Drug Name

Generic Name: Lenvatinib Mesilate Capsules Brand Name: LENVIMA

English Name: Lenvatinib Mesilate Capsules

Pinyin: Jiahuangsuan Lunfatini Jiaonang

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: [Image/Formula] Molecular Formula: C21H19ClN4O4·CH4O3S Molecular Weight: 522.96

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

Specification: 10 mg × 20 capsules/box

Dosage and Administration

(1) Thyroid Cancer: 24 mg orally once daily.

(2) Renal Cell Carcinoma: 18 mg Lenvatinib + 5 mg Everolimus orally once daily.

(3) Hepatocellular Carcinoma: 12 mg orally once daily.

(4) For patients with severe renal or hepatic impairment, the dosage for the treatment of thyroid cancer should be reduced to 14 mg once daily, and the dosage for the treatment of renal cell carcinoma should be reduced to 10 mg once daily.

Patients with Hepatic Impairment: Among patients enrolled in clinical studies for hepatocellular carcinoma, no dose adjustment based on hepatic function is required for patients with mild hepatic impairment (Child-Pugh A). Currently, study data for 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 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: For patients with mild or moderate renal impairment, no dose adjustment based on renal function is required. 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.

Adverse Reactions

This package insert 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, 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 Profile in the Global Population from 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 Performance Status (ECOG PS) 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 received prior radiotherapy or locoregional therapy, the target lesions must have shown radiological evidence of disease progression. Patients with liver occupancy ≥50%, or with imaging evidence of significant invasion into the bile ducts or the main trunk 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 of ≥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%). Grade 3 or higher adverse reactions occurred in 75% of patients in the Lenvatinib arm. 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%) 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 reduction or interruption of treatment in 62% of patients treated with Lenvatinib. The most common adverse reactions (≥5%) leading to dose reduction or interruption 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 for statistically significant reductions in the incidence of any specific adverse reaction listed in Table 3. Description of Specific Adverse Reactions: Hypertension. In the Phase 3 clinical trial for hepatocellular carcinoma, 44.5% of patients treated with Lenvatinib experienced hypertension (including diastolic hypertension, blood pressure increased, hypertension, and orthostatic hypertension), and 23.5% of patients experienced Grade 3 hypertension. The median time to onset of hypertension was 26 days. Most patients recovered after dose interruption or reduction; specifically, 3.6% of patients required dose interruption, and 3.4% required dose reduction. One patient (0.2%) discontinued Lenvatinib due to hypertension. Proteinuria. In the Phase 3 trial for hepatocellular carcinoma, 26.3% of patients treated with Lenvatinib experienced proteinuria, with a Grade 3 reaction rate of 5.9%. The median time to onset of proteinuria was 6.1 weeks. Most cases resolved after dose interruption or reduction; specifically, 6.9% of patients required dose interruption, and 2.5% required dose reduction. 0.6% of patients permanently discontinued treatment due to proteinuria. Renal Failure and Impairment: In the Phase 3 clinical trial for hepatocellular carcinoma (HCC), renal failure/impairment events occurred in 7.1% of patients treated with lenvatinib. Grade 3 or higher adverse reactions occurred in 1.9% of lenvatinib-treated patients. Cardiac Dysfunction: In the Phase 3 HCC clinical trial, cardiac dysfunction (including congestive heart failure, cardiogenic shock, and cardiopulmonary failure) occurred in 0.6% of lenvatinib-treated patients (0.4% were Grade ≥3). Reversible Posterior Encephalopathy Syndrome (PRES) / Reversible Posterior Leukoencephalopathy Syndrome (RPLS): In the Phase 3 HCC clinical trial, one case of PRES (Grade 2) occurred in the lenvatinib treatment group. Hepatotoxicity: In the Phase 3 HCC trial, 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. Hepatotoxic reactions of Grade ≥3 occurred in 26.1% of lenvatinib-treated patients. 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. Hepatotoxicity adverse reactions leading to dose interruption and dose reduction occurred in 12.2% and 7.4% of Lenvatinib-treated patients, respectively; hepatotoxicity 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 Lenvatinib-treated patients. Ten patients (0.45%) experienced fatal outcomes due to 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 whom 5.0% experienced Grade ≥3 events. The incidence of Grade 3 reactions was 3.4%, the incidence of Grade 4 reactions was 0.2%, and 7 patients (1.5%) experienced Grade 5 reactions, including cerebral hemorrhage, upper gastrointestinal hemorrhage, intestinal hemorrhage, and tumor hemorrhage. The median time from the start of treatment to the first occurrence of hemorrhage was 11.9 weeks. Due to hemorrhagic events, dose interruption occurred in 3.2% of patients, dose reduction occurred in 0.8% of patients, and permanent discontinuation occurred in 1.7% of patients. Gastrointestinal Perforation and Fistula Formation: In the Phase 3 clinical trial for hepatocellular carcinoma, gastrointestinal perforation or fistula events were reported in 1.9% of Lenvatinib-treated patients. Non-Gastrointestinal Fistula: Lenvatinib treatment has been associated with cases of fistula formation, including reactions resulting in death. 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, QT/QTc interval prolongation was reported in 6.9% of Lenvatinib-treated patients. The incidence of QTcF interval prolongation exceeding 500 ms was 2.4%. Diarrhea: In the Phase 3 trial for hepatocellular carcinoma, diarrhea was reported in 38.7% of Lenvatinib-treated patients (4.2% experienced Grade ≥3 events). Hypocalcemia: In the Phase III clinical trial for hepatocellular carcinoma, 1.1% of patients reported hypocalcemia, of whom 0.4% experienced Grade 3 reactions. One patient (0.2%) had treatment suspended due to hypocalcemia; no dose reductions or permanent discontinuations occurred. Elevated Thyroid-Stimulating Hormone (TSH): In the Phase III 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 were observed in 69.6% of patients treated with lenvatinib. Summary of Safety Profile in the Mainland China, Taiwan, and Hong Kong (CTH) Population in the REFLECT Study: In the Mainland China, Taiwan, and 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 subjects 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 observed in lenvatinib-treated patients (occurring in ≥20%)—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%). Adverse reactions of Grade 3 or higher occurred in 63% of patients receiving lenvatinib. Among patients treated with Lenvatinib, the most common Grade 3 or higher adverse reactions (occurring in ≥5%) 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 (occurring in ≥2%) among 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 (occurring in ≥5%) leading to Lenvatinib dose reduction or 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 (occurring in ≥1%) leading to Lenvatinib discontinuation were hemorrhagic events (2%) and cholestatic jaundice (1%). Table 5 summarizes the adverse reactions occurring in ≥10% of patients treated with Lenvatinib in the Mainland China, Taiwan, and Hong Kong populations. Table 6 summarizes Grade 3–4 laboratory abnormalities occurring in ≥2% of patients treated with Lenvatinib in the Mainland China, Taiwan, and Hong Kong populations.

Contraindications

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

Precautions

Hypertension: Hypertension has been reported in patients treated with Lenvatinib; this event typically occurs early in the course of treatment (see [Adverse Reactions]). Blood pressure (BP) should be well-controlled prior to initiating Lenvatinib treatment. If a patient is known to have hypertension, they should be on a stable dose of antihypertensive therapy for at least 1 week prior to initiating Lenvatinib treatment. Serious complications of poorly controlled hypertension (including aortic dissection) have been reported. Early detection and effective management of hypertension are crucial for minimizing interruptions to and dose reductions of lenvatinib administration. Once elevated blood pressure is confirmed, antihypertensive therapy should be initiated as soon as possible. Blood pressure should be monitored one week after initiating lenvatinib treatment, every two weeks thereafter for the following two months, and monthly thereafter. Antihypertensive treatment regimens should be individualized based on the patient's clinical status and should adhere to standard treatment guidelines. 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 their current medication may be increased—if appropriate—or an additional agent may be added.