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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 Prescribing Information for LENVIMA 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 Prescribing Information for LENVIMA 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

Osteonecrosis of the Jaw (ONJ)
＋

Monitoring and Management

  • Perform an oral examination prior to treatment with LENVIMA and periodically during LENVIMA treatment
  • Advise patients regarding good oral hygiene practices.
  • Avoid invasive dental procedures, if possible, while on LENVIMA treatment, particularly in patients at higher risk.

Severitya and Dosage Modification

  • Withhold LENVIMA for at least 1 week prior to scheduled dental surgery or invasive dental procedures if possible. For patients requiring invasive dental procedures, discontinuation of bisphoshonate treatment may reduce the risk of ONJ.
  • Withhold LENVIMA if ONJ develops and restart based on clinical judgement of adequate resolution.

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.

Help manage your patients’ adverse reactions to KEYTRUDA

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions.

  • Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments.
  • Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment.
  • In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection.
  • Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction.

  • In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less.
  • Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month.
  • Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (eg, endocrinopathies and dermatologic reactions) are shown below.

Additional monitoring and management considerations for selected immune-mediated adverse reactions are also shown.

Recommended Adverse Reaction Monitoring and Management for KEYTRUDA

Immune-mediated pneumonitis
＋

Severitya and Dosage Modification

Grade 2

  • Withholdb

Grade 3 or 4

  • Permanently discontinue

Immune-mediated colitis
＋

Monitoring and Management

  • Colitis may present with diarrhea
  • CMV infection/reactivation has been reported in patients with corticosteroid refractory immune-mediated colitis. In cases of corticosteroid refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Severitya and Dosage Modification

Grade 2 or 3

  • Withholdb

Grade 4

  • Permanently discontinue

Immune-mediated hepatitis with no tumor involvement of the liver
＋

Severitya and Dosage Modification

AST or ALT increases to more than 3 and up to 8 times ULN or total bilirubin increases to more than 1.5 and up to 3 times ULN

  • Withholdb

AST or ALT increases to more than 8 times ULN or total bilirubin increases to more than 3 times ULN

  • Permanently discontinue

Immune-mediated endocrinopathies
＋

Monitoring and Management

Adrenal insufficiency

  • KEYTRUDA can cause primary or secondary adrenal insufficiency.
  • For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity.

Hypophysitis

  • Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects.
  • Hypophysitis can cause hypopituitarism.
  • Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity.

Thyroid disorders

  • Thyroiditis can present with or without endocrinopathy.
  • Hypothyroidism can follow hyperthyroidism.
  • Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity.

Type 1 diabetes mellitus

  • Type 1 diabetes mellitus can present with diabetic ketoacidosis.
  • Monitor patients for hyperglycemia or other signs and symptoms of diabetes.
  • Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity.

Severitya and Dosage Modification

Grade 3 or 4

  • Withhold until clinically stable or permanently discontinue depending on severity

Immune-mediated nephritis with renal dysfunction
＋

Severitya and Dosage Modification

Grade 2 or 3 increased blood creatinine

  • Withholdb

Grade 4 increased blood creatinine

  • Permanently discontinue

Immune-mediated dermatologic adverse reactions
＋

Monitoring and Management

  • Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity.

Immune-mediated exfoliative dermatologic conditions
＋

Severitya and Dosage Modification

Suspected SJS, TEN, or DRESS

  • Withholdb

Confirmed SJS, TEN, or DRESS

  • Permanently discontinue

Immune-mediated myocarditis
＋

Severitya and Dosage Modification

Grade 2, 3, or 4

  • Permanently discontinue

Immune-mediated neurological toxicities
＋

Severitya and Dosage Modification

Grade 2

  • Withholdb

Grade 3 or 4

  • Permanently discontinue

Other immune-mediated adverse reactions
＋

Monitoring and Management

Ocular

  • Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment.
  • Various grades of visual impairment, including blindness, can occur.
  • If uveitis occurs in combination with other immune mediated adverse reactions, consider a Vogt Koyanagi Harada like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.

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.
  • For Grade 1 or Grade 2 reactions, interrupt or slow the rate of infusion.
  • For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Severitya and Dosage Modification

Grade 1 or 2

  • Interrupt or slow the rate of infusion

Grade 3 or 4

  • Permanently discontinue

Allogeneic HSCT before or after anti–PD-1/PD-L1 treatments
＋

Monitoring and Management

  • Follow patients closely for evidence of transplant related complications such as hyperacute GVHD, acute and chronic GVHD, hepatic VOD, and steroid requiring febrile syndrome.
  • Intervene promptly.
  • Consider the benefit vs risks of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic HSCT

aBased on Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.

bResume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids.

ALT = alanine aminotransferase; AST = aspartate aminotransferase; CMV = cytomegalovirus; DRESS = Drug Rash with Eosinophilia and Systemic Symptoms; GVHD = graft-versus-host disease; HSCT = hematopoietic stem cell transplantation; PD-1 = programmed death receptor-1; PD-L1 = programmed death ligand 1; SJS = Stevens Johnson Syndrome; TEN = toxic epidermal necrolysis; ULN = upper limit normal; VOD = veno-occlusive disease.

Selected Safety Information for
KEYTRUDA® (pembrolizumab)

Severe and Fatal Immune-Mediated Adverse Reactions

  • KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.
  • Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
  • Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

  • KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Immune-Mediated Colitis

  • KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

  • KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

  • KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

  • KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

  • KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.
  • Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

  • Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

  • KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

  • KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti–PD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

  • The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other anti–PD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

  • KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

  • Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatments. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between anti–PD-1/PD-L1 treatments and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

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 an anti–PD-1/PD-L1 treatment 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%), weight loss (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.

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.

Osteonecrosis of the Jaw (ONJ)

  • ONJ has been reported in patients receiving LENVIMA. Concomitant exposure to other risk factors, such as bisphosphonates, denosumab, dental disease or invasive dental procedures, may increase the risk of ONJ.

    Perform an oral examination prior to treatment with LENVIMA and periodically during LENVIMA treatment. Advise patients regarding good oral hygiene practices and to consider having preventive dentistry performed prior to treatment with LENVIMA and throughout treatment with LENVIMA.

    Avoid invasive dental procedures, if possible, while on LENVIMA treatment, particularly in patients at higher risk. Withhold LENVIMA for at least 1 week prior to scheduled dental surgery or invasive dental procedures, if possible. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk of ONJ.

    Withhold LENVIMA if ONJ develops and restart based on clinical judgement of adequate resolution.

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 13, 2020.
  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. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol. 2020;38(26):2981–2992.
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