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KEYTRUDA® (pembrolizumab) Injection 100 mg and LENVIMA® (lenvatinib) Capsules 10 mg and 4 mg

Adverse Reaction Management

LENVIMA KEYTRUDA

For patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation.

Help manage your patients’ adverse reactions to LENVIMA

Recommended dosage reductions for LENVIMA for adverse reaction managementa

Recommended dosage reductions for LENVIMA for adverse reaction managementa

How LENVIMA is supplied

Recommended dose

20 mg orally once daily

First dose reduction

14 mg orally once daily

Second dose reduction

10 mg orally once daily

Third dose reduction

8 mg orally once daily

  • Interrupt, reduce, and/or discontinue LENVIMA based on the type and/or severity (grade) of the adverse reaction.
  • The recommended dosage of LENVIMA for patients with endometrial carcinoma and severe renal impairment (creatinine clearance less than 30 mL/min calculated by Cockcroft-Gault equation using actual body weight) is 10 mg orally once daily.
  • The recommended dosage of LENVIMA for patients with endometrial carcinoma and severe hepatic impairment (Child-Pugh C) is 10 mg orally once daily.

aRefer to the LENVIMA Prescribing Information for full dosing information.

How LENVIMA is supplied

Capsules may not be shown at actual size.

LENVIMA capsules are supplied in cartons of 6 cards; each card is a 5-day blister card.

aRefer to the LENVIMA Prescribing Information for full dosing information.

Recommended Adverse Reaction Monitoring and Management for LENVIMA

Hypertension
＋

Monitoring and Management

  • Control blood pressure (BP) prior to initiating LENVIMA
  • Monitor BP after 1 week, then every 2 weeks for 2 months and then at least monthly thereafter during treatment

Severitya and Dosage Modification

Grade 3

  • Withhold for Grade 3 that persists despite optimal antihypertensive therapy
  • Resume at reduced dose when hypertension is controlled at ≤ Grade 2

Grade 4

  • Permanently discontinue

Cardiac Dysfunction
＋

Monitoring and Management

  • Monitor patients for clinical symptoms or signs of cardiac dysfunction

Severitya and Dosage Modification

Grade 3

  • Withhold until improves to Grade 0 to 1 or baseline
  • Resume at a reduced dose or discontinue depending on the severity and persistence of adverse reaction

Grade 4

  • Permanently discontinue

Arterial Thromboembolic Events
＋

Monitoring and Management

  • The safety of resuming LENVIMA after an arterial thromboembolic event has not been established and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months

Severitya and Dosage Modification

Any grade

  • Permanently discontinue

Hepatotoxicity
＋

Monitoring and Management

  • Monitor liver function prior to initiating LENVIMA
  • Monitor liver function every 2 weeks for the first 2 months and then at least monthly thereafter during treatment
  • Monitor patients with HCC closely for signs of hepatic failure, including encephalopathy

Severitya and Dosage Modification

Grade 3 or 4

  • Withhold until improves to Grade 0 to 1 or baseline
  • Either resume at a reduced dose or discontinue depending on severity and persistence of hepatotoxicity
  • Permanently discontinue for hepatic failure

Renal Failure or Impairment
＋

Monitoring and Management

  • Initiate prompt management of diarrhea or dehydration/hypovolemia

Severitya and Dosage Modification

Grade 3 or 4

  • Withhold until improves to Grade 0 to 1 or baseline
  • Resume at a reduced dose or discontinue depending on severity and persistence of renal impairment

Proteinuria
＋

Monitoring and Management

  • Monitor for proteinuria prior to initiating LENVIMA and periodically during treatment
  • If proteinuria ≥2+ on urine dipstick, obtain a 24-hour urine protein sample

Severitya and Dosage Modification

≥2 g proteinuria in 24 hours

  • Withhold until ≤2 grams of proteinuria per 24 hours
  • Resume at a reduced dose
  • Permanently discontinue for nephrotic syndrome

Gastrointestinal Perforation
＋

Severitya and Dosage Modification

Any grade

  • Permanently discontinue

Fistula Formation
＋

Severitya and Dosage Modification

Grade 3 or 4

  • Permanently discontinue

QT Prolongation
＋

Monitoring and Management

  • Monitor/correct electrolyte abnormalities at baseline and periodically during treatment
  • Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, or bradyarrhythmias, or in patients who are taking drugs known to prolong QT interval, including Class Ia and III antiarrhythmics

Severitya and Dosage Modification

>500 ms or >60 ms increase from baseline

  • Withhold until improves to ≤480 ms or baseline
  • Resume at a reduced dose

Reversible Posterior Leukoencephalopathy Syndrome
＋

Monitoring and Management

  • Confirm the diagnosis of RPLS with magnetic resonance imaging

Severitya and Dosage Modification

Any grade

  • Withhold until fully resolved
  • Resume at a reduced dose or discontinue depending on severity and persistence of neurologic symptoms

Impairment of Thyroid-Stimulating Hormone Suppression / Thyroid Dysfunction
＋

Monitoring and Management

  • Monitor thyroid function prior to initiating LENVIMA
  • Monitor thyroid function at least monthly during treatment
  • Treat hypothyroidism according to standard medical practice

Impaired Wound Healing
＋

Dosage Modification

  • Withhold for at least 1 week prior to elective surgery
  • Do not administer for at least 2 weeks following major surgery and until adequate wound healing
  • The safety of resumption of LENVIMA after resolution of wound healing complications has not been established

Other Adverse Reactions
＋

Monitoring and Management

Diarrhea

  • Promptly initiate management of diarrhea

Hypocalcemia

  • Monitor blood calcium levels at least monthly
  • Replace calcium as necessary during treatment

Hemorrhagic events

  • Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (eg, carotid artery)

Severitya and Dosage Modification

Persistent or intolerable Grade 2 or 3 adverse reaction or Grade 4 laboratory abnormalities

  • Withhold until improves to Grade 0 to 1 or baseline
  • Resume at reduced dose

Grade 4 adverse reaction

  • Permanently discontinue

aNational Cancer Institute-Common Terminology Criteria for Adverse Events v4.0.

HCC = unresectable hepatocellular carcinoma.

Help manage your patients’ adverse reactions to KEYTRUDA

Recommended Adverse Reaction Monitoring and Management for KEYTRUDA

Immune-mediated pneumonitis
＋

Monitoring and Management

  • Monitor for signs and symptoms of pneumonitis
  • If pneumonitis is suspected, evaluate with radiographic imaging

Severitya and Dosage Modification

Grade 2

  • Withholdb

Grade 3 or 4 or recurrent Grade 2

  • Permanently discontinue

Immune-mediated colitis
＋

Monitoring and Management

  • Monitor for signs and symptoms of colitis

Severitya and Dosage Modification

Grade 2 or 3

  • Withholdb

Grade 4

  • Permanently discontinue

Immune-mediated hepatitis in patients without hepatocellular carcinomac
＋

Monitoring and Management

  • Monitor for changes in liver function

Severitya and Dosage Modification

AST or ALT >3 but no more than 5 times the ULN or total bilirubin >1.5 but no more than 3 times the ULN

  • Withholdb

In patients without liver metastases, AST or ALT >5 times ULN or total bilirubin >3 times ULN

  • Permanently discontinue

In patients with liver metastasis and Grade 2 AST or ALT at baseline, with an increase in AST or ALT of ≥50% relative to baseline that persists for at least 1 week

  • Permanently discontinue

Immune-mediated endocrinopathies
＋

Monitoring and Management

  • Monitor for signs and symptoms of adrenal insufficiency, hypophysitis (including hypopituitarism), changes in thyroid function (prior to and periodically during treatment), and hyperglycemia.
  • For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated.
  • Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate.
  • Administer insulin for type 1 diabetes and administer antihyperglycemics in patients with severe hyperglycemia.

Severitya and Dosage Modification

Grade 2 adrenal insufficiency or hypophysitis

  • Withhold

Grade 3 or 4 adrenal insufficiency or hypophysitis

  • Withhold or discontinue

Grade 3 or 4 hyperthyroidism

  • Withhold or discontinue

Severe hyperglycemia

  • Withhold

Immune-mediated nephritis and renal dysfunction
＋

Monitoring and Management

  • Monitor for changes in renal function

Severitya and Dosage Modification

Grade 2

  • Withholdb

Grade 3 or 4

  • Permanently discontinue

Immune-mediated skin adverse reactions
＋

Monitoring and Management

  • Monitor for suspected severe skin reactions and exclude other causes. Immune-mediated rashes, including SJS, TEN (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur

Severitya and Dosage Modification

Grade 3 or suspected SJS or TEN

  • Withhold

Grade 4 or confirmed SJS or TEN

  • Permanently discontinue

Allogeneic HSCT prior to treatment with KEYTRUDA
＋

Monitoring and Management

  • Consider the benefit of treatment with KEYTRUDA versus the risk of possible GVHD in patients with a history of allogeneic HSCT

Allogeneic HSCT after treatment with KEYTRUDA
＋

Monitoring and Management

  • Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly

Other immune-mediated adverse reactions
＋

Monitoring and Management

  • These immune-mediated reactions can occur in any organ system or tissue
  • For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes
  • Consider the benefit of treatment with KEYTRUDA versus the risk of possible organ transplant rejection. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients

Severitya and Dosage Modification

Grade 2 or 3 based on the severity and type of reaction

  • Withholdb

Grade 3 based on the severity and type of reaction or Grade 4

  • Permanently discontinue

Recurrent immune-mediated adverse reactions
＋

Severitya and Dosage Modification

Recurrent Grade 2 pneumonitis
Recurrent Grade 3 or 4

  • Permanently discontinue

Inability to taper corticosteroid
＋

Severitya and Dosage Modification

Requirement for 10 mg per day or greater prednisone or equivalent for more than 12 weeks after last dose of KEYTRUDA

  • Permanently discontinue

Persistent Grade 2 or 3 adverse reaction (excluding endocrinopathy)
＋

Severitya and Dosage Modification

Grade 2 or 3 adverse reactions lasting 12 weeks or longer after last dose of KEYTRUDA

  • Permanently discontinue

Infusion-related reactions
＋

Monitoring and Management

  • Monitor for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever

Severitya and Dosage Modification

Grade 1 or 2

  • Interrupt or slow the rate of infusion

Grade 3 or 4

  • Permanently discontinue

aToxicity was graded per National Cancer Institute-Common Terminology Criteria for Adverse Events v4.0.

bResume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper.

cPlease refer to the dose modifications section of the Prescribing Information for specific guidance for patients with hepatocellular carcinoma.

ALT = alanine aminotransferase; AST = aspartate aminotransferase; HSCT = hematopoietic stem cell transplantation; GVHD = graft-versus-host disease; ULN = upper limit of normal; VOD = veno-occlusive disease.

Selected Safety Information for
KEYTRUDA® (pembrolizumab)

Immune-Mediated Pneumonitis

  • KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%), and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

  • KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis

  • KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Immune-Mediated Endocrinopathies

  • KEYTRUDA can cause adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%). Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.
  • Monitor patients for signs and symptoms of adrenal insufficiency, hypophysitis (including hypopituitarism), thyroid function (prior to and periodically during treatment), and hyperglycemia. For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 adrenal insufficiency or hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

  • KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

  • Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

  • Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.
  • The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.
  • Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

  • KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

  • Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.
  • In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

Increased Mortality in Patients With Multiple Myeloma

  • In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

  • Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

  • In KEYNOTE-146, when KEYTRUDA was administered in combination with LENVIMA to patients with endometrial carcinoma (n=94), fatal adverse reactions occurred in 3% of patients. Serious adverse reactions occurred in 52% of patients, the most common (≥3%) were hypertension (9%), abdominal pain (6%), musculoskeletal pain (5%), hemorrhage, fatigue, nausea, confusional state, and pleural effusion (4% each), adrenal insufficiency, colitis, dyspnea, and pyrexia (3% each).

    KEYTRUDA was discontinued for adverse reactions (Grade 1-4) in 19% of patients, regardless of action taken with LENVIMA; the most common (≥2%) leading to discontinuation of KEYTRUDA were adrenal insufficiency, colitis, pancreatitis, and muscular weakness (2% each).

    The most common adverse reactions (≥20%) observed with KEYTRUDA in combination with LENVIMA were fatigue, musculoskeletal pain and hypertension (65% each), diarrhea (64%), decreased appetite (52%), hypothyroidism (51%), nausea (48%), stomatitis (43%), vomiting (39%), decreased weight (36%), abdominal pain and headache (33% each), constipation (32%), urinary tract infection (31%), dysphonia (29%), hemorrhagic events (28%), hypomagnesemia (27%), palmar-plantar erythrodysesthesia syndrome (26%), dyspnea (24%), and cough and rash (21% each).

Lactation

  • Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the final dose.

PD-1 = programmed death receptor-1; PD-L1 = programmed death ligand 1

Before prescribing KEYTRUDA® (pembrolizumab), please read the accompanying Prescribing Information. The Medication Guide also is available.

Selected Safety Information for
LENVIMA® (lenvatinib)

Hypertension

  • In differentiated thyroid cancer (DTC), hypertension occurred in 73% of patients on LENVIMA (44% grade 3-4). In advanced renal cell carcinoma (RCC), hypertension occurred in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic blood pressure ≥160 mmHg occurred in 29% of patients, and 21% had diastolic blood pressure ≥100 mmHg. In unresectable hepatocellular carcinoma (HCC), hypertension occurred in 45% of LENVIMA-treated patients (24% grade 3). Grade 4 hypertension was not reported in HCC.
  • Serious complications of poorly controlled hypertension have been reported. Control blood pressure prior to initiation. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at reduced dose when hypertension is controlled or permanently discontinue based on severity.

Cardiac Dysfunction

  • Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC, and HCC, grade 3 or higher cardiac dysfunction occurred in 3% of LENVIMA-treated patients. Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Arterial Thromboembolic Events

  • Among patients receiving LENVIMA or LENVIMA + everolimus, arterial thromboembolic events of any severity occurred in 2% of patients in RCC and HCC and 5% in DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials. Permanently discontinue following an arterial thrombotic event. The safety of resuming after an arterial thromboembolic event has not been established and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

Hepatotoxicity

  • Across clinical studies enrolling 1,327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic failure, acute hepatitis and hepatorenal syndrome, occurred in 0.5% of patients. In HCC, hepatic encephalopathy occurred in 8% of LENVIMA-treated patients (5% grade 3-5). Grade 3-5 hepatic failure occurred in 3% of LENVIMA-treated patients. 2% of patients discontinued LENVIMA due to hepatic encephalopathy and 1% discontinued due to hepatic failure.
  • Monitor liver function prior to initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Renal Failure or Impairment

  • Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment was reported in 14% and 7% of LENVIMA-treated patients in DTC and HCC, respectively. Grade 3-5 renal failure or impairment occurred in 3% of patients with DTC and 2% of patients with HCC, including 1 fatal event in each study. In RCC, renal impairment or renal failure was reported in 18% of LENVIMA + everolimus–treated patients (10% grade 3).
  • Initiate prompt management of diarrhea or dehydration/ hypovolemia. Withhold and resume at reduced dose upon recovery or permanently discontinue for renal failure or impairment based on severity.

Proteinuria

  • In DTC and HCC, proteinuria was reported in 34% and 26% of LENVIMA-treated patients, respectively. Grade 3 proteinuria occurred in 11% and 6% in DTC and HCC, respectively. In RCC, proteinuria occurred in 31% of patients receiving LENVIMA + everolimus (8% grade 3). Monitor for proteinuria prior to initiation and periodically during treatment. If urine dipstick proteinuria ≥2+ is detected, obtain a 24-hour urine protein. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Diarrhea

  • Of the 737 LENVIMA-treated patients in DTC and HCC, diarrhea occurred in 49% (6% grade 3). In RCC, diarrhea occurred in 81% of LENVIMA + everolimus–treated patients (19% grade 3). Diarrhea was the most frequent cause of dose interruption/reduction, and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Fistula Formation and Gastrointestinal Perforation

  • Of the 799 patients treated with LENVIMA or LENVIMA + everolimus in DTC, RCC, and HCC, fistula or gastrointestinal perforation occurred in 2%. Permanently discontinue in patients who develop gastrointestinal perforation of any severity or grade 3-4 fistula.

QT Interval Prolongation

  • In DTC, QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%. In RCC, QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA + everolimus and QTc interval >500 ms occurred in 6%. In HCC, QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%.
  • Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose upon recovery based on severity.

Hypocalcemia

  • In DTC, grade 3-4 hypocalcemia occurred in 9% of LENVIMA-treated patients. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation with or without dose interruption or dose reduction. In RCC, grade 3-4 hypocalcemia occurred in 6% of LENVIMA + everolimus–treated patients. In HCC, grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

  • Across clinical studies of 1,823 patients who received LENVIMA as a single agent, RPLS occurred in 0.3%. Confirm diagnosis of RPLS with MRI. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity and persistence of neurologic symptoms.

Hemorrhagic Events

  • Serious including fatal hemorrhagic events can occur with LENVIMA. In DTC, RCC, and HCC clinical trials, hemorrhagic events, of any grade, occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria. In DTC, grade 3-5 hemorrhage occurred in 2% of LENVIMA-treated patients, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In RCC, grade 3-5 hemorrhage occurred in 8% of LENVIMA + everolimus–treated patients, including 1 fatal cerebral hemorrhage. In HCC, grade 3-5 hemorrhage occurred in 5% of LENVIMA-treated patients, including 7 fatal hemorrhagic events. Serious tumor-related bleeds, including fatal hemorrhagic events, occurred in LENVIMA-treated patients in clinical trials and in the postmarketing setting. In postmarketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than other tumors. Safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials.
  • Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (eg, carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.

Impairment of Thyroid Stimulating Hormone Suppression/
Thyroid Dysfunction

  • LENVIMA impairs exogenous thyroid suppression. In DTC, 88% of patients had baseline thyroid stimulating hormone (TSH) level ≤0.5 mU/L. In patients with normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. In RCC and HCC, grade 1 or 2 hypothyroidism occurred in 24% of LENVIMA + everolimus–treated patients and 21% of LENVIMA-treated patients, respectively. In patients with normal or low TSH at baseline, elevation of TSH was observed post baseline in 70% of LENVIMA-treated patients in HCC and 60% of LENVIMA + everolimus–treated patients in RCC.
  • Monitor thyroid function prior to initiation and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

Impaired Wound Healing

  • Impaired wound healing has been reported in patients who received LENVIMA. Withhold LENVIMA for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of LENVIMA after resolution of wound healing complications has not been established.

Embryo-fetal Toxicity

  • Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus; and advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 30 days after the last dose.

Adverse Reactions

  • In endometrial carcinoma, the most common adverse reactions (≥20%) observed in LENVIMA + KEYTRUDA-treated patients were fatigue (65%), hypertension (65%), musculoskeletal pain (65%), diarrhea (64%), decreased appetite (52%), hypothyroidism (51%), nausea (48%), stomatitis (43%), vomiting (39%), decreased weight (36%), abdominal pain (33%), headache (33%), constipation (32%), urinary tract infection (31%), dysphonia (29%), hemorrhagic events (28%), hypomagnesemia (27%), palmar-plantar erythrodysesthesia (26%), dyspnea (24%), cough (21%), and rash (21%).

    Adverse reactions led to dose reduction or interruption in 88% of patients receiving LENVIMA. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were fatigue (32%), hypertension (26%), diarrhea (18%), nausea (13%), palmar-plantar erythrodysesthesia (13%), vomiting (13%), decreased appetite (12%), musculoskeletal pain (11%), stomatitis (9%), abdominal pain (7%), hemorrhages (7%), renal impairment (6%), decreased weight (6%), rash (5%), headache (5%), increased lipase (5%), and proteinuria (5%).

    Fatal adverse reactions occurred in 3% of patients receiving LENVIMA + KEYTRUDA, including gastrointestinal perforation, RPLS with intraventricular hemorrhage, and intracranial hemorrhage.

    Serious adverse reactions occurred in 52% of patients receiving LENVIMA + KEYTRUDA. Serious adverse reactions in ≥3% of patients were hypertension (9%), abdominal pain (6%), musculoskeletal pain (5%), hemorrhage (4%), fatigue (4%), nausea (4%), confusional state (4%), pleural effusion (4%), adrenal insufficiency (3%), colitis (3%), dyspnea (3%), and pyrexia (3%).

    Permanent discontinuation due to adverse reaction (grade 1-4) occurred in 21% of patients who received LENVIMA + KEYTRUDA. The most common adverse reactions (>2%) resulting in discontinuation of LENVIMA were gastrointestinal perforation or fistula (2%), muscular weakness (2%), and pancreatitis (2%).

Use in Specific Populations

  • Because of the potential for serious adverse reactions in breastfed infants, advise women to discontinue breastfeeding during treatment and for at least 1 week after last dose. LENVIMA may impair fertility in males and females of reproductive potential.
  • No dose adjustment is recommended for patients with mild (creatinine clearance [CLcr] 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or endometrial carcinoma and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose for patients with DTC, RCC, or endometrial carcinoma and severe renal impairment. There is no recommended dose for patients with HCC and severe renal impairment. LENVIMA has not been studied in patients with end stage renal disease. No dose adjustment is recommended for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose for patients with HCC with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.
  • No dose adjustment is recommended for patients with DTC, RCC, or endometrial carcinoma and mild or moderate hepatic impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment. Reduce the dose for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment.

QTc = corrected QT interval; MRI = magnetic resonance imaging; CNS = central nervous system.

Before prescribing LENVIMA® (lenvatinib), please read the accompanying Prescribing Information and Patient Information.

References:
  1. National Cancer Institute. Drugs approved for endometrial cancer. https://www.cancer.gov/about-cancer/treatment/drugs/endometrial. Updated September 18, 2019. Accessed November 19, 2019.
  2. MEGESTROL ACETATE [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2016.
  3. Depo-Provera [package insert]. New York, NY: Pfizer Inc; 2017.
  4. Makker V, Taylor M, Aghajanian C, et al. Supplementary appendix to: Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. (J Clin Oncol. 2020;38:1–13. doi:10.1200/ JCO.19.02627. Epub ahead of print.) Accessed March 17, 2020.
  5. Makker V, Taylor M, Aghajanian C, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol. 2020;38:1–13. doi:10.1200/JCO.19.02627. Epub ahead of print.
  6. Data available on request from Merck, Professional Services-DAP, WP1-27, PO Box 4, West Point, PA 19486-0004. Please specify information package KEYNOTE-146/Study 111 Target Lesion Shrinkage Exploratory Post Hoc Analysis - A Description of Excluded Subjects DAP US-KLE-00179.
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