noted

            Hypertension (73%)

            Diarrhea (67%)

            Fatigue (67%)

            Arthralgia/myalgia (62%)

            Decreased appetite (54%)

            Weight decreased (51%)

            Nausea (47%)

            Hypertension, grades 3-4 (44%)

            Stomatitis (41%)

            Headache (38%)

            Vomiting (36%)

            Proteinuria (34%)

            Palmar-plantar erythrodysesthesia (32%)

            Abdominal pain (31%)

            Dysphonia (31%)

            Constipation (29%)

            Oral pain (25%)

            Cough (24%)

            Peripheral edema (21%)

            Rash (21%)

            Dysgeusia (18%)

            Dry mouth (17%)

            Dizziness (15%)

            Dyspepsia (13%)

            Alopecia (12%)

            Epistaxis (12%)

            Insomnia (12%)

            Urinary tract infection (11%)

            1-10%

            Percentages are for all grades of adverse effects unless otherwise noted

            Dental infections (10%)

            Hypotension (9%)

            Diarrhea, grades 3-4 (9%)

            Dehydration (9%)

            Prolonged QT interval (9%)

            Hypocalcemia (9%)

            Decreased appetite, grades 3-4 (7%)

            Hyperkeratosis (7%)

            Hypokalemia (6%)

            AST increased (5%)

            ALT increased (4%)

            Lipase increased (4%)

            Creatinine increased (3%)

            Nausea, grades 3-4 (2%)

            Platelet count decreased (2%)

            Postmarketing Reports

            Pancreatitis

            Amylase increased

            Cholecystitis

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            Warnings

            Contraindications

            None

            Cautions

            NOTE: Please refer to Dose Section (Dosage Modifications) for information on withholding and/or reducing dose, and for information regarding discontinuing the drug

            Hypertension reported in 73% of lenvatinib-treated patients in clinical trials (grade 3 hypertension was 44%); control blood pressure prior to treatment; monitor blood pressure after 1 week, then q2weeks for the first 2 months, and then at least monthly thereafter

            Cardiac dysfunction, defined as decreased left or right ventricular function, cardiac failure, or pulmonary edema, was reported in 7% of treated patients; monitor for clinical symptoms or signs of cardiac decompensation

            Arterial thromboembolic events reported in 5% of treated patients; discontinue drug following a thromboembolic event (see Dosage Modifications)

            Increased ALT and/or AST observed; rare reports of hepatic failure, including fatalities, were also reported

            Proteinuria reported in 34% of lenvatinib-treated patients in clinical trials (grade 3 proteinuria was 11%); monitor for proteinuria before initiation of, and periodically throughout, treatment

            Renal failure and impairment reported in 14% (3% ≥grade 3); the primary risk factor for severe renal impairment was dehydration/hypovolemia due to diarrhea and vomiting; initiate active management of diarrhea and any other gastrointestinal symptoms Grade 1 events

            Diarrhea may occur; initiate prompt medical management for diarrhea; monitor for dehydration; interrupt therapy for Grade 3 or 4 diarrhea; for Grade 3 diarrhea, resume at reduced dose when diarrhea resolves to Grade 1 or baseline; permanently discontinue therapy for Grade 4 diarrhea despite medical management

            Gastrointestinal (GI) perforation or fistula reported (2%); discontinue if patient develops a GI perforation or life-threatening fistula

            QT prolongation reported (9%); monitor ECG in patients with congenital long QT syndrome, CHF, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including class Ia and III antiarrhythmics; monitor and correct electrolyte abnormalities in all patients; monitor electrocardiograms in patients with congenital long QT syndrome; congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong QT interval, including Class Ia and III antiarrhythmics; withhold therapy for development of QTc interval prolongation >500 ms; resume therapy at reduced dose when QTc prolongation resolves to baseline

            Hypocalcemia reported (9% ≥grade 3); monitor blood calcium levels at least monthly and replace calcium as necessary during treatment

            Reversible posterior leukoencephalopathy syndrome (RPLS) reported rarely

            Hemorrhagic events occurred in 35% of treated patients

            Impairs exogenous thyroid suppression; monitor TSH levels monthly and adjust thyroid replacement medication as needed

            Based on its mechanism of action and data from animal reproduction studies, lenvatinib can cause fetal harm when administered to a pregnant woman

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            Pregnancy & Lactation

            Pregnancy

            Based on its mechanism of action and data from animal reproduction studies, lenvatinib can cause fetal harm when administered to a pregnant woman

            In animal reproduction studies, oral administration during organogenesis at doses below the recommended human dose (approximately 0.14 times the recommended human dose based on body surface area) resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits

            There are no available human data informing the drug-associated risk

            Advise pregnant women of the potential risk to a fetus

            Contraception

            • Advise females of reproductive potential to use effective contraception during treatment and for at least 2 weeks following completion of therapy

            Infertility

            • Females: May result in reduced fertility in females of reproductive potential
            • Males: May result in damage to male reproductive tissues, leading to reduced fertility of unknown duration

            Lactation

            Unknown if distributed in human breast milk; advise women to discontinue breastfeeding during treatment because of the potential for serious adverse reactions in nursing infants

            Lenvatinib and its metabolites are excreted in rat milk at concentrations higher than in maternal plasma (approximately 2 times higher [based on AUC] in milk compared with maternal plasma

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4)

            Also inhibits other RTKs that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; the platelet-derived growth factor receptor alpha (PDGFR-alpha), KIT, and RET

            Absorption

            Orally administered

            Peak plasma time: 1-4 hr after PO administration

            Administration with food does not affect the extent of absorption but can delay the mean peak plasma time from 2 hr to 4 hr

            Distribution

            Protein bound: 98-99%

            Substrate of P-gp and BCRP

            Metabolism

            Metabolized by the CYP3A enzymes and aldehyde oxidase

            Elimination

            Half-life: 28 hr

            Excretion (10 days after single dose): 64% feces; 25% urine

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            Administration

            Oral Administration

            Swallow capsule whole

            May take with or without food

            Take at the same time each day

            Missed dose: If a dose is missed and cannot be taken within 12 hr, skip that dose and take the next dose at the usual time of administration

            If unable to swallow capsule

            • Capsules can be dissolved in a small glass of liquid
            • Measure 1 tablespoon of water or apple juice and put the capsules into the liquid without breaking or crushing them
            • Leave the capsules in the liquid for at least 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 the contents a few times and swallow the additional liquid
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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

            To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

            Adding plans allows you to:

            • View the formulary and any restrictions for each plan.
            • Manage and view all your plans together – even plans in different states.
            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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