新型口服抗癌药LENVIMA(LENVATINIB MESYLATE)CAPSULE ORAL与依维莫司联合治疗方案，为治疗肾细胞癌的突破性药物
近日，FDA批准Lenvima（lenvatinib）联合Afinitor（everolimus 依维莫司）治疗之前接受过anti-VEGF疗法的晚期肾细胞癌（RCC）。lenvatinib+依维莫斯是目前唯一一个相比标准疗法可以显着延长这类患者无进展生存期（PFS）的组合疗法。
批准日期：2016年8月  公司：卫材 Eisai Inc
LENVIMA（乐伐替尼 lenvatinib）胶囊，用于口服使用
美国初步审批：2015年
近期主要变化
适应症和用法，肾细胞癌  05/2016
剂量和管理  05/2016
警告和注意事项  05/2016
作用机制
Lenvatinib是抑制血管内皮生长因子（VEGF）受体VEGFR1（FLT1），VEGFR2（KDR）和VEGFR3（FLT4）的激酶活性的受体酪氨酸激酶（RTK）抑制剂。 除了它们的正常细胞功能，包括成纤维细胞生长因子（FGF）受体FGFR1,2,3和4，Lenvatinib还抑制已经涉及病原性血管生成，肿瘤生长和癌症进展的其它RTK; 血小板衍生生长因子受体α（PDGFRα），KIT和RET。 Lenvatinib和依维莫司的组合显示增加的抗血管生成和抗肿瘤活性，如通过减少的人内皮细胞增殖，管形成和VEGF信号传导体外和肿瘤体积在小鼠异种移植模型中的人肾细胞癌大于每种药物单独。
适应症和用法
LENVIMA是一种激酶抑制剂，适用于：
分化型甲状腺癌（DTC）：用于局部复发性或转移性，进行性，放射性碘 - 难治性DTC的患者的单一药剂。
肾细胞癌（RCC）：与依维莫司组合，用于先前抗血管生成治疗的晚期RCC患者。
剂量和给药
推荐剂量（DTC）：24mg口服，每日一次。
推荐剂量（RCC）：18mg LENVIMA+5mg依维莫司，口服，每日一次。
管理说明。
DTC和RCC的剂量修改。
在患有严重肾或肝损伤的患者中，剂量为14mg，每日一次，在DTC中，10mg，每日一次，在RCC中。
剂量形式和强度
胶囊：4mg和10mg。
禁忌症
没有。
警告和注意事项
高血压：用LENVIMA治疗前控制血压。尽管进行了最佳的抗高血压治疗，但仍保留了3级高血压的LENVIMA。停止危及生命的高血压。
心力衰竭：监测临床症状或心脏代偿失调的征兆。LENVIMA 3级心功能不全。停止4级心功能不全。
动脉血栓栓塞事件：在动脉血栓栓塞事件后停止LENVIMA。
肝毒性：在开始LENVIMA之前和在治疗期间定期监测肝功能测试。
LENVIMA 3级或更大的肝功能损害。停止肝衰竭。
蛋白尿：在用LENVIMA治疗开始和周期性监测蛋白尿。扣留LENVIMA≥2克蛋白尿24小时。停止肾病综合征。
腹泻：可能严重和复发。使用标准的抗腹泻治疗。拒绝LENVIMA 3级和停止4级腹泻。
肾衰竭和损伤：LENVIMA 3或4级肾功能衰竭/损伤。
胃肠穿孔和瘘形成：停止LENVIMA在发展胃肠穿孔或危及生命的瘘的患者。
QT间期延长：监测和纠正所有患者的电解质异常。扣留LENVIMA用于开发3级或更大的QT间期延长。
低钙血症：至少每月监测血钙水平，必要时更换钙。
可逆后脑白质病综合征（RPLS）：保留LENVIMA用于RPLS直到完全消退。
出血事件：禁止LENVIMA 3级出血。停止4级出血。
甲状腺刺激激素抑制/甲状腺功能障碍的损伤：每月监测TSH水平，并根据需要使用甲状腺替代药物。
胚胎毒性：可引起胎儿伤害。对胎儿的潜在风险的建议和使用有效的避孕。
不良反应
在DTC中，LENVIMA最常见的不良反应（发生率大于或等于30％）是高血压，疲劳，腹泻，关节痛/肌痛，食欲降低，体重下降，恶心，口腔炎，头痛，呕吐，蛋白尿，红斑感觉综合征，腹痛和发音困难。
在RCC中，LENVIMA+依维莫司最常见的不良反应（大于30％）是腹泻，疲劳，关节痛/肌痛，食欲下降，呕吐，恶心，口腔炎/口腔炎症，高血压，外周水肿，咳嗽，腹痛，呼吸困难，皮疹，体重下降，出血事件和蛋白尿。
在特定人群中使用
哺乳：停止母乳喂养。
完整处方资料附：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f4bedd21-efde-44c6-9d9c-b48b78d7ed1e
LENVIMA(lenvatinib capsules)
FDA approved: Yes (First approved February 13th, 2015)
Brand name: Lenvima
Generic name: lenvatinib
Company: Eisai Inc.
Treatment for: Thyroid Cancer, Renal Cell Carcinoma
Lenvima (lenvatinib) is an oral multiple receptor tyrosine kinase (RTK) inhibitor for the treatment of progressive radioiodine-refractory differentiated thyroid cancer and advanced renal cell carcinoma.
Important Safety Information
Warnings and Precautions
In DTC, hypertension was reported in 73% of patients on LENVIMA vs 16% with placebo (44% vs 4% grade ≥3). In RCC, hypertension was reported in 42% of patients on LENVIMA + everolimus vs 10% with everolimus alone (13% vs 2% grade 3). Blood pressure should be controlled prior to treatment and monitored throughout. Withhold dose for grade 3 hypertension despite optimal antihypertensive therapy; resume at reduced dose when controlled at grade ≤2. Discontinue for life-threatening hypertension
In DTC, cardiac dysfunction was reported in 7% of patients on LENVIMA vs 2% with placebo (2% vs 0% grade ≥3). In RCC, cardiac dysfunction was reported in 10% of patients on LENVIMA + everolimus vs 6% with everolimus alone (3% vs 2% grade 3). Monitor for signs/symptoms of cardiac decompensation. Withhold for grade 3 cardiac dysfunction. Resume at reduced dose or discontinue based on severity and persistence of cardiac dysfunction. Discontinue for grade 4 cardiac dysfunction
In DTC, arterial thromboembolic events were reported in 5% of patients on LENVIMA vs 2% with placebo (3% vs 1% grade ≥3). In RCC, arterial thromboembolic events were reported in 2% of patients on LENVIMA + everolimus vs 6% with everolimus alone (2% vs 4% grade ≥3). Discontinue following an arterial thrombotic event. The safety of resuming LENVIMA after an arterial thromboembolic event has not been established, and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months
Across clinical studies in which 1,160 patients received LENVIMA monotherapy, hepatic failure (including fatal events) was reported in 3 patients and acute hepatitis in 1 patient. In DTC, ALT and AST increases (grade ≥3) occurred in 4% and 5% of patients on LENVIMA, respectively, vs 0% with placebo. In RCC, ALT and AST increases (grade ≥3) occurred in 3% of patients on LENVIMA + everolimus vs 2% and 0% with everolimus alone, respectively. Monitor liver function before initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Withhold dose for liver impairment grade ≥3 until resolved to grade 0, 1, or baseline. Resume at reduced dose or discontinue based on severity/persistence of hepatotoxicity. Discontinue for hepatic failure
In DTC, proteinuria was reported in 34% of patients on LENVIMA vs 3% with placebo (11% vs 0% grade 3). In RCC, proteinuria was reported in 31% of patients on LENVIMA + everolimus vs 14% with everolimus alone (8% vs 2% grade 3). Monitor for proteinuria before and during treatment. Withhold dose for proteinuria ≥2 g/24 h. Resume at reduced dose when proteinuria is <2 g/24 h. Discontinue for nephrotic syndrome
In RCC, diarrhea was reported in 81% of patients on LENVIMA + everolimus vs 34% with everolimus alone (19% vs 2% grade ≥3). Initiate prompt medical management for the development of diarrhea. Monitor for dehydration. Withhold dose for diarrhea grade ≥3. Resume at a reduced dose when diarrhea resolves to grade 1 or baseline. Discontinue for grade 4 diarrhea despite medical management
In DTC, events of renal impairment were reported in 14% of patients on LENVIMA vs 2% with placebo (3% vs 1% grade ≥3). In RCC, events of renal impairment were reported in 18% of patients on LENVIMA + everolimus vs 12% with everolimus alone (10% vs 2% grade ≥3). Withhold LENVIMA for grade 3 or 4 renal failure/impairment. Resume at reduced dose or discontinue, depending on severity/persistence of renal impairment. Active management of diarrhea and any other gastrointestinal (GI) symptoms should be initiated for grade 1 events
In DTC, events of GI perforation or fistula were reported in 2% of patients on LENVIMA vs 0.8% with placebo. In RCC, events of GI perforation, abscess, or fistula (grade ≥3) were reported in 2% of patients on LENVIMA + everolimus vs 0% with everolimus alone. Discontinue in patients who develop GI perforation or life-threatening fistula
In DTC, QT/QTc interval prolongation was reported in 9% of patients on LENVIMA vs 2% with placebo (2% vs 0% >500 ms). In RCC, QTc interval increases >60 ms were reported in 11% of patients on LENVIMA + everolimus (6% >500 ms) vs 0% with everolimus alone. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or patients taking drugs known to prolong the QT interval. Monitor and correct electrolyte abnormalities in all patients. Withhold dose for QTc interval prolongation >500 ms. Resume at reduced dose when QTc prolongation resolves to baseline
In DTC, hypocalcemia (grade ≥3) was reported in 9% of patients on LENVIMA vs 2% with placebo. In RCC, hypocalcemia (grade ≥3) was reported in 6% of patients on LENVIMA + everolimus vs 2% with everolimus alone. Monitor blood calcium levels at least monthly and replace calcium as necessary. Interrupt and adjust LENVIMA as necessary
Across clinical studies in which 1,160 patients received LENVIMA monotherapy, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 4 patients. Withhold LENVIMA for RPLS until fully resolved. Resume at reduced dose or discontinue based on the severity and persistence of neurologic symptoms
In DTC, hemorrhagic events occurred in 35% of patients on LENVIMA vs 18% with placebo (2% vs 3% grade ≥3). The most frequently reported hemorrhagic event was epistaxis (11% grade 1, 1% grade 2). Discontinuation due to hemorrhagic events occurred in 1% of patients on LENVIMA. There was 1 fatal intracranial hemorrhage case among 16 patients who received LENVIMA and had central nervous system metastases at baseline. In RCC, hemorrhagic events occurred in 34% of patients on LENVIMA + everolimus vs 26% with everolimus alone (8% vs 2% grade ≥3). The most frequently reported hemorrhagic event was epistaxis (23% for LENVIMA + everolimus vs 24% with everolimus alone). There was 1 fatal cerebral hemorrhage case. Discontinuation due to hemorrhagic events occurred in 3% of patients on LENVIMA + everolimus. Consider the risk of severe or fatal hemorrhage associated with tumor invasion/infiltration of major blood vessels (eg, carotid artery). Withhold dose for grade 3 hemorrhage. Resume at reduced dose or discontinue based on severity/persistence of hemorrhage. Discontinue for grade 4 hemorrhage
In DTC patients with normal baseline thyroid-stimulating hormone (TSH), elevation of TSH level above 0.5 mU/L was observed postbaseline in 57% of patients on LENVIMA vs 14% with placebo. In RCC, grade 1 or 2 hypothyroidism occurred in 24% of patients on LENVIMA + everolimus vs 2% with everolimus alone. In RCC patients with normal or low TSH at baseline, elevation of TSH was observed postbaseline in 60% of patients on LENVIMA + everolimus vs 3% with everolimus alone. Monitor thyroid function prior to treatment initiation and monthly thereafter. Treat hypothyroidism according to standard medical practice to maintain a euthyroid state
LENVIMA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy
Adverse Reactions
In DTC, the most common adverse reactions observed in LENVIMA-treated patients vs placebo-treated patients were hypertension (73% vs 16%), fatigue (67% vs 35%), diarrhea (67% vs 17%), arthralgia/myalgia (62% vs 28%), decreased appetite (54% vs 18%), weight decrease (51% vs 15%), nausea (47% vs 25%), stomatitis (41% vs 8%), headache (38% vs 11%), vomiting (36% vs 15%), proteinuria (34% vs 3%), palmar-plantar erythrodysesthesia syndrome (32% vs 1%), abdominal pain (31% vs 11%), and dysphonia (31% vs 5%)
In DTC, adverse reactions led to dose reductions in 68% of patients receiving LENVIMA and in 5% of patients receiving placebo; 18% of patients discontinued LENVIMA and 5% discontinued placebo for adverse reactions. The most common adverse reactions (≥10%) resulting in dose reductions of LENVIMA were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%)
In RCC, the most common adverse reactions observed in patients treated with LENVIMA + everolimus vs everolimus alone were diarrhea (81% vs 34%), fatigue (73% vs 40%), arthralgia/myalgia (55% vs 32%), decreased appetite (53% vs 18%), vomiting (48% vs 12%), nausea (45% vs 16%), stomatitis/oral inflammation (44% vs 50%), hypertension/increased blood pressure (42% vs 10%), peripheral edema (42% vs 20%), cough (37% vs 30%), abdominal pain (37% vs 8%), dyspnea/exertional dyspnea (35% vs 28%), rash (35% vs 40%), weight decreased (34% vs 8%), hemorrhagic events (32% vs 26%), and proteinuria/urine protein present (31% vs 14%)
In RCC, adverse reactions led to dose reductions or interruption in 89% of patients receiving LENVIMA + everolimus and in 54% of patients receiving everolimus. The most common adverse reactions (≥5%) resulting in dose reductions in the LENVIMA + everolimus–treated group were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients in the LENVIMA + everolimus–treated group and in 12% of patients in the everolimus-treated group
Use in Specific Populations
Because of the potential for serious adverse reactions in nursing infants, advise women to discontinue breastfeeding during treatment
LENVIMA may result in reduced fertility in females of reproductive potential and may result in damage to male reproductive tissues, leading to reduced fertility of unknown duration
完整使用资料附件：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3850cce2-6137-42e5-a792-d318c4a4b3b5