Warnings and Precautions
Hypertension. In DTC (differentiated
thyroid cancer), hypertension occurred in 73% of patients on
LENVIMA (44% grade 3-4). In RCC (renal cell carcinoma), 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 HCC (hepatocellular carcinoma), 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.
Among patients receiving LENVIMA with
pembrolizumab, arterial thrombotic events of any severity
occurred in 5% of patients in CLEAR, including myocardial infarction (3.4%) and cerebrovascular
accident
(2.3%).
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 1327 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 1823 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
LENVIMAtreated 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 30 days after the last dose.
Adverse Reactions
In DTC, the most common adverse reactions (≥30%) observed in LENVIMA-treated patients were
hypertension (73%), fatigue (67%), diarrhea (67%), arthralgia/myalgia (62%), decreased appetite
(54%),
decreased weight (51%), nausea (47%), stomatitis (41%), headache (38%), vomiting (36%),
proteinuria
(34%), palmar-plantar erythrodysesthesia syndrome (32%), abdominal pain (31%), and dysphonia
(31%).
The most common serious adverse reactions (≥2%) were pneumonia (4%), hypertension (3%), and
dehydration (3%). Adverse reactions led to dose reductions in 68% of LENVIMA-treated patients;
18%
discontinued LENVIMA. The most common adverse reactions (≥10%) resulting in dose reductions were
hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most
common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were hypertension (1%)
and
asthenia (1%).
In RCC, the most common adverse reactions (≥30%) observed in LENVIMA + everolimus-treated
patients were diarrhea (81%), fatigue (73%), arthralgia/myalgia (55%), decreased appetite (53%),
vomiting (48%), nausea (45%), stomatitis (44%), hypertension (42%), peripheral edema (42%),
cough
(37%), abdominal pain (37%), dyspnea (35%), rash (35%), decreased weight (34%), hemorrhagic
events
(32%), and proteinuria (31%). The most common serious adverse reactions (≥5%) were renal failure
(11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and
dyspnea (5%). Adverse reactions led to dose reductions or interruption in 89% of patients. The
most
common adverse reactions (≥5%) resulting in dose reductions were diarrhea (21%), fatigue (8%),
thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment
discontinuation
due to an adverse reaction occurred in 29% of patients.
In HCC, the most common adverse reactions (≥20%) observed in LENVIMA-treated patients were
hypertension (45%), fatigue (44%), diarrhea (39%), decreased appetite (34%), arthralgia/myalgia
(31%), decreased weight (31%), abdominal pain (30%), palmar-plantar erythrodysesthesia syndrome
(27%),
proteinuria (26%), dysphonia (24%), hemorrhagic events (23%), hypothyroidism (21%), and nausea
(20%). The most common serious adverse reactions (≥2%) were hepatic encephalopathy (5%), hepatic
failure (3%), ascites (3%), and decreased appetite (2%). Adverse reactions led to dose
reductions or
interruption in 62% of patients. The most common adverse reactions (≥5%) resulting in dose
reductions
were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%),
and
palmar-plantar erythrodysesthesia syndrome (5%). Treatment discontinuation due to an adverse
reaction occurred in 20% of patients. The most common adverse reactions (≥1%) resulting in
discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia
(1%),
and hepatic failure (1%).
