Approval Date.
Lenvatinib Mesylate Capsules Instructions
Please read the instructions carefully and use under medical supervision
[Drug Name]
Generic Name: Lenvatinib Mesylate Capsules
Trade Name: LENVIMA® LENVIMA®
English Name: Lenvatinib Mesilate Capsules
Hanyu Pinyin: Jiahuangsuan Lunfatini Jiaonang
[Ingredients]
The active ingredient of this product is: Lunfatinib mesylate
Chemical name: 4-[3-chloro-4-(N’-cyclopropylureido)phenoxy] -7-methoxyquinoline-6-carboxamide methanesulfonate
Chemical structure formula:
Molecular Formula: C21H19ClN4O4-CH4O3S
molecular weight: 522.96
Properties
The content of this product is white to off-white granules.
[Indications]
This product is indicated for patients with unresectable hepatocellular carcinoma who have not received prior systemic systemic therapy.
The pivotal study of this product excluded patients with hepatocellular carcinoma who could be treated locally, and there are no available study data for such patients.
[Specification]
4mg (based on C21H19ClN4O4)
[Dosage and Administration]
Recommended Dose
For patients weighing <60 kg, the recommended daily dose of this product is 8 mg (2 4 mg capsules) once daily; for patients weighing ≥60 kg, the recommended daily dose of this product is 12 mg (3 4 mg capsules) once daily. Treatment should be continued until disease progression or intolerable toxicities occur.
Dosing Method
Oral. This product should be taken at regular times of the day, either on an empty stomach or with food.
This product should be swallowed whole, or it can be mixed (not opened or crushed) with a tablespoon of water or apple juice in a glass to form a suspension. The capsule must be left in the liquid for at least 10 minutes, stirred for at least 3 minutes to dissolve the capsule shell, and then swallowed in suspension. After swallowing, the same amount of water or apple juice (one tablespoon) must be added to the glass, stirred several times, and then all the liquid in the glass must be drunk.
If a patient misses a dose and is unable to take it within 12 hours, there is no need to make up the dose and the next dose should be taken at the regular dosing time.
Adverse reactions such as nausea, vomiting, and diarrhea should be aggressively treated prior to dose adjustment (suspension, reduction) of this product; gastrointestinal toxic reactions should be aggressively treated to reduce the risk of developing renal insufficiency or renal failure (see [PRECAUTIONS]).
Monitoring, Dose Adjustment, and Discontinuation
Suspension of dosing, dose adjustment, or discontinuation of therapy with this product may be required to manage certain adverse reactions. Mild to moderate adverse reactions (e.g., Grade 1 or 2) generally do not require suspension of dosing unless they are not tolerated by the patient after active treatment. Severe (e.g., Grade 3) or intolerable adverse reactions require suspension of dosing until the adverse reaction improves to Grade 0-1 or baseline. See Table 1 for more information on dose adjustments based on adverse reactions. see Table 2 for more information on monitoring, dose adjustments, and discontinuation.
Table1.Dose adjustment based on adverse reactions
(despite optimal blood pressure-lowering therapy)
See Table 7 Recommendations for management of hypertension
| Starting Dose | Weight≥60 kg 12 mg (3 capsules4 mg orally, once daily) |
Weight<60 kg 8 mg (2 capsules4 mg orally, once daily) |
||
| Persistent and intolerableGrade 2 orGrade 3 adverse reactions< strong>a | ||||
| Adverse reactions | Adjustments | Adjusted doseb (Weight ≥ 60 kg ) |
Adjusted doseb (Weight<60 kg) |
|
| First occurrence of c | Suspension of dosing until remission to grade 0-1 or baseline d | 8 mg (2 4 mg capsules) Administered orally once daily |
4 mg (1 4 mg capsule) Administered orally once daily |
|
| Suspension of dosing until remission to grade 0-1 or baseline d | 4 mg (1 4 mg capsule) orally, once daily |
4 mg (1 4 mg capsule) Oral, every other day |
||
| Suspension of dosing until remission to grade 0-1 or baseline d | 4 mg (1 4 mg capsule) orally, every other day |
Discontinue |
||
| Life-threatening adverse reactions (Grade 4): discontinuatione | ||||
| a Treat adverse reactions such as nausea, vomiting, and diarrhea aggressively before suspending or reducing dosing of this product. b Based on previous dose levels, taper the dose in the order of 12 mg, 8 mg, 4 mg once daily, or 4 mg every other day. c First occurrence of hematologic adverse reactions or proteinuria – no dose adjustment required. d For hematologic adverse reactions or proteinuria, treatment may be restarted when remission is to Grade 2. e When adverse reactions are laboratory abnormalities grade 4, all may be treated as grade 3 adverse reactions if judged to be non-life-threatening. |
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Adverse reactions are graded according to the National Cancer Institute(NCI)Common Terminology Criteria for Adverse Events.
Special Populations
Patients 75 years of age and older, Caucasian patients, female patients, or patients with more severe hepatic insufficiency appear to be less tolerant of this product.
Except in patients with moderate or severe hepatic insufficiency or severe renal insufficiency, all patients with hepatocellular carcinoma should begin treatment with the recommended starting dose of 8 mg (two 4 mg capsules, weight <60 kg) or 12 mg (three 4 mg capsules, weight ≥60 kg), after which the dose should be further adjusted based on individual tolerability.
Patients with hepatic insufficiency
Patients with hepatic insufficiency
In patients enrolled in clinical studies of hepatocellular carcinoma, no dose adjustment based on liver function is required in patients with mild hepatic insufficiency (Child-Pugh A), and limited data are available in patients with moderate hepatic insufficiency (Child-Pugh B), who should be cautiously treated with this product under medical supervision and closely monitored. There are no data from studies in patients with severe hepatic insufficiency (Child-Pugh C), and this product is not recommended for patients with severe hepatic insufficiency.
Patients with renal insufficiency
In patients with mild or moderate renal insufficiency, no dose adjustment based on renal function is required. There are no data from studies in patients with severe renal insufficiency, and this product is not recommended for patients with severe renal insufficiency.
Pediatric Patients
There are no clinical data on the use of this product in pediatric or adolescent patients younger than 18 years of age, and its administration is not recommended.
Elderly Patients
[Adverse Reactions]
This instruction describes the adverse reactions observed in clinical studies judged to be possibly caused by lenvatinib mesylate and their approximate incidence. Because clinical studies are conducted under a variety of different conditions, the incidence of adverse reactions observed in one clinical study is not directly comparable to the incidence of adverse reactions observed in another clinical study and may not reflect the actual incidence in clinical practice.
REFLECT Summary of Safety Characteristics in the Global Population in the Study Summary of Safety Characteristics in the Global Population in the Study The clinical efficacy and safety of lenvatinib were evaluated in an international multicenter, open-label, randomized phase 3 study (REFLECT) in patients with unresectable hepatocellular carcinoma (HCC). A total of 954 patients were randomized in a 1:1 ratio to receive either lenvatinib (12 mg [baseline weight ≥60 kg] or 8 mg [baseline weight <60 kg]) or sorafenib 400 mg orally once daily or twice daily. Patients with a hepatic functional status of Child – Pugh Class A and Eastern Collaborative Oncology Group Physical Status (ECOG PS) 0 or 1 were eligible for enrollment. Patients with prior systemic anticancer therapy or any prior anti-vascular endothelial growth factor (VEGF) therapy for advanced/unresectable HCC were excluded. Target lesions previously treated with radiotherapy or local therapy must have radiographic evidence showing disease progression. Patients with ≥50% hepatic occupancy and imaging showing significant invasion into the bile duct or main branch of the portal vein (Vp4) were also excluded. The majority of patients in both treatment groups had a baseline ECOG PS of 0 (63%), a Child-Pugh score of 5 (76%) and weighed ≥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 group had at least one adverse reaction. The most common adverse reactions observed in lenvatinib-treated patients (≥20%) were as follows, 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 erythema syndrome (27%), proteinuria (26%), bleeding events ( 25%), dysphonia (24%), hypothyroidism (21%), and nausea (20%).
Grade 3 or higher adverse reactions occurred in 75% of patients in the lenvatinib group. The most common Grade 3 or higher adverse reactions observed in patients in the lenvatinib treatment group (≥5%) were hypertension (24%), weight loss (8%), fatigue (7%), elevated bilirubin (7%), proteinuria (6%), decreased platelet count (5%), hepatic encephalopathy (5%), elevated gamma-glutamyl transferase (5%), bleeding events (5%), and elevated aspartate aminotransferase (5%). (5%), elevated gamma-glutamyl transferase (5%), bleeding events (5%) and elevated aspartate aminotransferase (5%).
The most common serious adverse reactions (≥2%) in patients treated with lenvatinib were bleeding events (5%), hepatic encephalopathy (5%), liver failure (3%), ascites (3%), and decreased appetite (2%).
Adverse reactions led to dose reduction or discontinuation in 62% of patients treated with lenvatinib. The most common adverse reactions (≥5%) leading to dose reduction or discontinuation in the lenvatinib treatment arm were fatigue (10%), decreased appetite (8%), diarrhea ( 8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythema syndrome (5%).
In the lenvatinib treatment group, 20% of patients discontinued treatment due to adverse effects. The most common adverse reactions (≥1%) that led to discontinuation of lenvatinib were fatigue (2%), bleeding events (2%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and liver failure (1%).
Table 3 summarizes the adverse reactions that occurred in ≥10% of patients treated with lenvatinib in the REFLECT study. The REFLECT study was not designed to compare lenvatinib with sorafenib for a statistically significant reduction in the incidence of any of the specific adverse reactions listed in Table 3.
| Table3:REFLECT () HCC) in the lenvatinib group in ≥10% of patients with adverse reactions | ||||
| Adverse reactions | Lenvatinib 8 mg/12 mg N=476 |
Sorafenib 800 mg N=475 |
||
| Grades 1-4 (%) |
Grades 3-4 (%) |
Grades 1-4 (%) |
Grades 3-4 (%) |
|
| Endocrine System | ||||
| Hypothyroidisma | 21 | 0 | 3 | 0 |
| Gastrointestinal system | ||||
| Diarrhea | 39 | 4 | 46 | 4 |
| abdominal painb | 30 | 3 | 28 | 4 |
| disgusting | 20 | 1 | 14 | 1 |
| Vomiting | 16 | 1 | 8 | 1 |
| Constipation | 16 | 1 | 11 | 0 |
| Abdominal fluidc | 15 | 4 | 11 | 3 |
| Oral mucositisd | 11 | 0.4 | 14 | 1 |
| Full Body | ||||
| Fatiguee | 44 | 7 | 36 | 6 |
| Feverf | 15 | 0 | 14 | 0.2 |
| Peripheral edema | 14 | 1 | 7 | 0.2 |
| Metabolism and nutrition | ||||
| Decreased appetite | 34 | 5 | 27 | 1 |
| weight loss | 31 | 8 | 22 | 3 |
| Musculoskeletal and connective tissue | ||||
| Arthralgia/Myalgiag | 31 | 1 | 20 | 2 |
| Nervous system | ||||
| Headache | 10 | 1 | 8 | 0 |
| Kidney and urinary system | ||||
| Proteinuria h | 26 | 6 | 12 | 2 |
| Respiratory, thoracic and mediastinal | ||||
| Dysarthria | 24 | 0.2 | 12 | 0 |
| Dermal and subcutaneous tissue | ||||
| Palmar-plantar erythrodysostosis syndrome | 27 | 3 | 52 | 11 |
| Rashi | 14 | 0 | 24 | 2 |
| Vascular | ||||
| hypertensionj | 45 | 24 | 31 | 15 |
| bleeding eventsk | 23 | 4 | 15 | 4 |
| a Includes hypothyroidism, increased blood thyroid stimulating hormone. b Includes abdominal discomfort, abdominal pain, abdominal tenderness, epigastric discomfort, gastrointestinal pain, lower abdominal pain, and upper abdominal pain. c Includes ascites and malignant ascites. d Includes recurrent mouth ulcers, gingival erosions, gum ulcers, tongue inflammation, mouth ulcers, oral mucosal blistering and stomatitis. e Includes malaise, fatigue, sleepiness and malaise. f Includes elevated body temperature and fever. g Includes arthralgia, back pain, limb pain, musculoskeletal pain in the chest, musculoskeletal discomfort, musculoskeletal pain, and myalgia. h Includes proteinuria, increased urinary protein, and detection of urinary protein. i including erythema, erythematous eruption, exfoliative rash, genital rash, maculopapular rash, papular rash, pruritus rash, pustular rash, and skin rash j Includes elevated diastolic blood pressure, elevated blood pressure, hypertension, and upright hypertension k Includes all bleeding terms. Bleeding terms occurring in 5 or more subjects in any treatment group include: epistaxis, hematuria, gingival bleeding, hemoptysis, esophageal variceal bleeding, hemorrhoid bleeding, oral bleeding, rectal bleeding, and upper gastrointestinal bleeding. |
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In Table 4, grade 3 to 4 laboratory abnormalities that occurred in ≥2% of patients in the lenvatinib group in REFLECT (HCC) are presented.
| Table4:REFLECT( HCC) in lenvatinib group in ≥2% of patients with 3 to 4Grade 1 laboratory abnormalitiesa,b | ||
| Laboratory Anomalies | Lenvatinib (%) |
Sorafenib (%) |
| Chemistry | ||
| GGT elevation | 17 | 20 |
| hyponatremia | 15 | 9 |
| hyperbilirubinemia | 13 | 10 |
| Elevated aspartate aminotransferase (AST) | 12 | 18 |
| 8 | 9 | |
| Elevated alkaline phosphatase | 7 | 5 |
| Elevated lipase | 6 | 17 |
| Hypokalemia | 3 | 4 |
| Hyperkalemia | 3 | 2 |
| Decreased albumin | 3 | 1 |
| Elevated creatinine | 2 | 2 |
| Hematology | ||
| Thrombocytopenia | 10 | 8 |
| Lymphocytopenia | 8 | 9 |
| Neutropenia | 7 | 3 |
| Anemia | 4 | 5 |
| a Increase of at least 1 level from baseline b Percentage of laboratory abnormalities based on the number of patients with both baseline and at least one post-baseline laboratory measurement for each parameter. Lenvatinib (n = 278 to 470) and sorafenib (n = 260 to 473) |
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Description of specific adverse reactions Hypertension
In the phase III clinical trial in hepatocellular carcinoma, hypertension (including elevated diastolic blood pressure, elevated blood pressure, hypertension, and upright hypertension) occurred in 44.5% of lenvatinib-treated patients, and grade 3 hypertension occurred in 23.5% of patients. The median time from dosing to the onset of hypertension was 26 days. The majority of patients returned to normal after dose suspension or reduction, with 3.6% of patients requiring dose suspension and 3.4% requiring dose reduction. lenvatinib was discontinued in one patient (0.2%) due to hypertension.
Proteinuria
In the phase III trial in hepatocellular carcinoma, 26.3% of lenvatinib-treated patients developed proteinuria, with an incidence of grade 3 reactions of 5.9%. The median time from dosing to the appearance of proteinuria was 6.1 weeks. The majority of cases recovered after dose suspension or reduction, with 6.9% of patients requiring dose suspension and 2.5% requiring dose reduction. 0.6% of patients permanently discontinued the drug due to proteinuria.
Renal Failure and Renal Insufficiency
In phase III clinical trials in hepatocellular carcinoma, renal failure/renal insufficiency events occurred in 7.1% of lenvatinib-treated patients. 1.9% of lenvatinib-treated patients experienced grade 3 or higher adverse reactions.
Cardiac Dysfunction
Cardiac dysfunction (including congestive heart failure, cardiogenic shock, and cardiopulmonary failure) occurred in 0.6% of lenvatinib-treated patients in phase III clinical trials in hepatocellular carcinoma (0.4% were grade ≥3).
Reversible Posterior Encephalopathy Syndrome (PRES)/Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
In a phase III clinical trial in hepatocellular carcinoma, one PRES event (grade 2) occurred in the lenvatinib treatment arm.
Hepatotoxicity
In the phase III trial in hepatocellular carcinoma, the most frequently reported adverse hepatotoxic reactions were elevated blood bilirubin (14.9%), elevated aspartate aminotransferase (13.7%), elevated alanine aminotransferase (11.1%), hypoalbuminemia (9.2%), hepatic encephalopathy (8.0%), elevated gamma-glutamyl transferase (7.8%), and elevated blood alkaline phosphatase ( 6.7%). The median time from dosing to the onset of hepatotoxic adverse reactions was 6.4 weeks. 26.1% of lenvatinib-treated patients experienced grade ≥3 hepatotoxic reactions. 3.6% of patients experienced liver failure (including fatal events in 12 patients) (all ≥3). 8.4% of patients experienced hepatic encephalopathy (including fatal events in 4 patients) (5.5% of patients ≥3). Hepatotoxic events resulted in 17 deaths (3.6%) in the lenvatinib group and 4 deaths (0.8%) in the sorafenib group. Hepatotoxic adverse reactions leading to dose suspension and dose reduction occurred in 12.2% and 7.4% of lenvatinib-treated patients, respectively; in 5.5% of patients, hepatotoxic adverse reactions leading to permanent drug discontinuation occurred.
Arterial Thromboembolism
In the phase III trial in hepatocellular carcinoma, arterial thromboembolic events occurred in 2.3% of lenvatinib-treated patients. Ten (0.45%) patients with arterial thromboembolism (5 myocardial infarction and 5 cerebrovascular events) had a fatal outcome.
Hemorrhage
In the phase III clinical trial in hepatocellular carcinoma, bleeding was reported in 24.6% of patients, of which 5.0% were grade ≥3. The incidence of grade 3 reactions was 3.4%, grade 4 reactions was 0.2%, and grade 5 reactions, including cerebral hemorrhage, upper gastrointestinal hemorrhage, intestinal hemorrhage, and tumor hemorrhage, occurred in 7 patients (1.5%). The median time from dosing to the first occurrence of bleeding was 11.9 weeks. Dosing suspension occurred in 3.2% of patients, dose reduction in 0.8%, and discontinuation in 1.7% of patients due to bleeding events.
Gastrointestinal perforation and gastrointestinal fistula formation
In phase III clinical trials in hepatocellular carcinoma, 1.9% of lenvatinib-treated patients reported gastrointestinal perforation or gastrointestinal fistula events.
Non-gastrointestinal fistulaLenvatinib dosing was associated with fistula cases, including reactions that resulted in death. Fistulas involving body sites other than the stomach or intestines have been observed in a variety of indications. The reactions were reported at various time points during treatment, ranging from 2 weeks to >1 year after initiation of lenvatinib therapy, with a median delay of approximately 3 months.
Prolonged QT interval
In phase III trials in hepatocellular carcinoma, prolonged QT/QTc intervals were reported in 6.9% of lenvatinib-treated patients. the incidence of prolonged QTcF intervals greater than 500 ms was 2.4%.
Diarrhea
In the phase III trial in hepatocellular carcinoma, diarrhea was reported in 38.7% of lenvatinib-treated patients (4.2% were grade ≥3).
Hypocalcemia
In the phase III trial in hepatocellular carcinoma, hypocalcemia was reported in 1.1% of patients, of which 0.4% were grade 3 reactions. 1 patient (0.2%) had dosing suspended due to hypocalcemia and no dose reduction or discontinuation occurred.
Elevated Blood Thyrotropic Hormone(TSH)
In phase III clinical trials in hepatocellular carcinoma, 89.6% of patients had TSH levels that were less than the upper limit of normal baseline. TSH levels above the upper limit of normal at baseline were observed in 69.6% of lenvatinib-treated patients.
REFLECTSummary of Safety Characteristics in the Mainland China+Taiwan+Hong Kong (CTH) Population in the Study
In the CTH population, most patients in the lenvatinib group (97%) had at least one adverse reaction. The most common adverse reactions observed among lenvatinib-treated patients (≥20%), in descending order, included hypertension (44%), fatigue (35%), abdominal pain (32%), diarrhea (32%), weight loss (32%), decreased platelet count (28%), proteinuria (27%), palmar-plantar erythema syndrome (24%), elevated aspartate aminotransferase (24% ), arthralgia/myalgia (22%), decreased appetite (22%), bleeding events (22%), decreased white blood cell count (21%), and elevated alanine aminotransferase (20%).
Grade 3 or higher adverse reactions occurred in 63% of patients receiving lenvatinib. The most common Grade 3 or higher adverse reactions in patients treated with lenvatinib (≥5%) were hypertension (23%), decreased platelet count (10%), increased aspartate aminotransferase (8%), increased blood bilirubin (8%), proteinuria (6%), increased gamma-glutamyl transferase (6%), weight loss (6%), and decreased white blood cell count (6%).
In the CTH population, the most common serious adverse reactions (≥2%) among lenvatinib-treated patients were bleeding events (5%), cholestatic jaundice (3%), and respiratory failure (2%).
In the CTH population, 46% of patients receiving lenvatinib experienced adverse reactions that resulted in dose reduction or interruption. The most common adverse reactions (≥5%) leading to dose reduction or interruption of lenvatinib dosing were decreased platelet count (9%), proteinuria (7%), and hypertension (6%).
In the CTH population, 13% of patients in the lenvatinib treatment arm discontinued treatment due to adverse reactions. The most common adverse reactions leading to discontinuation of lenvatinib (≥1%) were bleeding events (2%) and cholestatic jaundice (1%)
Table 5 summarizes the adverse reactions that occurred in ≥10% of patients treated with lenvatinib in the mainland China + Taiwan + Hong Kong population.
| China + Taiwan + Hong Kong | ||||
| Adverse reactions | Lenvatinib 8mg/12mg N=144 |
Sorafenib 800mg N=144 |
||
| Grade 1-4 (%) | Grade 3-4 (%) | Grade 1-4 (%) | Grade 3-4 (%) | |
| Hypothyroidism a | 15 | 0 | 4 | 0 |
| Gastrointestinal system | ||||
| Abdominal pain b | 32 | 3 | 27 | 5 |
| Diarrhea | 32 | 2 | 42 | 3 |
| Distension | 19 | 1 | 9 | 0 |
| Full Body | ||||
| Fatiguec | 35 | 3 | 27 | 2 |
| Heatd | 12 | 0 | 13 | 0 |
| Metabolism and Nutrition | ||||
| weight loss | 32 | 6 | 24 | 1 |
| Loss of appetite | 22 | 3 | 19 | 0 |
| Musculoskeletal and connective tissue | ||||
| Arthralgia/Myalgia d | 22 | 0 | 15 | 2 |
| Renal and urinary system | ||||
| Proteinuria e | 27 | 6 | 11 | 1 |
| Respiratory, thoracic and mediastinal | ||||
| Dysarthria | 15 | 0 | 4 | 0 |
| Skin and subcutaneous tissue | ||||
| Palmar-plantar erythrodysostosis syndrome | 24 | 1 | 49 | 7 |
| Rash f | 15 | 0 | 23 | 1 |
| Vascular | ||||
| hypertension g | 44 | 23 | 31 | 15 |
| Bleeding events h | 19 | 3 | 9 | 2 |
| a Includes hypothyroidism, elevated blood thyroid stimulating hormone b Includes abdominal discomfort, abdominal pain, abdominal tenderness, epigastric discomfort, gastrointestinal pain, lower abdominal pain, and upper abdominal pain. c Includes malaise, fatigue and discomfort d Includes arthralgia, back pain, limb pain, musculoskeletal pain in the chest, musculoskeletal pain, and myalgia e Includes proteinuria and urinary protein detection. f Includes erythema, exfoliative rash, genital rash, maculopapular rash, papulopapular rash, pustular rash, and skin rash. g Includes elevated diastolic blood pressure, elevated blood pressure, and hypertension. h Includes all bleeding items. The term bleeding that occurs in 2 or more subjects in any treatment group in the CTH population includes epistaxis, hematuria, gingival bleeding, esophageal variceal bleeding, vomiting blood, oral bleeding, and upper gastrointestinal bleeding. |
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Grade 3-4 laboratory test abnormalities occurred in ≥2% of patients treated with lenvatinib in the mainland China + Taiwan + Hong Kong population are summarized in Table 6.
| Table 6 Abnormalities in grade 3-4 laboratory tests in ≥2% of patients in the lenvatinib group in the Mainland China+Taiwan+Hong Kong populationa,b | ||
| China + Taiwan + Hong Kong | ||
| Laboratory test abnormalities | Lenvatinib 8mg/12mg (%) |
Sorafenib 800mg (%) |
| GGT elevation | 17 | 18 |
| 12 | 10 | |
| Elevated aspartate aminotransferase (AST) | 11 | 15 |
| 11 | 11 | |
| 9 | 7 | |
| Elevated alkaline phosphatase | 7 | 6 |
| Hypokalemia | 6 | 6 |
| Decreased albumin | 2 | 0 |
| Hematology | ||
| Thrombocytopenia | 16 | 5 |
| 10 | 4 | |
| Lymphocytopenia | 7 | 9 |
| Anemia | 4 | 1 |
| a: increase of at least 1 level from baseline b: percentage of abnormal laboratory tests based on the number of patients with baseline and at least one post-baseline laboratory measurement for each parameter. Lenvatinib (n = 140-141) and sorafenib (n = 141-144) |
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[Contraindication]
Hypersensitivity to any of the ingredients of this product.
Lactating women (see [Pregnant and lactating women medication])
[Precautions]
HypertensionHypertension has been reported in patients treated with lenvatinib, and this event usually occurs early in treatment (see [Adverse Reactions]). Blood pressure (BP) should be well controlled prior to treatment with lenvatinib. If the patient is known to have hypertension, he or she should receive a stable dose of antihypertensive therapy for at least 1 week prior to treatment with lenvatinib. Serious complications of poorly controlled hypertension (including aortic coarctation) have been reported. Early detection and effective management of hypertension is important to reduce lenvatinib dose suspensions and reductions. Antihypertensive drug therapy should be initiated as soon as possible after the diagnosis of elevated blood pressure is confirmed. Blood pressure should be monitored after 1 week of lenvatinib treatment, then every 2 weeks for 2 months, and monthly thereafter. The choice of antihypertensive treatment regimen should be individualized to the patient’s clinical status and standard therapy should be followed. Monotherapy with an antihypertensive agent should be initiated in patients with previously normal blood pressure when an increase in blood pressure is observed. For patients already receiving antihypertensive medication, the dose of the current medication may be increased or one or more different types of antihypertensive medications may be added if appropriate. If necessary, manage hypertension as recommended in Table 7.
Table 7 Recommendations for Management of Hypertension
| Blood pressure (BP) levels |
Recommended Measures |
| 140 mmHg≤systolic<160 mmHg or 90 mmHg≤diastolic<100 mmHg |
Continuing lenvatinib therapy and initiating antihypertensive therapy (not previously given as antihypertensive therapy), the or Continue lenvatinib treatment and increase the dose of current antihypertensive drug or start adding other antihypertensive therapy |
| 1. withhold lenvatinib 2. If systolic blood pressure is ≤150 mmHg and diastolic blood pressure is ≤95 mmHg and the patient has received a stable dose of antihypertensive therapy for more than 48 hours, reduce the dose and restart lenvatinib therapy (see [Dosage]) |
|
| Urgent interventions are required. Discontinue lenvatinib therapy and treat appropriately. |
Proteinuria
Proteinuria
Proteinuria has been reported in patients treated with lenvatinib, and this event usually occurs early in treatment (see [Adverse Reactions]). Urine protein should be monitored regularly. If proteinuria ≥2+ is detected using the urine test paper method, dosing may need to be suspended or dose adjusted or discontinued (see [DOSAGE]). If nephrotic syndrome occurs, lenvatinib should be discontinued.
Renal Failure and Renal InsufficiencyRenal insufficiency and renal failure have been reported in patients treated with lenvatinib (see [Adverse Reactions]). The main risk factors identified were dehydration and/or hypovolemia due to gastrointestinal toxicity. Gastrointestinal toxicity should be treated aggressively to reduce the risk of renal insufficiency or renal failure. Suspend dosing, adjust dose, or discontinue as necessary (see [DOSAGE AND ADMINISTRATION]).
Cardiac Dysfunction
Heart failure (<1%) and reduced left ventricular ejection fraction have been reported in patients treated with lenvatinib (see [Adverse Reactions]). Patients should be monitored for clinical signs or symptoms related to cardiac failure and dosing should be suspended, adjusted, or discontinued as necessary. (See [DOSAGE]).
Reversible Posterior Encephalopathy Syndrome (PRES)/Reversible Posterior White Matter Encephalopathy Syndrome (RPLS)
PRES (also known as RPLS) has been reported in patients treated with lenvatinib (<1%; see [Adverse Reactions]).PRES is a neurological disorder that presents with headache, seizures, drowsiness, confusion, altered mental function, blindness, and other visual or neurological disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to establish the diagnosis of PRES. Appropriate measures should be taken to control blood pressure (see [Precautions]). Suspension of dosing, dose adjustment, or discontinuation may be necessary in patients with signs or symptoms of PRES (see [DOSAGE AND ADMINISTRATION]).
Hepatotoxicity
In patients with HCC treated with lenvatinib in the REFLECT trial, liver-related adverse reactions, including hepatic encephalopathy and liver failure (including lethal reactions), were reported more frequently than in patients treated with sorafenib (see [Adverse Reactions]). Patients with more severe hepatic insufficiency and/or greater hepatic tumor load at baseline were at higher risk for hepatic encephalopathy and liver failure. hepatic encephalopathy also occurred more frequently in patients 75 years of age and older. Approximately half of the liver failure events and one-third of the hepatic encephalopathy events were reported in patients who experienced disease progression.
Data in patients with HCC with moderate hepatic insufficiency (Child – Pugh B) are very limited, and no data are available for patients with HCC with severe hepatic insufficiency (Child – Pugh C). Because lenvatinib is eliminated primarily through hepatic metabolism, increased exposure is expected in patients with moderate to severe hepatic insufficiency.
Close monitoring for overall safety is recommended in patients with hepatic insufficiency (see [DOSAGE] and [ADVERSE REACTIONS]). Liver function should be monitored prior to initiation of therapy, then every 2 weeks for the first 2 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 dosing, adjust the dose, or discontinue the drug (see [DOSAGE AND ADMINISTRATION]).
Arterial ThromboembolismArterial thromboembolism (cerebrovascular accident, transient ischemic attack, and myocardial infarction) has been reported in patients treated with lenvatinib (see [ADVERSE REACTIONS]). Lenvatinib has not been studied in patients who have had arterial thromboembolism within the past 6 months and should therefore be administered with caution in such patients. Treatment decisions should be taken based on individual patient benefit/risk assessment. Lenvatinib should be discontinued after an arterial thrombotic event.
Hemorrhage
Serious tumor-related bleeding, including fatal bleeding events, occurred in clinical trials (see [Adverse Reactions]). The degree of tumor invasion/infiltration of large vessels (e.g., carotid arteries) should be considered because of the potential risk of severe bleeding associated with tumor crinkling/necrosis after lenvatinib treatment. Some cases of bleeding are secondary to tumor constriction and fistula formation, such as tracheoesophageal fistulas. Cases of fatal intracranial hemorrhage have been reported in some patients with or without brain metastases. Bleeding from sites other than the brain (e.g., tracheal, intra-abdominal, pulmonary) has also been reported. One fatal case of hemorrhage from a liver tumor has been reported in a patient with HCC.
Screening and subsequent treatment of esophageal vein-like varices in patients with cirrhosis should be performed in accordance with standard therapy prior to initiation of treatment with lenvatinib.
If bleeding occurs, dosing may need to be suspended, adjusted, or discontinued (see [DOSAGE AND ADMINISTRATION])
Gastrointestinal perforation and Gastrointestinal Fistula formation
Gastrointestinal perforation or gastrointestinal fistula has been reported in patients treated with lenvatinib (see [ADVERSE REACTIONS]). Most often, gastrointestinal perforations and gastrointestinal fistulas occur in patients with risk factors, such as prior surgery or radiation therapy. If gastrointestinal perforation or gastrointestinal fistula occurs, it may be necessary to withhold administration, adjust the dose, or discontinue the drug (see [DOSAGE AND ADMINISTRATION]).
Non-gastrointestinal Fistula
The risk of fistula may be increased in patients treated with lenvatinib. Cases of fistula formation or enlargement involving body sites other than the stomach or intestines (eg, tracheal fistula, tracheoesophageal fistula, esophageal fistula, cutaneous fistula, female genital tract fistula) have been observed in clinical trials and postmarketing experience. Prior surgery and radiation therapy may be contributing risk factors. Lenvatinib therapy should not be initiated in patients with fistulae to avoid worsening. Patients with esophageal or tracheobronchial fistula and any grade 4 fistula should permanently discontinue lenvatinib (see [DOSAGE AND ADMINISTRATION]); information on the use of dose suspension or dose reduction to manage other events is limited, but worsening has been observed in some cases and caution should be exercised. As with other drugs in its class, lenvatinib may adversely affect the wound healing process.
Prolonged QTinterval
A higher incidence of QT/QTc interval prolongation has been reported in lenvatinib-treated patients compared with placebo-treated patients (see [Adverse Reactions]). The ECG should be monitored in all patients, with special attention to patients with congenital long QT syndrome, congestive heart failure, slow-acting arrhythmias, and patients receiving drugs known to prolong the QT interval, including class Ia and III antiarrhythmics. If QT interval prolongation is greater than 500 ms, lenvatinib should be withheld. When QTc interval prolongation resolves to ≤480 ms or baseline, lenvatinib therapy should be restarted at a reduced dose.
Electrolyte disturbances (e.g., hypokalemia, hypocalcemia, or hypomagnesemia) can increase the risk of QT interval prolongation and therefore all patients should be monitored and corrected for electrolyte abnormalities prior to initiating therapy. Regular monitoring of electrocardiogram and electrolytes (magnesium, potassium and calcium) should be considered during treatment. Calcium levels should be monitored at least monthly and calcium should be changed as needed during lenvatinib therapy. Lenvatinib dosing should be suspended or dose adjusted as needed based on severity, presence of ECG changes, and persistence of hypocalcemia.
Diarrhea
Diarrhea has been reported frequently in lenvatinib-treated patients, and the event usually occurs early in treatment (see [Adverse Reactions]). Medical management of diarrhea should be performed immediately to prevent dehydration. If grade 4 diarrhea persists despite treatment, lenvatinib should be discontinued.
Impaired thyrotropin suppression/Thyroid dysfunction
Hypothyroidism has been reported in patients treated with lenvatinib (see [Adverse Reactions]). Thyroid function should be monitored prior to initiation of lenvatinib therapy and periodically during therapy. Hypothyroidism should be treated according to standard medical practice to maintain normal thyroid function.
Lenvatinib impairs exogenous thyroid suppression (see [Adverse Reactions]). Thyrotropin (TSH) levels should be monitored regularly and thyroid hormone dosing adjusted to achieve appropriate TSH levels according to the patient’s treatment goals.
Wound healing complications
Formal studies of the effects of lenvatinib on wound healing have not been performed. Delayed wound healing has been reported in patients treated with lenvatinib. Withholding lenvatinib therapy should be considered in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of lenvatinib reintroduction after major surgical procedures. Therefore, the decision to reintroduce lenvatinib after major surgery should be based on clinical judgment of good wound healing.
Embryonic–Fetal Toxicity
Based on its mechanism of action and toxicity data from animal reproduction studies, lenvatinib may cause fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of lenvatinib at doses lower than the recommended clinical dose during organogenesis in rats and rabbits resulted in embryotoxicity, fetal toxicity, and teratogenicity.
Pregnant women should be informed of the potential risk to the fetus. Women of childbearing 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
Studies in patients of races other than Caucasian or Asian and in patients ≥75 years of age are limited. Considering 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 patients (see [Adverse Reactions]).
There are no data on the immediate use of lenvatinib after sorafenib or other anticancer therapies, and there may be a potential risk of cumulative toxicity unless there is an adequate washout period between treatments. The minimum elution period in clinical trials was 4 weeks.
Effects on the ability to drive and operate machinery
Due to side effects (e.g., fatigue and dizziness), lenvatinib has a mild effect on the ability to drive and operate machinery. Patients who experience these symptoms should use caution when driving or operating machines.
[For pregnant and lactating women]
Contraception
Women of childbearing potential should avoid pregnancy and use highly effective contraception during lenvatinib treatment and for at least one month after treatment ends. It is not known whether lenvatinib decreases the effectiveness of hormonal contraceptives, so women using oral hormonal contraceptives should add a barrier method of contraception.
Pregnancy
There are no data on the use of lenvatinib in women during pregnancy. Lenvatinib was embryotoxic and teratogenic when administered in rats and rabbits (see [Pharmacologic Toxicology]).
Lenvatinib should not be used during pregnancy unless clearly necessary and the needs of the mother and the risks to the fetus have been carefully considered.
Lactation
Whether or not lenvatinib is secreted into human milk is not known. Lenvatinib and its metabolites may be secreted into rat milk (see [Pharmacologic Toxicology]). Because risks to the newborn or infant cannot be excluded, lenvatinib is contraindicated during breast-feeding and breast-feeding should not be initiated until one week after discontinuation of the drug. (See [Contraindications]).
Fertility
The role in humans is not known. However, testicular and ovarian toxicity has been observed in rats, dogs, and monkeys (see [Pharmacologic Toxicology]). Fertility may be impaired in fertile males and females.
[Pediatric Use]
There are no clinical data on the use of this product in pediatric or adolescent patients under 18 years of age and it is not recommended.
[Geriatric Use]
No age-based adjustment of starting dose is required. There are limited data from studies on patients aged ≥75 years.
[Drug Interactions]
Effects of other drugs on lenvatinib
Chemotherapy drugs
The combined administration of lenvatinib, carboplatin, and paclitaxel had no significant effect on the pharmacokinetics of any of these 3 drugs.
Effects of lenvatinib on other drugs
There are no data to rule out the risk that this product may be a gastrointestinal CYP3A4 or P-gp inducer. This may result in decreased exposure to oral drugs with CYP3A4/P-gp as the acting substrate and should therefore be fully considered if drugs with CYP3A4/P-gp as the acting substrate are taken concomitantly to ensure efficacy. Therefore, CYP3A4 substrates known to have a narrow therapeutic index (e.g., astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids (ergotamine, dihydroergotamine)) should be used with caution in patients receiving lenvatinib.
Oral contraceptives
It is not known whether lenvatinib decreases the effectiveness of hormonal contraceptives, so women using oral hormonal contraceptives should add a barrier method of contraception (see [Medications for Pregnant and Lactating Women]).
[Drug overdose]
In a phase III clinical trial in hepatocellular carcinoma, a patient experienced vomiting and acute kidney injury with tubular necrosis after an inadvertent dose of 120 mg of lenvatinib.
Two patients took double the dose of lenvatinib in one dose without any adverse events.
Other reports of lenvatinib overdose have involved single administration of 6 to 10 times the recommended daily dose. The adverse reactions that occurred in these cases were consistent with the known safety profile of lenvatinib or did not occur.
Symptoms and Management
For lenvatinib overdose, there is no specific antidote. In cases of suspected overdose, lenvatinib should be discontinued and appropriate supportive therapy should be given as needed.
[Clinical Trials]
The efficacy of lenvatinib was evaluated in a randomized, open, international multicenter clinical study (REFLECT; NCT0761266) in previously untreated patients with unresectable hepatocellular carcinoma (HCC). The study enrolled adult patients with Child-Pugh A and Barcelona Clinic hepatocellular carcinoma (BCLC) stage C or B HCC who could not receive local radical treatment for hepatocellular carcinoma; had an ECOG PS score of 0 or 1; had not received systemic treatment for HCC; and had at least one measurable target lesion according to the mRECISIT criteria.
Patients were randomized 1:1 to receive lenvatinib (12 mg for patients with baseline weight ≥60 kg or 8 mg for patients with baseline weight <60 kg) orally once daily in the study group; patients in the control group received sorafenib 400 mg orally twice daily until disease imaging progression or intolerable adverse effects occurred. Randomization was stratified by region (Western vs Asia-Pacific), presence of visually visible portal infiltration or extrahepatic metastases (yes vs no), ECOG PS (0 vs 1), and body weight (<60 kg vs ≥60 kg). The primary study endpoint was overall survival (OS).The REFLECT study was designed to show the non-inferiority of lenvatinib compared to sorafenib in terms of OS. The secondary study endpoints were progression-free survival (PFS) and objective remission rate (ORR) according to the HCC’s mRECISIT criteria.
A total of 954 patients were randomized, with 478 assigned to the lenvatinib arm and 476 to the sorafenib arm. The demographic characteristics of the study population were: median age 62 years (range: 20 to 88 years); 84% male; 69% Asian and 29% Caucasian; 63% of patients had an ECOG PS score of 0; and 69% of patients weighed ≥60 kg. Of the 590 patients (62%) with at least one distant metastatic lesion, 52% had pulmonary metastases, 45% had lymph node metastases, and 16% had bone metastases.
Seventy-seven percent of patients had visually visible portal infiltration, extrahepatic metastases, or both. 79% of patients were classified as Child-Pugh A and BCLC stage C, and 21% as Child-Pugh A and BCLC stage B. Seventy-five percent of patients had imaging evidence of cirrhosis at enrollment. The main factors associated with the development of HCC recorded by the investigators were hepatitis B (50%), hepatitis C (23%), alcohol consumption (6%), other (7%), and unknown etiology (14%).
Global Data Analysis
Lenvatinib was non-inferior to sorafenib (400 mg twice daily) in terms of OS. Median OS was 13.6 months in the lenvatinib group and 12.3 months in the sorafenib group with HR = 0.92 [95% CI (0.79, 1.06)].
Based on an independent imaging assessment based on mRECIST evaluation, a clinically significant and statistically significant improvement was obtained in the lenvatinib treatment group compared to sorafenib in the secondary endpoints progression-free survival (PFS), time to disease progression (TTP) and objective remission rate (ORR) (P <0.0001). Lenvatinib treatment significantly prolonged PFS and TTP compared to sorafenib treatment, with median PFS and TTP twice that of sorafenib treatment. These efficacy results are summarized in Table 8 and Figure 1.
| Table8: Efficacy results in hepatocellular carcinoma (global) | |||||
| Lenvatinib (N= 478) |
Sorafenib (N= 476) |
||||
| Total Survival | |||||
| 351 (73.4) | 350 (73.5) | ||||
| 13.6 (12.1, 14.9) | 12.3 (10.4, 13.9) | ||||
| 0.92 (0.79,1.06) | |||||
| 7.3 (5.6, 7.5) | 3.6 (3.6, 3.7) | ||||
| 0.64 (0.55, 0.75) | |||||
| <0.00001 | |||||
| Time to disease progression determined by independent imaging assessment (mRECIST)a > | |||||
| Median TTP, months (95% CI)a | 7.4 (7.2, 9.1) | 3.7 (3.6, 3.9) | |||
| 0.60 (0.51, 0.71) | |||||
| <0.00001 | |||||
| Objective remission rate determined by independent imaging assessment (mRECIST) | |||||
| 194 (40.6) | 59 (12.4) | ||||
| (95% CI)e | (36.2, 45.0) | (9.4, 15.4) | |||
| 5.01 (3.59, 7.01) | |||||
| <0.00001 | |||||
| Data cutoff date: November 13, 2016. The non-inferiority cut-off for HR for lenvatinib versus sorafenib was 1.08. Percentages are based on the total number of subjects within the relevant treatment groups in the full analysis set. CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group physical status; HR = hazard ratio; OS = overall survival. a Median was estimated using the Kaplan-Meier method, and 95% CI was estimated using the generalized Brookmeyer and Crowley method. b Calculated the risk ratio for lenvatinib compared with sorafenib based on a Cox model using treatment group as a factor. c Stratified by region (region 1: Asia-Pacific; region 2: Western), visually visible portal infiltration or extrahepatic spread or both (yes, no), ECOG PS (0, 1) and body weight (<60 kg, ≥60 kg). d P values were used for the test of superiority of lenvatinib versus sorafenib. e Asymptotic normal approximation was used to calculate 95% CI. f The Cochran-Mantel-Haenszel method was used to calculate the ratio and P-value (for the test of superiority), stratified by IxRS stratification factors. |
|||||
Figure1 Kaplan-Meier Curve for Overall Survival: Global Population
China subgroup analysis
In the mainland China + Taiwan + Hong Kong (CTH) population, a total of 288 subjects were randomly assigned to receive either lenvatinib (144 subjects) or sorafenib (144 subjects). In the mainland China population, a total of 213 subjects were randomly assigned to receive either lenvatinib (112 subjects) or sorafenib (101 subjects).
Median OS in the CTH population was 15.0 and 10.2 months in the lenvatinib and sorafenib groups, respectively (HR = 0.73, 95% CI 0.55-0.96). In the CTH population, the lenvatinib group significantly prolonged OS compared to the sorafenib group (P = 0.02620). Median OS was 14.7 and 10.5 months in the lenvatinib and sorafenib groups, respectively, in the mainland China population (HR = 0.82, 95% CI 0.59-1.14).
According to an independent imaging assessment evaluated by mRECIST, lenvatinib treatment significantly prolonged PFS compared to sorafenib in the CTH population (median 8.4 vs 3.6 months, HR = 0.47, 95% CI 0.35-0.64, P <0.00001) and the mainland Chinese population (median 9.2 vs 3.6 months, HR = 0.52,95% CI 0.37-0.73, P = 0.00012).
Compared with sorafenib in the CTH population, lenvatinib treatment significantly prolonged TTP (median 9.2 vs 3.6 months, HR = 0.45,95% CI 0.33-0.62, P<0.00001) and the mainland China population (median 9.2 vs 3.7 months, HR = 0.51,95% CI 0.35-0.73, P= 0.00016).
In the CTH population, ORR (CR+PR) was significantly higher with lenvatinib than in the sorafenib group (43.8% vs 13.2%, P<0.00001, including 7 lenvatinib subjects [4.9%] who achieved CR and 2 sorafenib subjects [1.4%] who achieved CR); and the mainland China population (44.6% vs 15.8%, P= 0.00001, including 7 lenvatinib subjects [6.3%] who achieved CR and 2 sorafenib subjects [2.0%] who achieved CR).
| China + Taiwan + Hong Kong | China | |||
| Lenvatinib (N = 144) |
Sorafenib (N = 144) |
Lenvatinib (N = 112) |
Sorafenib (N = 101) |
|
| Median (95% CI)a, months | 15.0 (13.4, 19.5) |
10.2 (8.4, 12.4) |
14.7 (11.4, 19.1) |
10.5 (8.3, 14.4) |
| 0.73 (0.55, 0.96) | 0.82 (0.59, 1.14) | |||
| 0.02620 | ||||
| PFS by independent imaging assessment (mRECIST) | ||||
| Median (95% CI)a, months | 8.4 (7.2, 10.9) |
3.6 (2.2, 3.7) |
9.2 (6.4, 11.0) |
3.6 (2.2, 5.5) |
| 0.47 (0.35, 0.64) | 0.52 (0.37, 0.73) | |||
| <0.00001 | 0.00012 | |||
| TTP for independent imaging assessment (mRECIST) | ||||
| Median (95% CI)a, months | 9.2 (7.4, 11.1) |
3.6 (3.5, 3.7) |
9.2 (7.4, 11.2) |
3.7 (3.6, 5.5) |
| 0.45 (0.33, 0.62) | 0.51 (0.35, 0.73) | |||
| <0.00001 | 0.00016 | |||
| Objective remission rate (CR + PR) on independent imaging assessment (mRECIST), n (%) | 63 (43.8) |
19 (13.2) |
50 (44.6) | 16 (15.8) |
| Ratio (95% CI)d, stratified by stratification factors in IxRS | 5.14 (2.84, 9.31) | 4.23 (2.16, 8.26) | ||
| <0.00001 | 0.00001 | |||
Data cutoff date: November 13, 2016.
Percentages are based on the total number of subjects within the relevant treatment group in the full analysis set.
CI = confidence interval; HR = hazard ratio.
a: Median estimated using Kaplan-Meier method and 95% CI estimated using generalized Brookmeyer and Crowley method.
b: Risk ratio for lenvatinib compared to sorafenib was calculated using treatment group as a factor based on a Cox model. the Efron method was used to treat the nodes.
c: Stratified by visually visible portal infiltration or extrahepatic spread or both (yes, no), ECOG PS (0, 1) and body weight (<60 kg, ≥60 kg).
d: The Cochran-Mantel-Haenszel method was used to calculate the ratio and P values (for superiority testing), stratified by IxRS.
e: for statistical tests that were not prespecified.
Figure2 Kaplan-Meier curves for overall survival: Mainland China + < strong>Taiwan + Hong Kong (CTH population)
In the CTH population, median OS was 14.9 and 9.9 months for patients in the lenvatinib and sorafenib groups with hepatitis B virus as the cause, respectively (HR = 0.72, 95% CI 0.53-0.97); in the mainland China population, median OS was 14.4 and 10.2 months for patients in the lenvatinib and sorafenib groups with hepatitis B virus as the cause, respectively (HR = 0.77. 95% CI 0.54-1.09) (see Table 10).
Table10 China + Taiwan + Hong Kongand overall survival of patients with hepatitis B virus as the cause in mainland China population
| China + Taiwan + Hong Kong | China | |||
| Lenvatinib (N = 123) |
Sorafenib (N = 119) |
Lenvatinib (N = 101) |
Sorafenib (N = 87) |
|
| 14.9 (12.0, 19.5) |
9.9 (8.2, 12.4) |
14.4 (10.9, 18.0) |
10.2 (7.5, 12.5) |
|
| 0.72 (0.53, 0.97) | 0.77 (0.54, 1.09) | |||
Data cutoff date: November 13, 2016.
CI = confidence interval; HR = risk ratio.
a: Median estimated using Kaplan-Meier method and 95% CI estimated using generalized Brookmeyer and Crowley method.
b: Risk ratio for lenvatinib compared to sorafenib based on Cox model with treatment group as a factor. efron method was used to treat nodes.
c: Stratified by visually visible portal infiltration or extrahepatic spread or both (yes, no), ECOG PS (0, 1), and body weight (<60 kg, ≥60 kg).
Pharmacology
Lenvatinib is a tyrosine kinase (RTK) receptor inhibitor that inhibits the kinase activity of the vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to other pro-angiogenic and tumorigenic pathway-related RTKs, including the fibroblast growth factor (FGF) The combination of lenvatinib and everolimus inhibited human endothelial cell proliferation, angiogenesis, and the VEGF signaling pathway in vitro and reduced tumor volume in vivo in human renal cell carcinoma-bearing mice, and the anti-angiogenic and anti-tumor activity of the combination was greater than that of single-agent use.
Toxicological studies
GenotoxicityThe results of the Ames test for lenvatinib mesylate, the mouse lymphoma test, and the in vivo rat micronucleus test were all negative.
Reproductive ToxicityFertility studies were not performed with lenvatinib, but repeated dosing toxicity studies in rats, monkeys, and dogs showed potential effects on fertility, with low testicular spermatogenic epithelial cell counts and shedding of spermatogenic epithelial cells in the epididymis seen in male dogs when lenvatinib exposure was approximately 0.02 to 0.09 times the recommended human dose exposure. Ovarian follicular atresia was observed in monkeys and rats when the exposure (AUC) of lenvatinib was 0.2-0.8 times and 10-44 times of the clinically used dose (24 mg), respectively. Reduced menstrual frequency was seen in monkeys when lenvatinib exposure was lower than the clinical dose (24 mg) exposure.
Embryonic/Fetal Developmental Toxicity Study: Oral administration of lenvatinib at doses below the recommended human dose during organogenesis in rats and rabbits caused embryotoxicity, fetal toxicity and teratogenic effects. In pregnant rats, oral administration of lenvatinib mesylate ≧ 0.3 mg/kg per day (approximately 0.14 times the recommended human dose based on body surface area) during the organogenesis period resulted in dose-related fetal weight loss, delayed ossification, fetal appearance (cranial top edema and caudal malformation), and skeletal and visceral abnormalities. Lenvatinib mesylate 1.0 mg/kg/day (approximately 0.5 times the recommended human dose based on body surface area) was seen as a post-arrival loss rate of ≧ 80%. In pregnant rabbits given orally during the organogenesis period, lenvatinib mesylate ≧ 0.03 mg/kg/day (approximately 0.03 times the human dose of 24 mg based on body surface area), abnormalities in fetal appearance (short tail), internal organs (posterior subclavian artery of the esophagus) and bone were seen. Lenvatinib mesylate 0.03 mg/kg/day caused an increased rate of post-arrival loss, including the death of one fetus. Lenvatinib 0.5 mg/kg/day (approximately 0.5 times the human dose of 24 mg based on body surface area) caused abortion in rabbits and caused late abortion in approximately 1/3 of pregnant rabbits.
Lenvatinib and its metabolites can be secreted into the milk of rats. In lactating SD rats given radiolabeled lenvatinib orally, the radioactivity associated with lenvatinib in breast milk was approximately twice that in maternal plasma.
Toxicity in Juvenile AnimalsDaily oral administration of lenvatinib mesylate at a dose ≥2 mg/kg (approximately 1.2 to 5 times the recommended human dose AUC) for 8 weeks in juvenile rats at 21 days postnatally (approximately 2 years of age in humans) caused delayed growth (decreased body weight gain, food intake, width and/or length of femur and tibia), secondary delay in physical development, and immaturity of reproductive organs. The reduction in femur and tibia length persisted after a 4-week recovery period. Although toxicity in juvenile rats occurred at earlier time points of administration (including tooth damage seen at all doses and death due to primary duodenal injury at 10 mg/kg/day), juvenile rats had a similar toxicity profile to adult rats.
Carcinogenicity
No carcinogenicity studies were performed with lenvatinib.
[Pharmacokinetics]
Pharmacokinetic parameters of lenvatinib have been studied in healthy adult subjects as well as in adult subjects with hepatic insufficiency, renal insufficiency, and solid tumors.
Absorption
After oral administration, lenvatinib is rapidly absorbed, with tmax typically observed 1 to 4 hours after dosing. Food does not affect the degree of absorption, but can slow it down. When given with food, peak plasma concentrations were delayed by 2 hours in healthy subjects. Absolute bioavailability in humans has not been determined; however, data from material balance studies suggest it is approximately 85%. Lenvatinib exhibited good bioavailability for oral administration in dogs (70.4%) and monkeys (78.4%).
Distribution
In vitro binding of lenvatinib to human plasma proteins is high, ranging from 98% – 99% (0.3 – 30 μg/mL, methanesulfonate). It binds primarily to albumin, with mild binding to α1-acidic glycoprotein and γ-globulin.
In vitro, the range of lenvatinib blood-plasma concentration ratios is 0.589 – 0.608 (0.1 – 10 μg/mL, methanesulfonate).
Lenvatinib is a substrate for P-gp and BCRP. Lenvatinib is not a substrate for OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2-K, or bile salt export pump (BSEP).
In patients, the median apparent volume of distribution (Vz/F) for the first dose ranged from 50.5 L to 92 L and was essentially consistent in the 3.2 mg to 32 mg dose group. Similar median steady-state apparent volume of distribution (Vz/Fss) was also generally consistent, ranging from 43.2 L to 121 L.
Biotransformation Cytochrome P450 3A4 was confirmed in in vitro studies to be the major (>80%) isoform involved in P450-mediated lenvatinib metabolism. However, in vivo data suggest that non-P450-mediated pathways contribute a large portion of the overall metabolism of lenvatinib. Therefore, in vivo, inducers and inhibitors of CYP 3A4 have a slight effect on lenvatinib exposure (see [Drug Interactions]).
In human liver microsomes, the demethylated form of lenvatinib (M2) is the major metabolite. The major metabolites in human feces are M2′ and M3′, formed from M2 and lenvatinib, respectively, in the presence of aldehyde oxidase.
In plasma samples collected within 24 hours of dosing, lenvatinib accounted for 97% of the radioactivity in the plasma radiochromatogram, while the M2 metabolite accounted for an additional 2.5%. Based on the AUC(0-inf), lenvatinib accounted for 60% and 64% of the total radioactivity in plasma and blood, respectively.
Data from human material balance/excretion studies suggest that lenvatinib is extensively metabolized in humans. The main metabolic pathways identified in humans are oxidation by aldehyde oxidase, demethylation by CYP3A4, elimination of partial binding of glutathione to O-aryl (chlorophenyl group), and co-existence of these three pathways followed by further biotransformation (e.g. glucuronidation, partial hydrolysis of glutathione, partial degradation of cysteine, intramolecular rearrangement of cysteinylglycine, and cysteine with subsequent dimer binding). These in vivo metabolic pathways are consistent with the data provided in in vitro studies using human biomaterials.
In Vitro Transfer Protein Studies
For the following transporter proteins, OAT1, OAT3, OATP1B1, OCT1, OCT2, and BSEP, no clinical inhibition was found based on cutoff values IC50> 50´ Cmaxunbound,.
Lenvatinib showed slight or no inhibition of P-gp-mediated as well as breast cancer resistance protein (BCRP)-mediated transport. Similarly, no induction of P-gp mRNA expression was observed.
Lenvatinib exhibited slight inhibition or no inhibition of OATP1B3 and MATE2-K. MATE1 was weakly inhibited by lenvatinib. In human liver cytosol, lenvatinib did not inhibit aldehyde oxidase activity.
Elimination
After administration of radiolabeled lenvatinib to six patients with solid tumors, approximately 2/3 and 1/4 of the radiolabel was eliminated in the feces and urine, respectively. M3 metabolites were the predominant form in the excretion (~17% of the dose), followed by M2′ (~11% of the dose) and M2 (~4.4% of the dose).
Linear/Nonlinear
Dose Proportionality andaccumulationproduct
In patients with solid tumors receiving single- and multiple-dose once-daily lenvatinib administration, lenvatinib exposure (Cmax and AUC) increased proportionally with increasing dose (3.2 to 32 mg once-daily).
The product accumulates slightly in vivo at steady state and beyond this range, with a median accumulation index (Rac) ranging from 0.96 (20 mg) to 1.54 (6.4 mg).
Special Populations
Hepatic Insufficiency
The pharmacokinetics of lenvatinib after a single 10 mg dose was evaluated in six subjects with mild and moderate hepatic insufficiency (Child-Pugh A and Child-Pugh B, respectively). The pharmacokinetics of the 5 mg dose were evaluated in 6 subjects with severe hepatic insufficiency (Child-Pugh C). 8 healthy, demographically matched subjects served as controls and received the 10 mg dose.
In subjects with mild, moderate, and severe hepatic insufficiency, lenvatinib exposure (based on dose-corrected AUC0-t and AUC0-inf data) was 119%, 107%, and 180% of that in normal subjects, respectively. The presence of changes in plasma protein binding in subjects with hepatic insufficiency has not been studied. For dosing recommendations, see [DOSAGE].
There are no adequate data on moderate hepatic insufficiency (Child-Pugh B) (only 3 patients) and no available data in patients with severe hepatic insufficiency (Child Pugh C) HCC. Lenvatinib is primarily eliminated by the liver, and exposure may be increased in this patient population.
In subjects with mild, moderate and severe hepatic insufficiency and normal liver function, the median half-life was similar, ranging from 26 hours to 31 hours. The percentage of lenvatinib dose excreted into the urine was low in all treatment groups (<2.16% in all treatment groups)
Renal insufficiency
The pharmacokinetics of lenvatinib after a single 24 mg dose were evaluated in 6 subjects with mild, moderate, and severe renal insufficiency, and 8 healthy, demographically matched subjects served as controls. Subjects with end-stage renal disease were not studied.
In subjects with mild, moderate, and severe renal insufficiency, lenvatinib exposure (based on AUC0-inf data) was 101%, 90%, and 122% of that in normal subjects, respectively. The presence of changes in plasma protein binding in subjects with renal insufficiency has not been studied. For dosing recommendations, see [DOSAGE].
Age, Sex, Weight, and Ethnicity
Based on population pharmacokinetic analysis of patients receiving up to 24 mg lenvatinib once daily, age, sex, weight, and ethnicity (Japanese vs. other, Caucasian vs. other) had no significant effect on clearance (see [DOSAGE]).
PediatricPatients
Pediatric patients have not been studied.
[Storage]
Store at no more than 30°C.
[Packaging]
Double aluminum blister pack, 10 capsules x 3 plates/box
[Expiration date]
48 months
[Executive Standard]
[Approval Number]
[Manufacturer]
Company name: Eisai Europe Ltd.
Address: European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, United Kingdom
Production Plant: Patheon Inc.
Address: 2100 Syntex Court, Mississauga, Ontario L5N 7K9, Canada.
Packing House: Eisai Manufacturing Limited
Address: European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, United Kingdom
Domestic Contact.
Company Name: Eisai (China) Pharmaceutical Co.
Address: No. 168 Xingpu Road, Suzhou Industrial Park
Customer Service Hotline: 021-62881220