[Product Name] Lenvima

[Generic Name] Lenvatinib Mesilate Capsules

[Chinese Pinyin] Jiahuangsuan Lunfatini Jiaonang

[English Name] Lenvatinib Mesilate Capsules

[Composition] The active ingredient of this product is: Lenvatinib Mesilate.

Chemical Name: 4-[3-chloro-4-(N'-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide mesilate

Chemical Structural Formula:

Molecular Formula: C21H19ClN4O4·CH4O3S

Molecular Weight: 522.96

[Description] The contents of this product consist of white to off-white granules.

[Specification] 20 capsules/box

[Indications] This product is indicated for patients with unresectable hepatocellular carcinoma (HCC) who have not previously received systemic therapy. The pivotal study for this product excluded patients with HCC who were eligible for locoregional therapy; therefore, no study data are currently available for this patient population.

[Dosage and Administration] Recommended Dosage: For patients weighing <60 kg, the recommended daily dose is 8 mg (two 4 mg capsules) taken once daily; for patients weighing ≥60 kg, the recommended daily dose is 12 mg (three 4 mg capsules) taken once daily. Treatment should be continued until disease progression or until intolerable toxicity occurs. Method of Administration: Oral. This product should be taken at the same time each day, either on an empty stomach or with food. The capsules should be swallowed whole; alternatively, the capsules (which must not be opened or crushed) may be mixed with one tablespoon of water or apple juice in a glass to form a suspension. The capsules must remain in the liquid for at least 10 minutes, stirred for at least 3 minutes to dissolve the capsule shell, and the resulting suspension then swallowed. After drinking, the same amount of water or apple juice (one tablespoon) must be added to the glass, stirred several times, and all the liquid in the glass then consumed. If a patient misses a dose and is unable to take it within 12 hours, the missed dose should be skipped, and the next dose taken at the regularly scheduled time. Prior to adjusting the dosage of this product (suspension or reduction), adverse reactions such as nausea, vomiting, and diarrhea should be actively treated; gastrointestinal toxicities should be actively managed to reduce the risk of developing renal insufficiency or renal failure (see [Precautions]). Monitoring, Dosage Adjustment, and Discontinuation: It may be necessary to suspend administration, adjust the dosage, or discontinue treatment with this product to manage certain adverse reactions. Mild to moderate adverse reactions (e.g., Grade 1 or 2) generally do not require suspension of administration, unless the patient remains unable to tolerate them despite active treatment. Severe (e.g., Grade 3) or intolerable adverse reactions require suspension of administration until the adverse reaction improves to Grade 0–1 or returns to baseline. Detailed information regarding dosage adjustments based on adverse reactions can be found in Table 1. Detailed information regarding monitoring, dosage adjustment, and discontinuation can be found in Table 2.

*When an adverse reaction presents as a Grade 4 laboratory abnormality, if it is determined not to be life-threatening, it may be managed and treated in the same manner as a Grade 3 adverse reaction.

Special Populations: Patients aged 75 years and older, Caucasian patients, female patients, or patients with more severe hepatic impairment appear to have lower tolerability to this product. With the exception of patients with moderate to severe hepatic impairment or severe renal impairment, all patients with hepatocellular carcinoma should initiate treatment at the recommended starting dose of 8 mg (two 4 mg capsules; body weight <60 kg) or 12 mg (three 4 mg capsules; body weight ≥60 kg); subsequent dosage adjustments should be made based on individual tolerability. Patients with Hepatic Impairment: Among patients enrolled in clinical studies for hepatocellular carcinoma, no dosage adjustment based on hepatic function is required for patients with mild hepatic impairment (Child-Pugh A). Currently, data regarding patients with moderate hepatic impairment (Child-Pugh B) are limited; patients with mild to moderate hepatic impairment should use this product with caution under the guidance of a physician and undergo close monitoring of hepatic function. No study data are currently available for patients with severe hepatic impairment (Child-Pugh C); therefore, the use of this product is not recommended for patients with severe hepatic impairment. Patients with Renal Impairment: No dosage adjustment based on renal function is required for patients with mild or moderate renal impairment. Currently, there are no study data available for patients with severe renal impairment; therefore, the use of this product is not recommended in patients with severe renal impairment. Pediatric Patients: Currently, there are no clinical data available regarding the use of this product in children or adolescents under 18 years of age; therefore, its use is not recommended in this population. Elderly Patients: No adjustment to the starting dose is required based on age; however, study data for patients aged ≥75 years are limited.

[Pharmacology and Toxicology] Pharmacological Action: Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activity of vascular endothelial growth factor (VEGF) receptors—specifically VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Additionally, it inhibits other RTKs associated with pro-angiogenic and oncogenic pathways, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet-derived growth factor (PDGF) receptor PDGFRα; KIT; and RET. In vitro studies of lenvatinib in combination with everolimus demonstrated inhibition of human endothelial cell proliferation, angiogenesis, and the VEGF signaling pathway. In vivo studies involving mice bearing human renal cell carcinoma xenografts showed that the combination therapy reduced tumor volume, with the anti-angiogenic and anti-tumor activities of the combination exceeding those of either agent used alone. Toxicology Studies: Genotoxicity: Results from the Ames test, mouse lymphoma assay, and in vivo rat micronucleus test for lenvatinib mesylate were all negative. Reproductive Toxicity: Fertility studies specifically for lenvatinib have not been conducted; however, repeated-dose toxicity studies in rats, monkeys, and dogs indicated that lenvatinib has the potential to affect fertility. At lenvatinib exposure levels approximately 0.02 to 0.09 times the exposure level at the recommended human dose, male dogs exhibited oligospermia (reduced numbers of seminiferous epithelial cells) in the testes and the presence of sloughed seminiferous epithelial cells in the epididymides. Furthermore, when lenvatinib exposure levels (AUC) in monkeys and rats reached approximately 0.2 to 0.8 times and 10 to 44 times the exposure level at the clinical therapeutic dose (24 mg), respectively, ovarian follicular atresia was observed in both species. When exposure to Lenvatinib in monkeys was lower than the exposure observed at the clinical dose (24 mg), a decrease in the frequency of menstruation was observed.

Embryo/Fetal Development Toxicity Studies: Oral administration of Lenvatinib to rats and rabbits during the period of organogenesis, at doses lower than the recommended human dose, resulted in embryotoxicity, fetotoxicity, and teratogenicity. In pregnant rats orally administered Lenvatinib mesylate daily during organogenesis at doses ≥ 0.3 mg/kg (approximately 0.14 times the recommended human dose based on body surface area), dose-related decreases in fetal body weight, delayed ossification, and abnormalities in fetal appearance (cranial edema and tail malformations), skeletal structure, and viscera were observed. At a dose of 1.0 mg/kg/day of Lenvatinib mesylate (approximately 0.5 times the recommended human dose based on body surface area), a post-implantation loss rate of ≥ 80% was observed. In pregnant rabbits orally administered Lenvatinib mesylate daily during organogenesis at doses ≥ 0.03 mg/kg (approximately 0.03 times the 24 mg human dose based on body surface area), abnormalities in fetal appearance (short tail), viscera (retroesophageal subclavian artery), and skeletal structure were observed. Lenvatinib mesylate at 0.03 mg/kg/day caused an increased rate of post-implantation loss, including one fetal death. Lenvatinib at 0.5 mg/kg/day (approximately 0.5 times the 24 mg human dose based on body surface area) caused abortions in rabbits, resulting in late-stage abortions in approximately one-third of the pregnant rabbits.

Lenvatinib and its metabolites are excreted into the milk of rats. Following oral administration of radiolabeled Lenvatinib to lactating SD rats, the radioactivity associated with Lenvatinib in the milk was approximately twice that found in the maternal plasma. **Juvenile Animal Toxicity**

In juvenile rats dosed orally daily for 8 weeks starting at 21 days of age (approximately equivalent to 2 years of age in humans), doses ≥ 2 mg/kg (approximately 1.2 to 5 times the human recommended dose AUC) caused delayed growth (decreased body weight gain, food consumption, and/or width and length of the femur and tibia), secondary delays in physical development, and immature development of reproductive organs. Following a 4-week recovery period, the reduced length of the femur and tibia persisted. Although toxicity in juvenile rats occurred at earlier time points of administration (including dental damage observed at all doses, and mortality at the 10 mg/kg/day dose due to primary duodenal injury), the toxicity profile in juvenile rats was similar to that observed in adult rats.

**Carcinogenicity**

Carcinogenicity studies with lenvatinib have not been conducted.

**[Pharmacokinetics]** The pharmacokinetic parameters of lenvatinib have been studied in healthy adult subjects, as well as in adult subjects with hepatic impairment, renal impairment, and solid tumors.

**Absorption**

Following oral administration, lenvatinib is rapidly absorbed, with the time to maximum plasma concentration (tmax) typically observed between 1 and 4 hours post-dose. Food does not affect the extent of absorption but may slow the rate of absorption. When administered with food, the time to peak plasma concentration in healthy subjects is delayed by 2 hours. The absolute bioavailability in humans has not been determined; however, data from mass balance studies suggest it is approximately 85%. Lenvatinib demonstrated good oral bioavailability in dogs (70.4%) and monkeys (78.4%).

**Distribution**

Lenvatinib exhibits high *in vitro* binding to human plasma proteins, ranging from 98% to 99% (at concentrations of 0.3 to 30 µg/mL, as the mesylate salt). It binds primarily to albumin, with minor binding to alpha-1 acid glycoprotein and gamma-globulin. In vitro, the blood-to-plasma concentration ratio of lenvatinib ranged from 0.589 to 0.608 (at concentrations of 0.1–10 μg/mL, as the mesylate salt). Lenvatinib is a substrate of P-gp and BCRP. Lenvatinib is not a substrate of OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2-K, or the bile salt export pump (BSEP). In patients, the median apparent volume of distribution (Vz/F) following the first dose ranged from 50.5 L to 92 L, remaining generally consistent across the 3.2 mg to 32 mg dose groups. Similarly, the median apparent volume of distribution at steady state (Vz/Fss) was also generally consistent, ranging from 43.2 L to 121 L.

Biotransformation

In vitro studies confirmed that cytochrome P450 3A4 is the primary (>80%) isoform involved in the P450-mediated metabolism of lenvatinib. However, in vivo data indicate that non-P450-mediated pathways contribute a substantial portion to the overall metabolism of lenvatinib. Consequently, in vivo, inducers and inhibitors of CYP3A4 have only a minor effect on lenvatinib exposure (see [Drug Interactions]).

In human liver microsomes, the demethylated form of lenvatinib (M2) is the major metabolite. The major metabolites found in human feces are M2’ and M3’, which are formed from M2 and lenvatinib, respectively, through the action of aldehyde oxidase.

[Adverse Reactions] This prescribing information describes adverse reactions observed in clinical studies that were judged to be possibly caused by lenvatinib mesylate, along with their approximate incidence rates. Because clinical studies are conducted under widely varying conditions, the adverse reaction rates observed in one clinical study cannot be directly compared to rates observed in another clinical study, and may not reflect the actual rates observed in clinical practice. Summary of Safety Characteristics in the Global Population in the REFLECT Study

The clinical efficacy and safety of lenvatinib were evaluated in an international, multicenter, open-label, randomized Phase 3 study (REFLECT) involving patients with unresectable hepatocellular carcinoma (HCC). A total of 954 patients were randomized in a 1:1 ratio to receive either lenvatinib (12 mg [for baseline body weight ≥ 60 kg] or 8 mg [for baseline body weight < 60 kg]) orally once daily, or sorafenib 400 mg orally twice daily. Patients with Child-Pugh Class A liver function and an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 were eligible for enrollment. Patients who had received prior systemic anticancer therapy for advanced/unresectable HCC, or any prior anti-vascular endothelial growth factor (VEGF) therapy, were excluded. For patients who had previously received radiation therapy or locoregional therapy, target lesions were required to show radiological evidence of disease progression. Patients with liver occupancy ≥ 50%, or with imaging evidence of marked invasion into the bile duct or the main trunk/branches of the portal vein (Vp4), were also excluded. In both treatment arms, the majority of patients had a baseline ECOG PS of 0 (63%), a Child-Pugh score of 5 (76%), and a body weight ≥ 60 kg (69%). The median age of the subjects was 62 years; 84% were male, 16% were female, 69% were Asian, 29% were White, and 1% were Black. In the REFLECT study (see [Clinical Trials]), the majority of patients (99%) in the lenvatinib arm experienced at least one adverse reaction. The most common adverse reactions (≥20%) observed in patients treated with Lenvatinib are listed below in descending order of frequency: hypertension (45%), fatigue (44%), diarrhea (39%), decreased appetite (34%), weight loss (31%), arthralgia/myalgia (31%), abdominal pain (30%), palmar-plantar erythrodysesthesia syndrome (27%), proteinuria (26%), hemorrhagic events (25%), dysphonia (24%), hypothyroidism (21%), and nausea (20%). In the Lenvatinib treatment group, 75% of patients experienced Grade 3 or higher adverse reactions. The most common Grade 3 or higher adverse reactions (≥5%) observed in patients treated with Lenvatinib were hypertension (24%), weight loss (8%), fatigue (7%), increased blood bilirubin (7%), proteinuria (6%), decreased platelet count (5%), hepatic encephalopathy (5%), increased gamma-glutamyltransferase (5%), hemorrhagic events (5%), and increased aspartate aminotransferase (5%).

The most common serious adverse reactions (≥2%) observed in patients treated with Lenvatinib were hemorrhagic events (5%), hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%).

Adverse reactions led to dose reductions or interruptions in 62% of patients treated with Lenvatinib. The most common adverse reactions (≥5%) leading to dose reductions or interruptions in the Lenvatinib treatment group were fatigue (10%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%). In the Lenvatinib treatment group, 20% of patients discontinued treatment due to adverse reactions. The most common adverse reactions (≥1%) leading to discontinuation of Lenvatinib were fatigue (2%), hemorrhagic events (2%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%). Table 3 summarizes the adverse reactions occurring in ≥10% of patients treated with lenvatinib in the REFLECT study. The REFLECT study was not designed to compare lenvatinib with sorafenib regarding a statistically significant reduction in the incidence of any specific adverse reaction listed in Table 3.

Table 4 lists Grade 3 or 4 laboratory abnormalities occurring in ≥2% of patients in the Lenvatinib arm of the REFLECT (HCC) study.

Description of Selected Adverse Reactions

Hypertension

In the Phase 3 clinical trial for hepatocellular carcinoma, hypertension (including diastolic hypertension, blood pressure increased, hypertension, and orthostatic hypertension) occurred in 44.5% of patients treated with Lenvatinib; Grade 3 hypertension occurred in 23.5% of patients. The median time to onset of hypertension was 26 days. Most patients recovered following dose interruption or dose reduction; dose interruption was required in 3.6% of patients, and dose reduction was required in 3.4% of patients. One patient (0.2%) permanently discontinued Lenvatinib due to hypertension.

Proteinuria

In the Phase 3 trial for hepatocellular carcinoma, proteinuria occurred in 26.3% of patients treated with Lenvatinib, with a Grade 3 incidence rate of 5.9%. The median time to onset of proteinuria was 6.1 weeks. Most cases resolved following dose interruption or dose reduction; dose interruption was required in 6.9% of patients, and dose reduction was required in 2.5% of patients. 0.6% of patients permanently discontinued treatment due to proteinuria.

Renal Failure and Impairment

In the Phase 3 clinical trial for hepatocellular carcinoma, renal failure/impairment events occurred in 7.1% of patients treated with Lenvatinib. Grade 3 or higher adverse reactions occurred in 1.9% of patients treated with Lenvatinib.

Cardiac Dysfunction

In the Phase 3 clinical trial for hepatocellular carcinoma, cardiac dysfunction (including congestive cardiac failure, cardiogenic shock, and cardiopulmonary failure) occurred in 0.6% of patients treated with Lenvatinib (0.4% were Grade ≥3).

Reversible Posterior Encephalopathy Syndrome (PRES) / Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

In the Phase 3 clinical trial for hepatocellular carcinoma, one case of PRES (Grade 2) occurred in the Lenvatinib treatment arm. Hepatotoxicity

In the Phase 3 trial for hepatocellular carcinoma, the most frequently reported hepatotoxic adverse reactions were increased blood bilirubin (14.9%), increased aspartate aminotransferase (13.7%), increased alanine aminotransferase (11.1%), hypoalbuminemia (9.2%), hepatic encephalopathy (8.0%), increased gamma-glutamyltransferase (7.8%), and increased blood alkaline phosphatase (6.7%). The median time from the start of treatment to the onset of a hepatotoxic adverse reaction was 6.4 weeks. Grade ≥3 hepatotoxic reactions occurred in 26.1% of patients treated with Lenvatinib. Hepatic failure occurred in 3.6% of patients (including fatal events in 12 patients) (all were Grade ≥3). Hepatic encephalopathy occurred in 8.4% of patients (including fatal events in 4 patients) (5.5% of patients were Grade ≥3). Hepatotoxic events resulted in 17 deaths (3.6%) in the Lenvatinib group, compared to 4 deaths (0.8%) in the Sorafenib group. Hepatotoxic adverse reactions leading to treatment interruption and dose reduction occurred in 12.2% and 7.4% of Lenvatinib-treated patients, respectively; hepatotoxic adverse reactions leading to permanent discontinuation occurred in 5.5% of patients.

Arterial Thromboembolic Events

In the Phase 3 trial for hepatocellular carcinoma, arterial thromboembolic events occurred in 2.3% of patients treated with Lenvatinib. Ten patients (0.45%) experienced fatal outcomes from arterial thromboembolic events (5 cases of myocardial infarction and 5 cases of cerebrovascular events).

Hemorrhage

In the Phase 3 clinical trial for hepatocellular carcinoma, hemorrhage was reported in 24.6% of patients, of which 5.0% were Grade ≥3. The incidence of Grade 3 reactions was 3.4%, and the incidence of Grade 4 reactions was 0.2%; Grade 5 reactions occurred in 7 patients (1.5%), including cerebral hemorrhage, upper gastrointestinal hemorrhage, intestinal hemorrhage, and tumor hemorrhage. The median time from the start of treatment to the first occurrence of bleeding was 11.9 weeks. Due to bleeding events, 3.2% of patients experienced treatment interruption, 0.8% experienced dose reduction, and 1.7% experienced treatment discontinuation.

**Gastrointestinal Perforation and Fistula Formation**

In the Phase 3 clinical trial for hepatocellular carcinoma, 1.9% of patients treated with lenvatinib reported events of gastrointestinal perforation or fistula formation.

**Non-Gastrointestinal Fistula**

Lenvatinib use has been associated with cases of fistula, including fatal reactions. Fistulas involving body sites other than the stomach or intestines have been observed across various indications. These reactions were reported at various time points during treatment, ranging from 2 weeks to more than 1 year after the initiation of lenvatinib therapy, with a median latency of approximately 3 months.

**QT Interval Prolongation**

In the Phase 3 trial for hepatocellular carcinoma, 6.9% of patients treated with lenvatinib reported QT/QTc interval prolongation. The incidence of QTcF interval prolongation exceeding 500 ms was 2.4%.

**Diarrhea**

In the Phase 3 trial for hepatocellular carcinoma, 38.7% of patients treated with lenvatinib reported diarrhea (4.2% were Grade ≥3).

**Hypocalcemia**

In the Phase 3 clinical trial for hepatocellular carcinoma, 1.1% of patients reported hypocalcemia, of which 0.4% were Grade 3 reactions. One patient (0.2%) experienced treatment interruption due to hypocalcemia; no dose reductions or discontinuations occurred.

**Elevated Blood Thyroid-Stimulating Hormone (TSH)**

In the Phase 3 clinical trial for hepatocellular carcinoma, 89.6% of patients had baseline TSH levels below the upper limit of normal. TSH levels exceeding the upper limit of normal at baseline were observed in 69.6% of patients treated with lenvatinib.

**Summary of Safety Profile in the Mainland China + Taiwan + Hong Kong (CTH) Population in the REFLECT Study**

In the Mainland China + Taiwan + Hong Kong (CTH) population, a total of 288 subjects were randomized to receive treatment with either lenvatinib (144 subjects) or sorafenib (144 subjects). The median age was 57 years; 85% of patients were male, and 15% were female.

In the CTH population, the majority of patients (97%) in the lenvatinib group experienced at least one adverse reaction. The most common adverse reactions (≥20%) observed in patients treated with lenvatinib, listed in descending order of frequency, included hypertension (44%), fatigue (35%), abdominal pain (32%), diarrhea (32%), weight loss (32%), decreased platelet count (28%), proteinuria (27%), palmar-plantar erythrodysesthesia syndrome (24%), increased aspartate aminotransferase (24%), arthralgia/myalgia (22%), decreased appetite (22%), hemorrhagic events (22%), decreased white blood cell count (21%), and increased alanine aminotransferase (20%).

Among patients receiving lenvatinib, 63% experienced Grade 3 or higher adverse reactions. The most common Grade 3 or higher adverse reactions (≥5%) in patients treated with lenvatinib were hypertension (23%), decreased platelet count (10%), increased aspartate aminotransferase (8%), increased blood bilirubin (8%), proteinuria (6%), increased gamma-glutamyltransferase (6%), weight loss (6%), and decreased white blood cell count (6%).

In the CTH population, the most common serious adverse reactions (≥2%) in patients treated with lenvatinib were hemorrhagic events (5%), cholestatic jaundice (3%), and respiratory failure (2%).

In the CTH population, 46% of patients receiving lenvatinib experienced adverse reactions that led to dose reduction or interruption. The most common adverse reactions (≥5%) leading to lenvatinib dose reduction or treatment interruption were decreased platelet count (9%), proteinuria (7%), and hypertension (6%).

In the CTH population, 13% of patients in the lenvatinib treatment group discontinued treatment due to adverse reactions. The most common adverse reactions (≥1%) leading to Lenvatinib discontinuation were hemorrhagic events (2%) and cholestatic jaundice (1%).

[Precautions] Hypertension

Hypertension has been reported in patients treated with Lenvatinib; this event typically occurs early in treatment (see [Adverse Reactions]). Blood pressure (BP) should be well-controlled prior to initiating Lenvatinib treatment. If a patient has a history of hypertension, it should be controlled with a stable dose of antihypertensive therapy for at least 1 week prior to starting Lenvatinib treatment. Serious complications of poorly controlled hypertension (including aortic dissection) have been reported. Early detection and effective management of hypertension are important to minimize interruptions in Lenvatinib administration and dose reductions. Once elevated blood pressure is confirmed, antihypertensive therapy should be initiated as soon as possible. Blood pressure should be monitored 1 week after initiating Lenvatinib treatment, every 2 weeks thereafter for the next 2 months, and monthly thereafter. The antihypertensive treatment regimen should be individualized based on the patient's clinical status and should follow standard medical practice. For patients with previously normal blood pressure, monotherapy with a single antihypertensive agent should be initiated upon observation of elevated blood pressure. For patients already receiving antihypertensive therapy, the dosage of current medications may be increased, or one or more additional antihypertensive agents of a different class may be added, as appropriate. If necessary, manage hypertension according to the recommendations in Table 7.

Proteinuria

Proteinuria has been reported in patients treated with Lenvatinib; this event typically occurs early in treatment (see [Adverse Reactions]). Urine protein should be monitored periodically. If proteinuria of ≥2+ is detected using a urine dipstick test, temporary interruption of administration, dose adjustment, or discontinuation of the drug may be required (see [Dosage and Administration]). If nephrotic syndrome occurs, Lenvatinib should be discontinued.

Renal Failure and Renal Impairment

Renal impairment and renal failure have been reported in patients treated with Lenvatinib (see [Adverse Reactions]). The primary identified risk factors are dehydration and/or hypovolemia resulting from gastrointestinal toxicity. Gastrointestinal toxicity should be actively managed to reduce the risk of developing renal impairment or renal failure. If necessary, temporarily interrupt administration, adjust the dose, or discontinue the drug (see [Dosage and Administration]). Cardiac Dysfunction

Cardiac failure (<1%) and decreased left ventricular ejection fraction have been reported in patients treated with Lenvatinib (see [Adverse Reactions]). Patients should be monitored for clinical signs or symptoms of cardiac decompensation; Lenvatinib should be withheld, dose-reduced, or discontinued as necessary (see [Dosage and Administration]).

Reversible Posterior Leukoencephalopathy Syndrome (PRES)/Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

PRES (also known as RPLS) has been reported in patients treated with Lenvatinib (<1%; see [Adverse Reactions]). PRES is a neurological disorder characterized by headache, seizures, lethargy, confusion, altered mental function, blindness, and other visual or neurological disturbances. Mild to severe hypertension may be present. Magnetic Resonance Imaging (MRI) is necessary to confirm the diagnosis of PRES. Appropriate measures should be taken to control blood pressure (see [Precautions]). In patients presenting with signs or symptoms of PRES, it may be necessary to withhold, dose-reduce, or discontinue Lenvatinib (see [Dosage and Administration]).

Hepatotoxicity

In HCC patients treated with Lenvatinib in the REFLECT trial, liver-related adverse reactions—including hepatic encephalopathy and hepatic failure (including fatal events)—were reported at a higher frequency compared to patients treated with Sorafenib (see [Adverse Reactions]). Patients with more severe hepatic impairment and/or a larger tumor burden at baseline are at a higher risk of developing hepatic encephalopathy and hepatic failure. Hepatic encephalopathy was also reported more frequently in patients aged 75 years and older. Approximately half of the hepatic failure events and one-third of the hepatic encephalopathy events were reported in patients who experienced disease progression.

Data regarding HCC patients with moderate hepatic impairment (Child-Pugh B) are very limited, and currently, no data are available for HCC patients with severe hepatic impairment (Child-Pugh C). Since Lenvatinib is primarily eliminated via hepatic metabolism, increased exposure is expected in patients with moderate to severe hepatic impairment.

Close monitoring for overall safety is recommended in patients with hepatic impairment (see [Dosage and Administration] and [Adverse Reactions]). Liver function should be monitored prior to initiating treatment, every two weeks during the first two months of treatment, and monthly thereafter. Patients with HCC should be monitored for worsening liver function (including hepatic encephalopathy). If hepatotoxicity occurs, it may be necessary to interrupt administration, adjust the dosage, or discontinue the drug (see [Dosage and Administration]).

Arterial Thromboembolism

Arterial thromboembolic events (cerebrovascular accident, transient ischemic attack, and myocardial infarction) have been reported in patients treated with Lenvatinib (see [Adverse Reactions]). Lenvatinib has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months; therefore, the drug should be used with caution in such patients. Treatment decisions should be based on an individual patient’s benefit-risk assessment. Lenvatinib should be discontinued following an arterial thromboembolic event.

Hemorrhage

Serious tumor-related hemorrhage, including fatal hemorrhagic events, has occurred in clinical trials (see [Adverse Reactions]). Because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following Lenvatinib treatment, the degree of tumor invasion/infiltration into major blood vessels (e.g., carotid artery) should be considered. Some cases of hemorrhage were secondary to tumor shrinkage and fistula formation (e.g., tracheoesophageal fistula). Fatal intracranial hemorrhage has been reported in some patients with or without brain metastases. Hemorrhage at sites other than the brain (e.g., trachea, intra-abdominal, pulmonary) has also been reported. One fatal case of hepatic tumor hemorrhage was reported in a patient with HCC.

Screening for and subsequent treatment of esophageal varices in patients with cirrhosis should be conducted according to standard medical practice prior to initiating Lenvatinib treatment.

If hemorrhage occurs, interruption of dosing, dose adjustment, or discontinuation of the drug may be necessary (see [Dosage and Administration]).

Gastrointestinal Perforation and Fistula Formation

Gastrointestinal perforation or fistula formation has been reported in patients treated with Lenvatinib (see [Adverse Reactions]). In most cases, gastrointestinal perforation and fistula formation occurred in patients with risk factors, such as a history of surgery or radiation therapy. If gastrointestinal perforation or fistula formation occurs, interruption of dosing, dose adjustment, or discontinuation of the drug may be necessary (see [Dosage and Administration]).

Non-Gastrointestinal Fistula

The risk of fistula formation may be increased in patients treated with Lenvatinib. Cases of fistula formation or enlargement involving body parts other than the stomach or intestine (e.g., tracheal fistula, tracheoesophageal fistula, esophageal fistula, cutaneous fistula, female genital tract fistula) have been observed in clinical trials and post-marketing experience. Prior surgery and radiotherapy may be contributing risk factors. Lenvatinib treatment should not be initiated in patients with fistulas, to avoid exacerbation. Lenvatinib should be permanently discontinued in patients with esophageal or tracheobronchial fistulas, as well as in any patient with a Grade 4 fistula (see [Dosage and Administration]). Information regarding the management of other events through dose interruption or dose reduction is limited; however, worsening has been observed in some cases, and caution should be exercised. As with other drugs in this class, lenvatinib may adversely affect wound healing processes.

**QT Interval Prolongation**

A higher incidence of QT/QTc interval prolongation has been reported in patients treated with lenvatinib compared to those treated with placebo (see [Adverse Reactions]). ECGs should be monitored in all patients, with particular attention paid to those with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those taking medications known to prolong the QT interval, including Class Ia and Class III antiarrhythmics. Lenvatinib should be interrupted if the QT interval exceeds 500 ms. Once the QTc interval prolongation resolves to ≤480 ms or returns to baseline, lenvatinib treatment should be resumed at a reduced dose.

Electrolyte abnormalities (e.g., hypokalemia, hypocalcemia, or hypomagnesemia) may increase the risk of QT interval prolongation; therefore, electrolyte abnormalities should be monitored and corrected in all patients prior to initiating treatment. Periodic monitoring of ECGs and electrolytes (magnesium, potassium, and calcium) should be considered during treatment. Serum calcium levels should be monitored at least monthly, and calcium supplementation should be administered as needed during lenvatinib treatment. Lenvatinib dosing should be interrupted or adjusted as needed, based on the severity, the presence of ECG changes, and the persistence of hypocalcemia.

**Diarrhea**

Diarrhea has been frequently reported in patients treated with lenvatinib; this event typically occurs early in the course of treatment (see [Adverse Reactions]). Medical management of diarrhea should be initiated immediately to prevent dehydration. If Grade 4 diarrhea persists despite treatment, Lenvatinib should be discontinued.

**Impaired Thyroid-Stimulating Hormone Suppression / Thyroid Dysfunction**

Hypothyroidism has been reported in patients treated with Lenvatinib (see [Adverse Reactions]). Thyroid function should be monitored prior to the initiation of Lenvatinib treatment and periodically throughout treatment. Hypothyroidism should be treated in accordance with standard medical practice to maintain euthyroid status.

Lenvatinib impairs exogenous thyroid suppression (see [Adverse Reactions]). Thyroid-stimulating hormone (TSH) levels should be monitored periodically, and thyroid hormone replacement therapy should be adjusted to achieve appropriate TSH levels based on the patient's treatment goals.

**Wound Healing Complications**

Formal studies evaluating the effect of Lenvatinib on wound healing have not been conducted. Delayed wound healing has been reported in patients receiving Lenvatinib. Temporary discontinuation of Lenvatinib should be considered in patients undergoing major surgical procedures. Clinical experience regarding the timing of re-initiation of Lenvatinib after major surgery is limited. Therefore, the decision to resume Lenvatinib after major surgery should be based on clinical judgment regarding adequate wound healing.

**Embryo-Fetal Toxicity**

Based on its mechanism of action and toxicity data from animal reproductive studies, Lenvatinib may cause fetal harm when administered to pregnant women. In animal reproductive studies, oral administration of Lenvatinib to rats and rabbits during organogenesis at doses lower than the recommended clinical dose resulted in embryotoxicity, fetotoxicity, and teratogenicity.

Pregnant women should be advised of the potential risk to the fetus. Women of reproductive potential are advised to use effective contraception during Lenvatinib treatment and for at least 30 days after the last dose (see [Pharmacology and Toxicology]).

**Special Populations**

There are limited data available regarding patients of races other than Caucasian or Asian, as well as patients aged ≥75 years. Given the reduced tolerability of Lenvatinib in elderly patients, female patients, and patients with impaired hepatic or renal function, Lenvatinib should be used with caution in these patient populations (see [Adverse Reactions]).

There are no data regarding the immediate use of Lenvatinib following treatment with Sorafenib or other anti-cancer therapies; unless a sufficient washout period is observed between treatments, there may be a potential risk of additive toxicity. The minimum washout period observed in clinical trials was 4 weeks.

Effects on Ability to Drive and Use Machines

Due to potential side effects (e.g., fatigue and dizziness), Lenvatinib has a minor influence on the ability to drive and use machines. Patients experiencing such symptoms should exercise caution when driving or operating machinery.

[Contraindications] Hypersensitivity to any component of this product. Breastfeeding women (see [Use in Pregnant and Breastfeeding Women]).

[Use in Pregnant and Breastfeeding Women] Contraception

Women of childbearing potential should avoid pregnancy and use highly effective contraceptive measures during Lenvatinib treatment and for at least one month following the cessation of therapy. It is currently unknown whether Lenvatinib reduces the efficacy of hormonal contraceptives; therefore, women using oral hormonal contraceptives should utilize an additional barrier method of contraception.

Pregnancy

There are currently no data regarding the use of Lenvatinib in pregnant women. Lenvatinib has demonstrated embryotoxicity and teratogenicity in rats and rabbits (see [Pharmacology and Toxicology]). Lenvatinib should not be used during pregnancy unless clearly necessary and after careful consideration of the potential benefits to the mother versus the potential risks to the fetus.

Breastfeeding

It is not known whether Lenvatinib is excreted in human milk. Lenvatinib and its metabolites are excreted in the milk of rats (see [Pharmacology and Toxicology]). As a risk to the newborn or infant cannot be excluded, Lenvatinib is contraindicated during breastfeeding; breastfeeding should not be resumed until at least one week after the last dose of Lenvatinib (see [Contraindications]).

Fertility

The effects on human fertility are currently unknown. However, testicular and ovarian toxicity have been observed in rats, dogs, and monkeys (see [Pharmacology and Toxicology]). Lenvatinib may impair fertility in men and women of childbearing potential. [Pediatric Use] Currently, there are no clinical data available regarding the use of this product in children or adolescents under 18 years of age; therefore, its use is not recommended in this population.

[Geriatric Use] No adjustment to the starting dose is required based on age. Data regarding patients aged ≥75 years are limited.

[Drug Interactions] Effects of Other Drugs on Lenvatinib

Concomitant administration of lenvatinib with the chemotherapeutic agents carboplatin and paclitaxel did not result in any significant changes to the pharmacokinetics of any of these three drugs.

Effects of Lenvatinib on Other Drugs

No data are available to rule out the potential for this product to act as an inducer of gastrointestinal CYP3A4 or P-gp. This could lead to decreased exposure to orally administered drugs that serve as substrates for CYP3A4/P-gp; therefore, this possibility should be carefully considered when co-administering such drugs to ensure therapeutic efficacy. Consequently, caution should be exercised when administering CYP3A4 substrates known to have a narrow therapeutic index (e.g., astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, or ergot alkaloids [ergotamine, dihydroergotamine]) to patients receiving lenvatinib.

Oral Contraceptives

It is currently unknown whether lenvatinib reduces the efficacy of hormonal contraceptives; therefore, women using oral hormonal contraceptives should employ an additional barrier method of contraception (see [Use in Pregnant and Lactating Women]).

[Overdosage] In a Phase III clinical trial for hepatocellular carcinoma, one patient experienced vomiting and acute renal injury accompanied by renal tubular necrosis following the accidental ingestion of 120 mg of lenvatinib.

Two patients each took a single dose of lenvatinib that was double the prescribed amount; neither patient experienced any adverse events.

There have been other reports of lenvatinib overdosage involving single doses ranging from 6 to 10 times the recommended daily dose. The adverse reactions observed in these cases were consistent with the known safety profile of lenvatinib, or no adverse reactions occurred.

Symptoms and Management

There is no specific antidote for lenvatinib overdosage. In the event of suspected overdose, Lenvatinib should be discontinued, and appropriate supportive therapy administered as needed.

[Packaging Specifications] 4 mg × 20 capsules

[Storage] Store at a temperature not exceeding 30°C.

[Shelf Life] 48 months

[Manufacturer] Eisai Europe Ltd

Product Name: Eisai Lenvatinib Mesylate Capsules (Lenvima) (Lenvatinib) 4 mg × 20 Capsules

Common Name: Lenvima

Active Ingredient: Lenvatinib Mesylate

Dosage Form: Capsules

Specification: 4 mg × 20 Capsules

Manufacturer: Eisai Pharmaceutical

Indications: This product is indicated for patients with unresectable hepatocellular carcinoma who have not previously received systemic therapy. The pivotal studies for this product excluded patients with hepatocellular carcinoma eligible for locoregional therapy; therefore, no study data are currently available for this patient population. **Dosage and Administration:** "Recommended Dosage: For patients weighing <60 kg, the recommended daily dose is 8 mg (two 4 mg capsules), taken once daily; for patients weighing ≥60 kg, the recommended daily dose is 12 mg (three 4 mg capsules), taken once daily. Treatment should be continued until disease progression or the occurrence of intolerable toxicity. Method of Administration: Oral. This product should be taken at a fixed time each day, either on an empty stomach or with food. The capsules should be swallowed whole; alternatively, the capsules (which must not be opened or crushed) may be mixed with one tablespoon of water or apple juice in a glass to form a suspension. The capsules must remain in the liquid for at least 10 minutes and be stirred for at least 3 minutes to dissolve the capsule shell, after which the suspension should be swallowed. After drinking, an equal amount of water or apple juice (one tablespoon) must be added to the glass, stirred several times, and then the entire contents of the glass consumed. If a patient misses a dose and is unable to take it within 12 hours, the missed dose should not be taken; the next dose should be taken at the regularly scheduled time. Prior to adjusting the dosage of this product (e.g., by suspending or reducing the dose), adverse reactions such as nausea, vomiting, and diarrhea should be actively treated; gastrointestinal toxicities should be actively managed to reduce the risk of renal insufficiency or renal failure (see [Precautions]). Monitoring, Dose Adjustment, and Discontinuation: It may be necessary to suspend administration, adjust the dose, or discontinue treatment with this product to manage certain adverse reactions. Mild to moderate adverse reactions (e.g., Grade 1 or 2) generally do not require suspension of administration, unless the patient remains intolerant despite active treatment. Severe (e.g., Grade 3) or intolerable adverse reactions require suspension of administration until the adverse reaction improves to Grade 0–1 or returns to baseline."