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| Selected Safety Information for LENVIMA (continued) |
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| Cardiac Dysfunction |
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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. |
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| Arterial Thromboembolic Events |
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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. |
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Among patients receiving LENVIMA with KEYTRUDA, arterial thrombotic events of any severity occurred in 5% of patients in CLEAR, including myocardial infarction (3.4%) and cerebrovascular accident
(2.3%). |
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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. |
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| Hepatotoxicity |
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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. |
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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. |
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| Renal Failure or Impairment |
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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). |
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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. |
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| Proteinuria |
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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. |
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| Diarrhea |
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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. |
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| Fistula Formation and Gastrointestinal Perforation |
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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. |
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| QT Interval Prolongation |
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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%. |
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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. |
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| Hypocalcemia |
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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. |
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| Reversible Posterior Leukoencephalopathy Syndrome (RPLS) |
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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. |
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| Hemorrhagic Events |
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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. |
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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. |
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| Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction |
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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. |
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Monitor thyroid function prior to initiation and at least monthly during treatment. Treat hypothyroidism according to standard medical practice. |
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| Impaired Wound Healing |
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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. |
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| Osteonecrosis of the Jaw (ONJ) |
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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. |
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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. |
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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. |
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Withhold LENVIMA if ONJ develops and restart based on clinical judgement of adequate resolution. |
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| Embryo-Fetal Toxicity |
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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
LENVIMA 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. |
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| Adverse Reactions |
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In endometrial carcinoma, the most common adverse reactions (≥20%) observed in LENVIMA + KEYTRUDA-treated patients were hypothyroidism (67%), hypertension (67%), fatigue (58%), diarrhea (55%),
musculoskeletal disorders (53%), nausea (49%), decreased appetite (44%), vomiting (37%), stomatitis (35%), decreased weight (34%), abdominal pain (34%), urinary tract infection (31%), proteinuria
(29%), constipation (27%), headache (26%), hemorrhagic events (25%), palmar-plantar erythrodysesthesia (23%), dysphonia (22%), and rash (20%). |
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Fatal adverse reactions among these patients occurred in 4.7% of those treated with LENVIMA and KEYTRUDA, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute
myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome,
myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction. |
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Serious adverse reactions occurred in 50% of these patients receiving LENVIMA and KEYTRUDA. Serious adverse reactions with frequency ≥3% were hypertension (4.4%), and urinary tract infection
(3.2%). |
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Discontinuation of LENVIMA due to an adverse reaction occurred in 26% of these patients. The most common (≥1%) adverse reactions leading to discontinuation of LENVIMA were hypertension (2%),
asthenia (1.8%), diarrhea (1.2%), decreased appetite (1.2%), proteinuria (1.2%), and vomiting (1.2%). |
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Dose reductions of LENVIMA due to adverse reactions occurred in 67% of patients. The most common (≥5%) adverse reactions resulting in dose reduction of LENVIMA were hypertension (18%), diarrhea
(11%), palmar-plantar erythrodysesthesia syndrome (9%), proteinuria (7%), fatigue (7%), decreased appetite (6%), asthenia (5%), and weight decreased (5%). |
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Dose interruptions of LENVIMA due to an adverse reaction occurred in 58% of these patients. The most common (≥2%) adverse reactions leading to interruption of LENVIMA were hypertension (11%),
diarrhea (11%), proteinuria (6%), decreased appetite (5%), vomiting (5%), increased alanine aminotransferase (3.5%), fatigue (3.5%), nausea (3.5%), abdominal pain (2.9%), weight decreased (2.6%),
urinary tract infection (2.6%), increased aspartate aminotransferase (2.3%), asthenia (2.3%), and palmar-plantar erythrodysesthesia (2%). |
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| Use in Specific Populations |
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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. |
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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. |
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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. |
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| QTc = corrected QT interval; MRI = magnetic resonance imaging; CNS = central nervous system. |
