等待内容更新

  文案整理：Dr. Jasmine Ding

 

 

乐伐替尼使用说明书

美国FDA首次批准：2015

请仔细阅读说明书并在医师指导下使用

 

【药品名称】 

通用名称：乐伐替尼 

商品名称：LENVIMA

英文名称：Lenvatinib Mesilate

其他名称：7080

 

【成份】 

本品主要成份为乐伐替尼

化学名称为4- [3氯-4-（N'-环丙基脲基）苯氧基] -7-甲氧基喹啉-6-甲酰胺甲磺酸。 

分子式为C21H19ClN4O4·CH4O3S

分子量为522.96

 

 

[规格型号]

胶囊：4mg和10mg.

4mg为硬质羟丙甲纤维素胶囊，带有黄红色身体和黄红色的帽子，帽子上印有黑色的“Є”，身上印有“LENV4mg”。 

10mg为硬质羟丙甲醚胶囊,带有黄色身体和黄红色帽子，帽子上印有黑色的“Є“，身上印有“LENV 10 mg”。 

 

【适应证/功能主治】
LENVIMA是一种激酶抑制剂，适用与有局部地复发或转移，进展性，放射性碘-难治性分化型甲状腺癌患者的治疗。 

 

2016年5月13日，FDA批准Lenvatinib（乐伐替尼）联合Everolimus（依维莫司）治疗既往接受抗血管生成治疗的晚期肾细胞癌。比如多吉美或索坦耐药后，可以尝试乐伐替尼联合依维莫司这样的治疗方案。 

【剂量和给药方法】
⑴ 推荐剂量：24mg口服，每天一次。继续LENVIMA直到疾病进展或直到不可接受的毒性发生。
⑵ 在有严重肾或肝受损患者，剂量是14mg每天一次。 

 

 

储存于25°C（77°F）; 游览时间可达15-30°C（59-86°F） 

 

【禁忌证】
无。 

 

【警告和注意事项】
⑴ 高血压：用LENVIMA治疗前控制血压。对尽管优化高血压治疗的3级高血压不给LENVIMA。对危及生命高血压终止药物。
⑵ 心力衰竭：监视心脏代偿失调的临床症状和体征。对3级不给LENVIMA心功能不全。对4级心功能不全终止药物。
⑶ 动脉血栓栓塞事件：一次动脉血栓栓塞事件后终止LENVIMA。
⑷ 肝毒性: LENVIMA开始前和治疗自始至终定期地监视肝功能检验. 对3级或更大肝受损不给LENVIMA。对肝衰竭终止治疗(5.4)。
⑸ 蛋白尿：用LENVIMA开始治疗前，和自始至终定期地，监视蛋白尿。对24小时尿蛋白≥2克不给LENVIMA。对肾病综合征终止用药。
⑹ 肾衰竭和肾受损： 对3或4级肾衰竭/受损不给LENVIMA。
⑺ 胃肠道穿孔和瘘管形成：发生胃肠道穿孔或危及生命瘘管患者中终止LENVIMA。
⑻ QT间期延长：在所有患者中监视和纠正电解质异常。对发生3级或更大QT间期延长不给LENVIMA
⑼ 低钙血症：监视血钙水平至少每月和需要时给予替代钙。
⑽ 可逆性后部白质脑病综合征(RPLS)：对RPLS不给LENVIMA直至完全解决。
⑾ 出血事件：对3级出血不给LENVIMA。对4级出血终止治疗。
⑿ 甲状腺刺激激素抑制的受损：每月监视TSH水平和有DTC患者需要时调整甲状腺取代药物。
⒀ 胚胎胎儿毒性：可能致胎儿危害。忠告对胎儿潜在风险和使用有效避孕。 

【不良反应】 

 

1、在甲状腺癌患者治疗中 

 

最常见的不良反应(发生率大于或等于30%)为高血压，疲劳，腹泻，关节痛肌痛，食欲下降，体重下降，恶心，口腔炎，头痛，呕吐，蛋白尿，手足综合症，腹部疼痛，发音困难。 

 

 

2、在肾癌患者治疗中 

 

最常见的不良反应(大于30%)为腹泻，疲劳，关节痛肌痛，食欲不振，呕吐，恶心，口腔炎口腔炎症，高血压，外周水肿，咳嗽，腹痛，呼吸困难降低，皮疹，体重明显下降，出血事件，蛋白尿。 

 

3、在肝癌患者治疗中 

最常见的不良反应(发生率大于或等于30%)为高血压，疲劳，腹泻，关节痛肌痛，食欲下降，体重下降，恶心，口腔炎，头痛，呕吐，手足综合症，腹部疼痛，发音困难。 

 

 

特殊人群中使用

 

【孕妇及哺乳期妇女用药】

妊娠期使用：基于乐伐替尼胶囊的作用机制，妊娠妇女服用可能会给胎儿带来伤害。目前尚无妊娠妇女服用乐伐 替尼胶囊足够的临床数据。要警告孕妇对胎儿潜在的风险。 

哺乳期使用：乐伐替尼在人乳汁中的分泌数据不详。但在哺乳的大鼠乳汁中有分泌，所以建议在接受乐伐替尼治疗期间，应停止母乳喂养。

 

【儿童用药】
目前尚无乐伐替尼用于儿童患者的安全性与疗效的资料。 

 

【老年用药】

老年人用药安全性与有效性方面与年轻患者无显著差异。

 

【药理作用】

 

Lenvatinib是一种受体酪氨酸激酶(RTK)抑制剂，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。Lenvatinib还抑制涉及到病理性血管生成，肿瘤生长，和癌症进展的其他RTKS，包括纤维母细胞生长因子(FGF)受体FGFR1，2，3，和4；血小板衍生生长因子受体α (PDGFRα)，KIT，和RET。 

 

[药代动力学]  

 

吸收：口服LENVIMA后，通常在给药后1至4小时达到峰值血浆浓度（Tmax）。食物不影响吸收程度，但吸收速率降低，将中位数Tmax从2小时延迟至4小时。在实体瘤患者每天服用一次和多次剂量的LENVIMA后，最大血浆浓度（Cmax）和浓度 - 时间曲线下面积（AUC）在3.2至32 mg的剂量范围内成比例增加，中位数累积指数为0.96（20mg）至1.54（6.4mg）。 

 

分布：lenvatinib与人血浆蛋白的体外结合范围为98％〜99％（0.3〜30μg/ mL）。在体外，lenvatinib血 - 血浆浓度比范围为0.589至0.608（0.1-10μg/ mL）。基于体外数据，lenvatinib是P-gp和BCRP的底物，但不是有机阴离子转运蛋白（OAT）1，OAT3，有机阴离子转运多肽（OATP）1B1，OATP1B3，有机阳离子转运蛋白（OCT）1， OCT2或胆汁盐出口泵（BSEP）。 

 

请除：等离子体浓度在Cmax之后呈双指数下降。 lenvatinib的终末消除半衰期约为28小时。 

 

代谢：CYP3A是lenvatinib的主要代谢酶之一。人体中lenvatinib的主要代谢途径被鉴定为酶（CYP3A和醛氧化酶）和非酶过程。 

 

排泄：在6例实体瘤患者单次给予放射性标记的lenvatinib后10天，分别在粪便和尿液中排除了约64％和25％的放射性标记物。 

 

特殊人群：

 

肾损伤在轻度（CLcr 60-89mL / min），中度（CLcr 30-59mL / min）和严重（CLcr< 30mL / min）的受试者中，评估单一24mg剂量后的lenvatinib的药代动力学）肾损伤，并与健康受试者比较。终末期肾病患者未做研究。 

在单次24mg口服LENVIMA剂量后，与健康受试者相比，肾损伤受试者的AUC0-inf相似。 

 

肝损伤在轻度（Child Pugh A）和中度（Child Pugh B）肝损伤的受试者中评估了单一10mg剂量的LENVIMA后，lenvatinib的药代动力学。在具有严重（Child Pugh C）肝损伤的受试者中评估单次5mg剂量的药代动力学。与肝功能正常的受试者相比，轻度，中度和重度肝损伤受试者的lenvatinib剂量调整AUC0-inf分别为119％，107％和180％[参见剂量和给药（2.1），使用在特定人口（8.7）]。 

 

年龄，性别和种族的影响根据人群PK分析，年龄，性别和种族对lenvatinib的明显清除率（Cl / F）没有显著影响。 

 

【药物相互作用】

研究其他药物对Lenvatinib CYP3A，P-gp和BCRP抑制剂的影响： 

酮康唑（400mg，18天）增加了lenvatinib（在第5天作为单一剂量施用），AUC为15％，C max为19％专门临床试验。 P-gp抑制剂：在专门的临床试验中，利福平（600mg作为单一剂量）增加了lenvatinib（24mg作为单次剂量）AUC 31％，C max降低33％。 

CYP3A和P-gp诱导剂：在专门的临床试验中，利福平（每天600 mg，持续21天）降低了lenvatinib（第15天施用的单次24 mg）AUC 18％。 Cmax不变。 

 

Lenvatinib对其他药物的影响CYP3A4或CYP2C8底物： 

联合维拉滨和咪达唑仑（CYP3A4底物）或瑞格列奈（CYP2C8底物）之间没有显着的药物 - 药物相互作用风险。 

 CYP2C8，CYP2B6，CYP2C9，CYP2C19，CYP2D6和CYP3A的体外研究，Lenvatinib抑制CYP2C8，CYP2A2，CYP2C6，CYP2D6和CYP3A的表达，但不影响安非他酮暴露的增加。 

Lenvatinib不抑制CYP2A6和CYP2E1。 Lenvatinib诱导CYP3A，但是不太可能会影响效力的氯芬太尼暴露下降。 Lenvatinib不诱导CYP1A1，CYP1A2，CYP2B6和CYP2C9。伦伐他汀直接抑制UGT1A1和UGT1A4。这一发现的临床意义是未知的。 

伦伐他汀对UGT1A6，UGT1A9，UGT2B7或醛氧化酶的抑制作用很小或没有抑制作用。伦伐他汀不诱导UGT1A1，UGT1A4，UGT1A6，UGT1A9或UGT2B7。 

药物转运系统底物的体外研究：Lenvatinib抑制OAT1，OAT3，OCT1，OCT2，OATP1B1和BSEP。这一发现的临床意义是未知的。 Lenvatinib对OATP1B3显示很少或没有抑制作用。 

 

 

非毒性毒理学

致癌，诱变，生育力减，退致癌性研究尚未在人体进行。

在体外细菌反向突变（Ames）测定中Lenvatinib未导致突变。在体外小鼠淋巴瘤胸苷激酶测定或体内大鼠微核试验中，Lenvatinib未导致突变。在动物中没有进行具体的lenvatinib研究来评估对生育力的影响; 然而，在大鼠，猴子和狗的一般毒理学研究的结果表明，Lenvatinib有可能削弱生育力。在推荐的人剂量下，雄性狗在附睾药物中在露那巴利暴露下显示出临床暴露约0.02至0.09倍的附睾发生的上皮细胞和脱屑生精上皮细胞的睾丸细胞不足。分别在猴和大鼠中观察卵巢卵泡闭锁，分别以24mg临床剂量的AUC暴露于临床暴露的0.2至0.8倍和10至44倍。此外，在猴子中，在24mg临床剂量下，在联和伊马替尼暴露的人群中，月经发生率降低。 

 

 

【贮藏】

 

保存于25°C（77°F）;外出时间可达15-30°C 

 

Drug Description

 

 

LENVIMA®
(lenvatinib) Capsules

DESCRIPTION

LENVIMA, a kinase inhibitor, is the mesylate salt of lenvatinib. Its chemical name is 4-[3- chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate. The molecular formula is C21H19ClN4O4 • CH4O3S, and the molecular weight of the mesylate salt is 522.96. The chemical structure of lenvatinib mesylate is:

Lenvatinib mesylate is a white to pale reddish yellow powder. It is slightly soluble in water and practically insoluble in ethanol (dehydrated). The dissociation constant (pKa value) of lenvatinib mesylate is 5.05 at 25°C. The partition coefficient (log P value) is 3.3.

LENVIMA capsules for oral administration contain 4 mg or 10 mg of lenvatinib, equivalent to 4.90 mg or 12.25 mg of lenvatinib mesylate, respectively. Following are inactive ingredients: Calcium Carbonate, USP; Mannitol, USP; Microcrystalline Cellulose, NF; Hydroxypropyl Cellulose, NF; Low-substituted Hydroxypropyl Cellulose, NF; and Talc, USP. The hypromellose capsule shell contains titanium dioxide, ferric oxide yellow, and ferric oxide red. The printing ink contains shellac, black iron oxide, potassium hydroxide, and propylene glycol.

Indications & Dosage

INDICATIONS

Differentiated Thyroid Cancer

LENVIMA is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory DTC.

Renal Cell Carcinoma

LENVIMA is indicated in combination with everolimus for the treatment of patients with advanced RCC following one prior anti-angiogenic therapy.

DOSAGE AND ADMINISTRATION

Recommended Dose For DTC

The recommended daily dose of LENVIMA is 24 mg (two 10 mg capsules and one 4 mg capsule) orally taken once daily with or without food [see CLINICAL PHARMACOLOGY]. Continue LENVIMA until disease progression or until unacceptable toxicity.

Take LENVIMA at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.

Recommended Dose For RCC

The recommended daily dose of LENVIMA is 18 mg (one 10 mg capsule and two 4 mg capsules) in combination with 5 mg everolimus orally taken once daily with or without food [see CLINICAL PHARMACOLOGY]. Continue LENVIMA plus everolimus until disease progression or until unacceptable toxicity.

Take LENVIMA and everolimus at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.

Administration Instructions

LENVIMA capsules should be swallowed whole. Alternatively, the capsules can be dissolved in a small glass of liquid. Measure 1 tablespoon of water or apple juice and put the capsules into the liquid without breaking or crushing them. Leave the capsules in the liquid for at least 10 minutes. Stir for at least 3 minutes. Drink the mixture. After drinking, add the same amount (1 tablespoon) of water or apple juice to the glass. Swirl the contents a few times and swallow the additional liquid.

Dose Modifications For DTC And RCC

Table 1: Adverse Reactions Requiring Dose Modification of LENVIMA in DTC and RCC

Manage other adverse reactions according to the instructions in Table 2 for DTC or Table 3 for RCC.

Recommendations For Dose Modifications In DTC

Table 2: Dose Modifications for LENVIMA for Persistent and Intolerable Grade 2 or Grade 3 Adverse Reactions or Grade 4 Laboratory Abnormalities in DTCa

Severe Renal or Hepatic Impairment in DTC

For patients with DTC, the recommended dose of LENVIMA is 14 mg taken orally once daily in patients with severe renal impairment (creatinine clearance [CLcr] less than 30 mL/min calculated by the Cockcroft-Gault equation) or severe hepatic impairment (Child-Pugh C) [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].

Recommendations For Dose Modifications In RCC

Table 3: Dose Modifications for LENVIMA for Persistent and Intolerable Grade 2 or Grade 3 Adverse Reactions or Grade 4 Laboratory Abnormalities in RCCa

Recommendations for Dose Modification of Everolimus in RCC

Review the Full Prescribing Information for everolimus for recommended dose modifications. For toxicities thought to be related to everolimus alone, discontinue, interrupt, or use alternate day dosing. For toxicities thought to be related to both LENVIMA and everolimus, first reduce LENVIMA and then everolimus.

Severe Renal or Hepatic Impairment in RCC

For patients with RCC, the recommended dose of LENVIMA is 10 mg taken orally once daily in patients with severe renal impairment (CLcr less than 30 mL/min calculated by the Cockcroft-Gault equation) or severe hepatic impairment (Child-Pugh C) [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].

HOW SUPPLIED

Dosage Forms And Strengths

4 mg hard capsule: A yellowish-red body and yellowish-red cap, marked in black ink with “∈” on the cap and “LENV 4 mg” on the body.

10 mg hard capsule: A yellow body and yellowish-red cap, marked in black ink with “∈” on the cap and “LENV 10 mg” on the body.

Storage And Handling

LENVIMA 4 mg capsules are supplied as hard hypromellose capsules with yellowish-red body and yellowish-red cap, marked in black ink with “∈” on the cap and “LENV 4 mg” on the body.

LENVIMA 10 mg capsules are supplied as hard hypromellose capsules with yellow body and yellowish-red cap, marked in black ink with “∈” on the cap and “LENV 10 mg” on the body.

LENVIMA capsules are supplied in cartons of 6 cards. Each card is a 5-day blister card as follows:

· NDC 62856-724-30: 24 mg, carton with 6 cards NDC 62856-724-05 (ten 10 mg capsules and five 4 mg capsules per card).

· NDC 62856-720-30: 20 mg, carton with 6 cards NDC 62856-720-05 (ten 10 mg capsules per card).

· NDC 62856-718-30: 18 mg, carton with 6 cards NDC 62856-718-05 (five 10 mg capsules and ten 4 mg capsules per card).

· NDC 62856-714-30: 14 mg, carton with 6 cards NDC 62856-714-05 (five 10 mg capsules and five 4 mg capsules per card).

· NDC 62856-710-30: 10 mg, carton with 6 cards NDC 62856-710-05 (five 10 mg capsules per card).

· NDC 62856-708-30: 8 mg, carton with 6 cards NDC 62856-708-05 (ten 4 mg capsules per card).

Store at 25°C (77°F); excursions permitted to 15 – 30°C (59 – 86°F) [see USP Controlled Room Temperature].

Distributed by: Eisai Inc., Woodcliff Lake, NJ 07677. Revised: June 2018

Side Effects & Drug Interactions

SIDE EFFECTS

The following adverse reactions are discussed elsewhere in the label:

· Hypertension [see WARNINGS AND PRECAUTIONS]

· Cardiac Dysfunction [see WARNINGS AND PRECAUTIONS]

· Arterial Thromboembolic Events [see WARNINGS AND PRECAUTIONS]

· Hepatotoxicity [see WARNINGS AND PRECAUTIONS]

· Proteinuria [see WARNINGS AND PRECAUTIONS]

· Diarrhea [see WARNINGS AND PRECAUTIONS]

· Renal Failure and Impairment [see WARNINGS AND PRECAUTIONS]

· Gastrointestinal Perforation and Fistula Formation [see WARNINGS AND PRECAUTIONS]

· QT Interval Prolongation [see WARNINGS AND PRECAUTIONS]

· Hypocalcemia [see WARNINGS AND PRECAUTIONS]

· Reversible Posterior Leukoencephalopathy Syndrome [see WARNINGS AND PRECAUTIONS]

· Hemorrhagic Events [see WARNINGS AND PRECAUTIONS]

· Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction [see WARNINGS AND PRECAUTIONS]

· Wound Healing Complications [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in the Warnings and Precautions section reflect exposure to LENVIMA as a single agent in 261 DTC patients (Study 1) and LENVIMA + everolimus in 62 RCC patients (Study 2). Safety data obtained in 1160 patients with advanced solid tumors who received LENVIMA as a single agent across multiple clinical studies was used to further characterize the risks of serious adverse reactions [see WARNINGS AND PRECAUTIONS]. In the entire single agent population, the median age was 60 years (range 21-89 years), the dose range was 0.2 mg to 32 mg, and the median duration of exposure was 5.5 months.

Differentiated Thyroid Cancer

The safety data described below are derived from Study 1 which randomized (2:1) patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) to LENVIMA (n=261) or placebo (n=131) [see Clinical Studies]. The median treatment duration was 16.1 months for LENVIMA and 3.9 months for placebo. Among 261 patients who received LENVIMA in Study 1, median age was 64 years, 52% were women, 80% were White, 18% were Asian, and 2% were Black; 4% identified themselves as having Hispanic or Latino ethnicity.

In Study 1, the most common adverse reactions observed in LENVIMA-treated patients (greater than or equal to 30%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, weight decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. The most common serious adverse reactions (at least 2%) were pneumonia (4%), hypertension (3%), and dehydration (3%).

Adverse reactions led to dose reductions in 68% of patients receiving LENVIMA and 5% of patients receiving placebo; 18% of patients discontinued LENVIMA and 5% discontinued placebo for adverse reactions. The most common adverse reactions (at least 10%) resulting in dose reductions of LENVIMA were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (at least 1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%).

Table 4 presents the percentage of patients in Study 1 experiencing adverse reactions at a higher rate in LENVIMA-treated patients than patients receiving placebo in the double-blind phase of the DTC study.

Table 4: Adverse Reactions Occurring in Patients with a Between-Group Difference of Greater than or Equal to 5% in All Grades or Greater than or Equal to 2% in Grades 3 and 4>

A clinically important adverse reaction occurring more frequently in LENVIMA-treated patients than patients receiving placebo, but with an incidence of less than 5% was pulmonary embolism (3%, including fatal reports vs 2%, respectively).

Table 5: Laboratory Abnormalities with a Difference of at Least ≥2% in Grade 3 - 4 Events and at a Higher Incidence in LENVIMA-Treated Patientsa

In addition the following laboratory abnormalities (all Grades) occurred in greater than 5% of LENVIMA-treated patients and at a rate that was two-fold or higher than in patients who received placebo: hypoalbuminemia, increased alkaline phosphatase, hypomagnesemia, hypoglycemia, hyperbilirubinemia, hypercalcemia, hypercholesterolemia, increased serum amylase, and hyperkalemia.

Renal Cell Carcinoma

The data described below are derived from Study 2 which randomized (1:1:1) patients with unresectable advanced or metastatic renal cell carcinoma (RCC) to LENVIMA 18 mg + everolimus 5 mg (n=51), LENVIMA 24 mg (n=52), or everolimus 10 mg (n=50) once daily [see Clinical Studies]. This data also includes patients on the dose escalation portion of the study who received LENVIMA 18 mg + everolimus 5 mg (n=11). The median treatment duration was 8.1 months for LENVIMA + everolimus and 4.1 months for everolimus. Among 62 patients who received LENVIMA + everolimus in Study 2, the median age was 61 years, 71% were men, and 98% were White.

The most common adverse reactions observed in the LENVIMA + everolimus-treated group (> 30%) were, in order of decreasing frequency, diarrhea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, weight decreased, hemorrhagic events, and proteinuria. The most common serious adverse reactions (≥ 5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%).

Adverse reactions led to dose reductions or interruption in 89% of patients receiving LENVIMA + everolimus and 54% in 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 12% of patients in the everolimus-treated group.

Table 6 presents the adverse reactions in > 15% of patients in the LENVIMA + Everolimus arm.

Table 6: Grades 1-4 Adverse Reactions in > 15% of Patients in the LENVIMA + Everolimus Arm

Table 7: Grade 3-4 Laboratory Abnormalities in ≥ 3% of Patients in the LENVIMA + Everolimus Arma,b

Postmarketing Experience

The following adverse reactions have been identified during post approval use of LENVIMA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal Disorders: pancreatitis, amylase increased
General Disorders: impaired wound healing
Hepatobiliary Disorders: cholecystitis
Musculoskeletal and Connective Tissue Disorders: fistula
Vascular Disorders: aortic dissection

DRUG INTERACTIONS

Effect Of Other Drugs On Lenvatinib

No dose adjustment of LENVIMA is recommended when co-administered with CYP3A, Pglycoprotein (P-gp), and breast cancer resistance protein (BCRP) inhibitors and CYP3A and P-gp inducers [see CLINICAL PHARMACOLOGY].

Warnings & Precautions

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Hypertension

In Study 1 in DTC, hypertension was reported in 73% of LENVIMA-treated patients and 16% of patients in the placebo group [see ADVERSE REACTIONS]. The median time to onset of new or worsening hypertension was 16 days for LENVIMA-treated patients. The incidence of Grade 3 hypertension was 44% as compared to 4% for placebo, and the incidence of Grade 4 hypertension was less than 1% in LENVIMA-treated patients and none in the placebo group.

In Study 2 in RCC, hypertension was reported in 42% of patients in the LENVIMA + everolimus-treated group and 10% of patients in the everolimus-treated group. The median time to onset of new or worsening hypertension was 35 days for LENVIMA + everolimus-treated patients. The incidence of Grade 3 hypertension was 13% in the LENVIMA + everolimus-treated group as compared to 2% in the everolimus-treated group. Systolic blood pressure ≥ 160mmHg occurred in 29% and 21% of patients had a diastolic blood pressure ≥100 in the LENVIMA + everolimus-treated group [see ADVERSE REACTIONS].

Serious complications of poorly controlled hypertension have been reported.

Control blood pressure prior to treatment with LENVIMA. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment with LENVIMA. Withhold LENVIMA for Grade 3 hypertension despite optimal antihypertensive therapy; resume at a reduced dose when hypertension is controlled at less than or equal to Grade 2. Discontinue LENVIMA for life-threatening hypertension [see DOSAGE AND ADMINISTRATION].

Cardiac Dysfunction

In Study 1 in DTC, cardiac dysfunction, defined as decreased left or right ventricular function, cardiac failure, or pulmonary edema, was reported in 7% of LENVIMA-treated patients (2% Grade 3 or greater) and 2% (no Grade 3 or greater) of patients in the placebo group. The majority of these cases in LENVIMA-treated patients (14 of 17 cases) were based on findings of decreased ejection fraction as assessed by echocardiography. Six of 261 (2%) LENVIMA-treated patients in Study 1 had greater than 20% reduction in ejection fraction as measured by echocardiography compared to no patients who received placebo.

In Study 2 in RCC, decreased ejection fraction and cardiac failure were reported in 10% of patients in the LENVIMA + everolimus-treated group and 6% of patients in the everolimustreated group. Grade 3 events occurred in 3% of LENVIMA + everolimus-treated patients and 2% of everolimus-treated patients. In the LENVIMA + everolimus-treated group there were two patients with a Grade 2 to 4 decrease in LVEF as assessed by MUGA.

Monitor patients for clinical symptoms or signs of cardiac decompensation. Withhold LENVIMA for development of Grade 3 cardiac dysfunction until improved to Grade 0 or 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of cardiac dysfunction. Discontinue LENVIMA for Grade 4 cardiac dysfunction [see DOSAGE AND ADMINISTRATION].

Arterial Thromboembolic Events

In Study 1 in DTC, arterial thromboembolic events were reported in 5% of LENVIMA-treated patients and 2% of patients in the placebo group. The incidence of arterial thromboembolic events of Grade 3 or greater was 3% in LENVIMA-treated patients and 1% in the placebo group.

In Study 2 in RCC, 2% of patients in the LENVIMA + everolimus-treated group and 6% of patients in the everolimus-treated group had arterial thromboembolic events reported. The incidence of arterial thromboembolic events of Grade 3 or greater was 2% with LENVIMA + everolimus-treated patients and 4% in the everolimus-treated group.

Discontinue LENVIMA 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 [see DOSAGE AND ADMINISTRATION].

Hepatotoxicity

Across clinical studies in which 1160 patients received LENVIMA monotherapy, hepatic failure (including fatal events) was reported in 3 patients and acute hepatitis was reported in 1 patient.

In Study 1 in DTC, 4% of LENVIMA-treated patients experienced an increase in alanine aminotransferase (ALT) and 5% experienced an increase in aspartate aminotransferase (AST) that was Grade 3 or greater. No patients in the placebo group experienced Grade 3 or greater increases in ALT or AST.

The incidence of ALT and AST elevation was similar in Study 2 in RCC. In Study 2, 3% of LENVIMA + everolimus-treated patients experienced an increase in ALT and 3% experienced an increase in AST that was Grade 3 or greater. Two percent of patients in the everolimus-treated group experienced an increase in ALT and none experienced an increase in AST that was Grade 3 or greater.

Monitor liver function before initiation of LENVIMA, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Withhold LENVIMA for the development of Grade 3 or greater liver impairment until resolved to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hepatotoxicity. Discontinue LENVIMA for hepatic failure [see DOSAGE AND ADMINISTRATION].

Proteinuria

In Study 1 in DTC, proteinuria was reported in 34% of LENVIMA-treated patients and 3% of patients in the placebo group [see ADVERSE REACTIONS]. The incidence of Grade 3 proteinuria in LENVIMA-treated patients was 11% compared to none in the placebo group. In Study 2 in RCC, proteinuria was reported in 31% of patients in the LENVIMA + everolimus-treated group and 14% of patients in the everolimus-treated group. The incidence of Grade 3 proteinuria in LENVIMA + everolimus-treated patients was 8% compared to 2% in everolimus-treated patients.

Monitor for proteinuria before initiation of, and periodically throughout treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24 hour urine protein. Withhold LENVIMA for ≥2 grams of proteinuria/24 hours and resume at a reduced dose when proteinuria is <2 gm/24 hours. Discontinue LENVIMA for nephrotic syndrome [see DOSAGE AND ADMINISTRATION].

Diarrhea

In Study 2 in RCC, diarrhea was reported in 81% of LENVIMA + everolimus-treated patients and 34% of everolimus-treated patients. Grade 3 or 4 events occurred in 19% of LENVIMA + everolimus-treated patients and 2% of everolimus-treated patients. Diarrhea was the most frequent cause of dose interruption/reduction and recurred despite dose reduction. Diarrhea resulted in discontinuation in one patient [see ADVERSE REACTIONS].

Initiate prompt medical management for the development of diarrhea. Monitor for dehydration. Interrupt LENVIMA for Grade 3 or 4 diarrhea. For Grade 3 diarrhea, resume at a reduced dose of LENVIMA when diarrhea resolves to Grade 1 or baseline. Permanently discontinue LENVIMA for Grade 4 diarrhea despite medical management.

Renal Failure And Impairment

In Study 1 in DTC, events of renal impairment were reported in 14% of LENVIMA-treated patients compared to 2% of patients in the placebo group. The incidence of Grade 3 or greater renal failure or impairment was 3% in LENVIMA-treated patients and 1% in the placebo group.

In Study 2 in RCC, renal impairment was reported in 18% of LENVIMA + everolimustreated group and 12% in the everolimus-treated group. The incidence of Grade 3 or greater renal failure or impairment was 10% in the LENVIMA + everolimus-treated group and 2% in the everolimus-treated group.

One risk factor for severe renal impairment in LENVIMA-treated patients was dehydration/hypovolemia due to diarrhea and vomiting. Active management of diarrhea and any other gastrointestinal symptoms should be initiated for Grade 1 events.

Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment until resolved to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of renal impairment [see DOSAGE AND ADMINISTRATION].

Gastrointestinal Perforation And Fistula Formation

In Study 1 in DTC, events of gastrointestinal perforation or fistula were reported in 2% of LENVIMA-treated patients and 0.8% of patients in the placebo group.

In Study 2 in RCC, Grade 3 or greater gastrointestinal perforation, abscess or fistula was reported in 2% of patients in the LENVIMA + everolimus-treated group and no patients in the everolimus-treated group. The events resolved in all patients.

Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula [see DOSAGE AND ADMINISTRATION].

QT Interval Prolongation

In Study 1 in DTC, QT/QTc interval prolongation was reported in 9% of LENVIMA-treated patients and 2% of patients in the placebo group. The incidence of QT interval prolongation of greater than 500 ms was 2% in LENVIMA-treated patients compared to no reports in the placebo group.

In Study 2 in RCC, QTc interval increases greater than 60 ms were reported in 11% of patients in the LENVIMA + everolimus-treated group. The incidence of QTc interval greater than 500 ms was 6% in the LENVIMA + everolimus-treated group. No reports of QTc interval prolongation greater than 500 ms or increase greater than 60 ms occurred in the everolimus-treated group.

Monitor and correct electrolyte abnormalities in all patients. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold LENVIMA for the development of QTc interval prolongation greater than 500 ms. Resume LENVIMA at a reduced dose when QTc prolongation resolves to baseline [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Hypocalcemia

In Study 1 in DTC, 9% of LENVIMA-treated patients experienced Grade 3 or greater hypocalcemia compared to 2% in the placebo group. In most cases hypocalcemia responded to replacement and dose interruption/dose reduction.

In Study 2 in RCC, 6% of patients in the LENVIMA + everolimus-treated group and 2% of patients in the everolimus-treated group experienced Grade 3 or greater hypocalcemia. No patients discontinued due to hypocalcemia [see ADVERSE REACTIONS].

Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment. Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia [see DOSAGE AND ADMINISTRATION].

Reversible Posterior Leukoencephalopathy Syndrome

Across clinical studies in which 1160 patients received LENVIMA monotherapy, there were 4 reported events of reversible posterior leukoencephalopathy syndrome (RPLS). Confirm the diagnosis of RPLS with MRI. Withhold for RPLS until fully resolved. Upon resolution, resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of neurologic symptoms [see DOSAGE AND ADMINISTRATION].

Hemorrhagic Events

Across clinical studies in which 1160 patients received LENVIMA monotherapy, Grade 3 or greater hemorrhage was reported in 2% of patients.

In Study 1 in DTC, hemorrhagic events occurred in 35% of LENVIMA-treated patients and in 18% of the placebo group. However, the incidence of Grade 3 to 5 hemorrhage was similar between arms at 2% and 3%, respectively. There was 1 case of fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. The most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2). Discontinuation due to hemorrhagic events occurred in 1% of LENVIMA- treated patients.

In Study 2 in RCC, hemorrhagic events occurred in 34% of patients in the LENVIMA + everolimus-treated group and 26% of patients in the everolimus-treated group. The most frequently reported hemorrhagic event was epistaxis (LENVIMA + everolimus 23% and everolimus 24%). Grade 3 or greater events occurred in 8% of LENVIMA + everolimus-treated patients and in 2% of everolimus-treated patients. In the LENVIMA + everolimus-treated patients, this included one fatal cerebral hemorrhage. Discontinuation due to a hemorrhagic event occurred in 3% of patients in the LENVIMA + everolimustreated group.

Serious tumor related bleeds, including fatal hemorrhagic events in LENVIMA-treated patients, have occurred in clinical trials and been reported in post-marketing experience. In post-marketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than in other tumor types. The safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials.

Consider the risk of severe or fatal hemorrhage associated with tumor invasion/infiltration of major blood vessels (e.g. carotid artery). Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hemorrhage. Discontinue LENVIMA in patients who experience Grade 4 hemorrhage [see DOSAGE AND ADMINISTRATION].

Impairment Of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction

LENVIMA impairs exogenous thyroid suppression. In Study 1 in DTC, 88% of all patients had a baseline thyroid stimulating hormone (TSH) level less than or equal to 0.5 mU/L. In those patients with a normal TSH at baseline, elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients as compared with 14% of patients receiving placebo.

In Study 2 in RCC, Grade 1 or 2 hypothyroidism occurred in 24% of patients in the LENVIMA + everolimus-treated group and 2% of patients in the everolimus-treated group. In those patients with a normal or low TSH at baseline, an elevation of TSH was observed post baseline in 60 % of LENVIMA + everolimus-treated patients as compared with 3% of patients receiving everolimus monotherapy.

Monitor thyroid function before initiation of, and at least monthly throughout, treatment with LENVIMA. Treat hypothyroidism according to standard medical practice to maintain a euthyroid state.

Wound Healing Complications

Wound healing complications, including fistula formation and wound dehiscence, can occur with LENVIMA. Withhold LENVIMA for at least 6 days prior to scheduled surgery. Resume LENVIMA after surgery based on clinical judgment of adequate wound healing. Permanently discontinue LENVIMA in patients with wound healing complications.

Embryo-Fetal Toxicity

Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy [see Use In Specific Populations].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Hypertension

Advise patients to undergo regular blood pressure monitoring and to contact their health care provider if blood pressure is elevated [see WARNINGS AND PRECAUTIONS].

Cardiac Dysfunction

Advise patients that LENVIMA can cause cardiac dysfunction and to immediately contact their healthcare provider if they experience any clinical symptoms of cardiac dysfunction such as shortness of breath or swelling of ankles [see WARNINGS AND PRECAUTIONS].

Arterial Thrombotic Events

Advise patients to seek immediate medical attention for new onset chest pain or acute neurologic symptoms consistent with myocardial infarction or stroke [see WARNINGS AND PRECAUTIONS].

Hepatotoxicity

Advise patients that they will need to undergo laboratory tests to monitor for liver function and to report any new symptoms indicating hepatic toxicity or failure [see WARNINGS AND PRECAUTIONS].

Diarrhea

Advise patients when to start standard anti-diarrheal therapy and to maintain adequate hydration. Advise patients to contact their healthcare provider if they are unable to maintain adequate hydration [see WARNINGS AND PRECAUTIONS].

Proteinuria And Renal Failure/Impairment

Advise patients that they will need to undergo regular laboratory tests to monitor for kidney function and protein in the urine [see WARNINGS AND PRECAUTIONS].

Gastrointestinal Perforation Or Fistula Formation

Advise patients that LENVIMA can increase the risk of gastrointestinal perforation or fistula and to seek immediate medical attention for severe abdominal pain [see WARNINGS AND PRECAUTIONS].

QTc Interval Prolongation Advise patients who are at risk for QTc prolongation that they will need to undergo regular ECGs. Advise all patients that they will need to undergo laboratory tests to monitor electrolytes [see WARNINGS AND PRECAUTIONS].

Hemorrhagic Events

Advise patients that LENVIMA can increase the risk for bleeding and to contact their healthcare provider for bleeding or symptoms of severe bleeding [see WARNINGS AND PRECAUTIONS].

Wound Healing Complications

Advise patients that LENVIMA can increase the risk of wound healing complications. Advise patients to inform their healthcare provider of any planned surgical procedure [see WARNINGS AND PRECAUTIONS].

Embryofetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].

Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy [see Use In Specific Populations].

Lactation

Advise nursing women to discontinue breastfeeding during treatment with LENVIMA [see Use In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies have not been conducted with lenvatinib. Lenvatinib mesylate was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. Lenvatinib was not clastogenic in the in vitro mouse lymphoma thymidine kinase assay or the in vivo rat micronucleus assay.

No specific studies with lenvatinib have been conducted in animals to evaluate the effect on fertility; however, results from general toxicology studies in rats, monkeys, and dogs suggest there is a potential for lenvatinib to impair fertility. Male dogs exhibited testicular hypocellularity of the seminiferous epithelium and desquamated seminiferous epithelial cells in the epididymides at lenvatinib exposures approximately 0.02 to 0.09 times the clinical exposure by AUC at the recommended human dose. Follicular atresia of the ovaries was observed in monkeys and rats at exposures 0.2 to 0.8 times and 10 to 44 times the clinical exposure by AUC at the 24 mg clinical dose, respectively. In addition, in monkeys, a decreased incidence of menstruation was reported at lenvatinib exposures lower than those in humans at the 24 mg clinical dose.

Use In Specific Populations

Pregnancy

Risk Summary

Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY]. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits [see Data]. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

Data

Animal Data

In an embryofetal development study, daily oral administration of lenvatinib mesylate at doses greater than or equal to 0.3 mg/kg [approximately 0.14 times the recommended human dose based on body surface area (BSA)] to pregnant rats during organogenesis resulted in dose-related decreases in mean fetal body weight, delayed fetal ossifications, and dose-related increases in fetal external (parietal edema and tail abnormalities), visceral, and skeletal anomalies. Greater than 80% postimplantation loss was observed at 1.0 mg/kg/day (approximately 0.5 times the recommended human dose based on BSA).

Daily oral administration of lenvatinib mesylate to pregnant rabbits during organogenesis resulted in fetal external (short tail), visceral (retroesophageal subclavian artery), and skeletal anomalies at doses greater than or equal to 0.03 mg/kg (approximately 0.03 times the human dose of 24 mg based on body surface area). At the 0.03 mg/kg dose, increased post-implantation loss, including 1 fetal death, was also observed. Lenvatinib was abortifacient in rabbits, resulting in late abortions in approximately one-third of the rabbits treated at a dose level of 0.5 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA).

Lactation

Risk Summary

It is not known whether LENVIMA is present in human milk. However, lenvatinib and its metabolites are excreted in rat milk at concentrations higher than in maternal plasma [see Data]. Because of the potential for serious adverse reactions in nursing infants from LENVIMA, advise women to discontinue breastfeeding during treatment with LENVIMA.

Data

Animal Data

Following administration of radiolabeled lenvatinib to lactating Sprague Dawley rats, lenvatinib-related radioactivity was approximately 2 times higher (based on AUC) in milk compared to maternal plasma.

Females And Males Of Reproductive Potential

Contraception

Based on its mechanism of action, LENVIMA can cause fetal harm when administered to a pregnant woman [see Pregnancy]. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy.

Infertility

Females

LENVIMA may result in reduced fertility in females of reproductive potential [see Nonclinical Toxicology].

Males

LENVIMA may result in damage to male reproductive tissues leading to reduced fertility of unknown duration [see Nonclinical Toxicology].

Pediatric Use

The safety and effectiveness of LENVIMA in pediatric patients have not been established.

Juvenile Animal Data

Daily oral administration of lenvatinib mesylate to juvenile rats for 8 weeks starting on postnatal day 21 (approximately equal to a human pediatric age of 2 years) resulted in growth retardation (decreased body weight gain, decreased food consumption, and decreases in the width and/or length of the femur and tibia) and secondary delays in physical development and reproductive organ immaturity at doses greater than or equal to 2 mg/kg (approximately 1.2 to 5 times the clinical exposure by AUC at the recommended human dose). Decreased length of the femur and tibia persisted following 4 weeks of recovery. In general, the toxicologic profile of lenvatinib was similar between juvenile and adult rats, though toxicities including broken teeth at all dose levels and mortality at the 10 mg/kg/day dose level (attributed to primary duodenal lesions) occurred at earlier treatment time-points in juvenile rats.

Geriatric Use

Of 261 patients who received LENVIMA in Study 1, 118 (45.2%) were greater than or equal to 65 years of age and 29 (11.1%) were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Of the 62 patients who received LENVIMA + everolimus in Study 2, 22 (35.5%) were greater than or equal to 65 years of age. Conclusions are limited due to the small sample size, but there appeared to be no overall differences in safety or effectiveness between these subjects and younger subjects.

Renal Impairment

No dose adjustment is recommended in patients with mild or moderate renal impairment. In patients with severe renal impairment, the recommended dose is 14 mg in the treatment of DTC and 10 mg in the treatment of RCC, either taken orally once daily. Patients with end stage renal disease were not studied [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].

Hepatic Impairment

No dose adjustment is recommended in patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, the recommended dose is 14 mg in the treatment of DTC and 10 mg in the treatment of RCC, either taken orally once daily [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Overdosage & Contraindications

OVERDOSE

There is no specific antidote for overdose with LENVIMA. Due to the high plasma protein binding, lenvatinib is not expected to be dialyzable [see CLINICAL PHARMACOLOGY]. Adverse reactions in patients receiving single doses of LENVIMA as high as 40 mg were similar to the adverse events reported in the clinical studies at the recommended dose for DTC and RCC.

CONTRAINDICATIONS

None.

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism Of Action

Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib also inhibits other RTKs that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. The combination of lenvatinib and everolimus showed increased antiangiogenic and antitumor activity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF signaling in vitro and tumor volume in mouse xenograft models of human renal cell cancer greater than each drug alone.

Pharmacodynamics

Cardiac Electrophysiology

A single 32 mg dose (1.3 times the recommended daily dose) of lenvatinib did not prolong the QT/QTc interval in a thorough QT study in healthy subjects. However, QT prolongation was observed in clinical studies [see WARNINGS AND PRECAUTIONS].

Pharmacokinetics

Absorption

After oral administration of LENVIMA, time to peak plasma concentration (Tmax) typically occurred from 1 to 4 hours post-dose. Administration with food did not affect the extent of absorption, but decreased the rate of absorption and delayed the median Tmax from 2 hours to 4 hours.

In patients with solid tumors administered single and multiple doses of LENVIMA once daily, the maximum lenvatinib plasma concentration (Cmax) and the area under the concentration-time curve (AUC) increased proportionally over the dose range of 3.2 to 32 mg with a median accumulation index of 0.96 (20 mg) to 1.54 (6.4 mg).

Distribution

In vitro binding of lenvatinib to human plasma proteins ranged from 98% to 99% (0.3 – 30 μg/mL). In vitro, the lenvatinib blood-to-plasma concentration ratio ranged from 0.589 to 0.608 (0.1 – 10 μg/mL).

Based on in vitro data, lenvatinib is a substrate of P-gp and BCRP but not a substrate for organic anion transporter (OAT) 1, OAT3, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, or the bile salt export pump (BSEP).

Elimination

Plasma concentrations declined bi-exponentially following Cmax. The terminal elimination half-life of lenvatinib was approximately 28 hours.

Metabolism

CYP3A is one of the main metabolic enzymes of lenvatinib. The main metabolic pathways for lenvatinib in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes.

Excretion

Ten days after a single administration of radiolabeled lenvatinib to 6 patients with solid tumors, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively.

Specific Populations

Renal Impairment

The pharmacokinetics of lenvatinib following a single 24 mg dose were evaluated in subjects with mild (CLcr 60-89 mL/min), moderate (CLcr 30-59 mL/min), and severe (CLcr <30 mL/min) renal impairment, and compared to healthy subjects. Subjects with end stage renal disease were not studied. After a single 24 mg oral dose of LENVIMA, the AUC0-inf for subjects with renal impairment were similar compared to those for healthy subjects [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, Use In Specific Populations].

Hepatic Impairment

The pharmacokinetics of lenvatinib following a single 10 mg dose of LENVIMA were evaluated in subjects with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. The pharmacokinetics of a single 5 mg dose were evaluated in subjects with severe (Child-Pugh C) hepatic impairment. Compared to subjects with normal hepatic function, the dose-adjusted AUC0-inf of lenvatinib for subjects with mild, moderate, and severe hepatic impairment were 119%, 107%, and 180%, respectively [see DOSAGE AND ADMINISTRATION, Use In Specific Populations].

Effects Of Age, Sex, And Race

Based on a population PK analysis, weight, age, sex, and race did not have a significant effect on apparent clearance (Cl/F) of lenvatinib.

Drug Interaction Studies

Effect Of Other Drugs On Lenvatinib

CYP3A, P-gp, and BCRP Inhibitors:

Ketoconazole (400 mg for 18 days) increased lenvatinib (administered as a single dose on Day 5) AUC by 15% and Cmax by 19% in a dedicated clinical trial.

P-gp Inhibitors:

Rifampicin (600 mg as a single dose) increased lenvatinib (24 mg as a single dose) AUC by 31% and Cmax by 33% in a dedicated clinical trial.

CYP3A and P-gp Inducers:

Rifampicin (600 mg administered daily for 21 days) decreased lenvatinib (a single 24 mg administered on Day 15) AUC by 18% in a dedicated clinical trial. The Cmax was unchanged.

Effect Of Lenvatinib On Other Drugs

CYP3A4 or CYP2C8 Substrates:

There is no projected significant drug-drug interaction risk between lenvatinib and midazolam (a CYP3A4 substrate) or repaglinide (a CYP2C8 substrate).

In Vitro Studies with CYP or UDP-glucuronosyltransferase (UGT) Substrates:

Lenvatinib inhibits CYP2C8, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A, but an increase in lenvatinib exposure that impacts safety is unlikely. Lenvatinib does not inhibit CYP2A6 and CYP2E1.

Lenvatinib induces CYP3A, but a decrease in lenvatinib exposure that impacts efficacy is unlikely. Lenvatinib does not induce CYP1A1, CYP1A2, CYP2B6, and CYP2C9. Lenvatinib directly inhibits UGT1A1 and UGT1A4. The clinical implication of this finding is unknown. Lenvatinib shows little or no inhibition on UGT1A6, UGT1A9, UGT2B7, or aldehyde oxidase.

Lenvatinib does not induce UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7.

In Vitro Studies with Drug Transporter System Substrates:

Lenvatinib inhibits OAT1, OAT3, OCT1, OCT2, OATP1B1, and BSEP. The clinical implication of this finding is unknown. Lenvatinib shows little or no inhibition on OATP1B3.

Clinical Studies

Differentiated Thyroid Cancer

A multicenter, randomized (2:1), double-blind, placebo-controlled trial was conducted in 392 patients with locally recurrent or metastatic radioactive iodine-refractory differentiated thyroid cancer and radiographic evidence of disease progression within 12 months prior to randomization, confirmed by independent radiologic review. Radioactive iodine-refractory was defined as 1 or more measurable lesions with no iodine uptake on RAI scan, iodine uptake with progression within 12 months of RAI therapy, or having received cumulative RAI activity of >600 mCi (22 GBq) with the last dose administered at least 6 months prior to study entry. Patients were randomized to receive LENVIMA 24 mg once daily (n=261) or placebo (n=131) until disease progression. Randomization was stratified by geographic region, prior VEGF/VEGFR-targeted therapy, and age. The major efficacy outcome measure was progression-free survival as determined by blinded independent radiologic review using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Independent review confirmation of disease progression was required prior to discontinuing patients from the randomization phase of the study. Other efficacy outcome measures included objective response rate and overall survival. Patients in the placebo arm could receive lenvatinib following independent review confirmation of disease progression.

Of the 392 patients randomized, 51% were male, the median age was 63 years, 40% were older than 65 years, 79% were White, 54% had an ECOG performance status of 0, and 24% had received 1 prior VEGF/VEGFR-targeted therapy. Metastases were present in 99% of the patients: lungs in 89%, lymph nodes in 52%, bone in 39%, liver in 18%, and brain in 4%. The histological diagnoses were papillary thyroid cancer (66%) and follicular thyroid cancer (34%); of those with follicular histology, 44% had Hürthle cell and 11% had clear cell subtypes. In the LENVIMA arm, 67% of patients did not demonstrate iodine uptake on any radioiodine scan compared to 77% in the placebo arm. Additionally, 59% of patients on the LENVIMA arm and 61% of patients on placebo arm progressed, according to RECIST 1.1, within 12 months of prior 131I therapy; 19.2% of patients on the LENVIMA arm and 17.6% of patients on placebo arm received prior cumulative activity of >600 mCi or 22 gigabecquerels (GBq) 131I, with the last dose administered at least 6 months prior to study entry. The median cumulative RAI activity administered prior to study entry was 350 mCi (12.95 GBq).

A statistically significant prolongation in PFS was demonstrated in LENVIMA-treated patients compared to those receiving placebo (see Table 8 and Figure 1). Upon confirmation of progression, 109 (83%) patients randomly assigned to placebo crossed over to receive open-label LENVIMA.

Table 8: Efficacy Results for Study 1

Figure 1: Kaplan-Meier Plot of Progression-Free Survival (Study 1)

Renal Cell Carcinoma

A multicenter study (Study 2) randomized 153 patients with advanced or metastatic renal cell carcinoma who have previously received anti-angiogenic therapy 1:1:1 to LENVIMA 18 mg plus everolimus 5 mg, LENVIMA 24 mg monotherapy, or everolimus 10 mg monotherapy. All medications were administered orally once daily. Patients were required to have histological confirmation of clear cell RCC and ECOG Performance Status of 0 or 1. Patients were stratified by hemoglobin level (≤ or > 13 g/dL for males and ≤ or > 11.5 g/dL for females) and corrected serum calcium (≥10 mg/dL vs. <10 mg/dL).

Of the 101 patients randomly allocated to the LENVIMA + everolimus arm and everolimus monotherapy arm, 72% were male, the median age was 60 years, 31% were older than 65 years, 96% were White. Metastases were present in 95% of the patients and unresectable advanced disease was present in 5%. All patients had a baseline ECOG PS of either 0 (54%) or 1 (46%) with similar distribution across the 2 treatment arms. Memorial Sloan Kettering Cancer Center (MSKCC) favorable, intermediate, and poor risk categories were observed respectively, in 24%, 37%, and 39% of patients in the LENVIMA + everolimus arm, and 24%, 38%, and 38% of patients in the everolimus arm.

The major efficacy outcome measure was investigator-assessed PFS evaluated according to RECIST 1.1. Efficacy results from Study 2 are summarized in Table 9 and Figures 2 and 3. The treatment effect of the combination on PFS was supported by a retrospective independent review of radiographs with an observed hazard ratio (HR) of 0.43 (95% CI: 0.24, 0.75) compared with the everolimus arm.

Table 9: Efficacy Results in Renal Cell Carcinoma Per Investigator Assessment (Study 2)

Figure 2: Kaplan-Meier Plot of Progression-Free Survival (Investigator Assessment-Study 2)

Figure 3: Kaplan-Meier Plot of Overall Survival (Study 2)

Medication Guide

PATIENT INFORMATION

LENVIMA®
(lehn-veema)
(lenvatinib) capsules

What is LENVIMA?

LENVIMA is a prescription medicine that is used to treat certain kinds of cancer.

· LENVIMA is used by itself to treat differentiated thyroid cancer (DTC), a type of thyroid cancer that can no longer be treated with radioactive iodine and is progressing.

· LENVIMA is used along with another medicine everolimus to treat advanced renal cell carcinoma (RCC), a type of kidney cancer, after one course of treatment with another anti-cancer medicine.

It is not known if LENVIMA is safe and effective in children.

What should I tell my healthcare provider before taking LENVIMA?

Before you take LENVIMA, tell your healthcare provider if you:

· have high blood pressure

· have heart problems

· have a history of blood clots in your arteries (type of blood vessel), including stroke, heart attack, or change in vision

· have or have had kidney or liver problems

· have a history of a tear (perforation) in your stomach or intestine, or an abnormal connection between two parts of your gastrointestinal tract (fistula)

· have headaches, seizures, or vision problems

· have any bleeding problems

· are pregnant or plan to become pregnant. LENVIMA can harm your unborn baby.

o Females who are able to become pregnant should use an effective method of birth control during treatment with LENVIMA and for at least 2 weeks after the last dose of LENVIMA. Talk with your healthcare provider about birth control methods you can use during this time.

o Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with LENVIMA.

· are breastfeeding or plan to breastfeed. It is not known if LENVIMA passes into your breast milk. Do not breastfeed during treatment with LENVIMA.

Tell your healthcare provider about all the medicines you take, including prescription and overthe- counter medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list of your medicines to show to your healthcare provider and pharmacist when you get a new medicine.

How should I take LENVIMA?

· Take LENVIMA exactly as your healthcare provider tells you to take it.

· Your healthcare provider will tell you how much LENVIMA to take and when to take it. Your healthcare provider may change your dose during treatment, stop treatment for some time, or completely stop treatment with LENVIMA if you have side effects.

· Take LENVIMA 1 time each day at the same time, with or without food.

· If you miss a dose of LENVIMA, take it as soon as you remember. If your next dose is due within 12 hours, skip the missed dose and take the next dose at your regular time.

· If you cannot swallow LENVIMA capsules whole:

o Use a medicine cup to measure about one tablespoon of water or apple juice and place into a small glass.

o Place the LENVIMA capsules into the small glass without breaking or crushing them.

o Leave the capsules in the liquid for at least 10 minutes.

o Stir the contents of the glass for at least 3 minutes.

o Drink the mixture. After drinking, rinse the glass with a small amount of additional water or apple juice and swallow the liquid.

· If you take too much LENVIMA, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of LENVIMA?

LENVIMA may cause serious side effects, including:

· high blood pressure (hypertension). High blood pressure is a common side effect of LENVIMA and can be serious. Your blood pressure should be well controlled before you start taking LENVIMA. Your healthcare provider should check your blood pressure regularly during treatment with LENVIMA. If you develop blood pressure problems, your healthcare provider may prescribe medicine to treat your high blood pressure, lower your dose of LENVIMA, or stop your treatment with LENVIMA.

· heart problems. Call your healthcare provider right away if you get symptoms of heart problems, such as shortness of breath or swelling of your ankles.

· problem with blood clots in your blood vessels (arteries). Get emergency medical help right away if you get any of the following symptoms:

o severe chest pain or pressure o trouble talking

o pain in your arms, back, neck or jaw o sudden severe headache

o shortness of breath o sudden vision changes

o numbness or weakness on one side of your body

· liver problems. LENVIMA may cause liver problems that may lead to liver failure and death. Your healthcare provider will check your liver function before and during treatment with LENVIMA. Tell your healthcare provider right away if you have any of the following symptoms:

o your skin or the white part of your eyes turns yellow (jaundice)

o dark “tea colored” urine

o light-colored bowel movements (stools)

· increased protein in your urine (proteinuria). Proteinuria is a common side effect of LENVIMA and can be serious. Your healthcare provider should check your urine for protein before and during your treatment with LENVIMA. If you develop protein in your urine, your healthcare provider may decrease your dose of LENVIMA or stop your treatment.

· diarrhea. Diarrhea is a common side effect of LENVIMA and can be serious. If you get diarrhea, ask your healthcare provider about what medicines you can take to treat your diarrhea. It is important to drink more water when you get diarrhea. Tell your healthcare provider or go to the emergency room, if you are unable to drink enough liquids and your diarrhea is not able to be controlled.

· kidney problems. Kidney failure has happened with LENVIMA treatment. Your healthcare provider should do regular blood tests to check your kidneys.

· an opening in the wall of your stomach or intestines (perforation) or an abnormal connection between two parts of your gastrointestinal tract (fistula). Get emergency medical help right away if you have severe stomach (abdomen) pain.

· changes in the electrical activity of your heart called QT prolongation. QT prolongation can cause irregular heartbeats that can be life threatening. Your healthcare provider will do blood tests during your treatment with LENVIMA to check the levels of potassium, magnesium, and calcium in your blood, and check the electrical activity of your heart with an ECG.

· low levels of blood calcium (hypocalcemia). Your healthcare provider will check your blood calcium levels during treatment with LENVIMA.

· a condition called Reversible Posterior Leukoencephalopathy Syndrome (RPLS). Call your healthcare provider right away if you get: severe headache, seizures, weakness, confusion, or blindness or change in vision.

· bleeding. LENVIMA may cause serious bleeding problems that may lead to death. Tell your healthcare provider if you have any signs or symptoms of bleeding during treatment with LENVIMA, including:

o severe and persistent nose bleeds

o coughing up blood or blood clots

o vomiting blood

o heavy or new onset vaginal bleeding

o red or black (looks like tar) stools

· change in thyroid hormone levels. You may have changes in your thyroid hormone levels when taking LENVIMA. Your healthcare provider may need to change your dose of thyroid medicine while you are taking LENVIMA. Your healthcare provider should check your thyroid hormone levels every month during treatment with LENVIMA.

· wound healing problems. If you need to have a surgical procedure, tell your healthcare provider that you are taking LENVIMA. LENVIMA should be stopped until your wound heals.

The most common side effects of LENVIMA in people treated for thyroid cancer include:

· tiredness

· joint and muscle pain

· weight loss

· mouth sores

· vomiting

· stomach (abdomen) pain

· decreased appetite

· nausea

· headache

· rash, redness, itching, or peeling of your skin on your hands and feet

· hoarseness

The most common side effects of LENVIMA in people treated for kidney cancer include:

· tiredness

· decreased appetite

· nausea

· swelling in your arms and legs

· stomach (abdomen) pain

· rash

· bleeding

· joint and muscle pain

· vomiting

· mouth sores

· cough

· trouble breathing

· weight loss

LENVIMA may cause fertility problems in males and females. Talk to your healthcare provider if this is a concern for you.

These are not all the possible side effects of LENVIMA.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800FDA- 1088.

How should I store LENVIMA?

· Store LENVIMA at room temperature, between 68°F to 77°F (20°C to 25°C).

Keep LENVIMA and all medicines out of the reach of children.

General information about the safe and effective use of LENVIMA.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use LENVIMA for a condition for which it was not prescribed. Do not give LENVIMA to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about LENVIMA that is written for health professionals.

What are the ingredients in LENVIMA?

Active ingredient: lenvatinib

Inactive ingredients: calcium carbonate, mannitol, microcrystalline cellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, and talc.

The capsule shell contains: titanium dioxide, ferric oxide yellow, and ferric oxide red. The printing ink contains shellac, black iron oxide, potassium hydroxide, and propylene glycol.