7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on Lenvatinib No dose adjustment of LENVIMA is recommended when co-administered with CYP3A, P glycoprotein (P-gp), and breast cancer resistance protein (BCRP) inhibitors and CYP3A and P-gp inducers [see Clinical Pharmacology (12.3)].

 Novel Drug Approvals for 2015

1.Name    LENVIMA

2. Active Ingredient-     Lenvatinib

3. Indication-    ..

Date of Approval  2/13/2015

HIGHLIGHTS OF PRESCRIBING INFORMATION-

• Renal Failure and Impairment: Withhold LENVIMA for Grade 3 or 4 renal These highlights do not include all the information needed to use failure/impairment . LENVIMA™ safely and effectively. See full prescribing information for

• Gastrointestinal Perforation and Fistula Formation: Discontinue LENVIMA. LENVIMA in patients who develop gastrointestinal perforation or life threatening fistula .                LENVIMA (lenvatinib) capsules, for oral use

• QT Interval Prolongation: Monitor and correct electrolyte abnormalities in all patients

 Withhold LENVIMA for the development of Grade 3 or greater QT interval prolongation

Initial U.S. Approval: 2015

INDICATIONS AND USAGE-

• Hypocalcemia: Monitor blood calcium levels at least monthly and replace LENVIMA is a kinase inhibitor indicated for the treatment of patients with calcium as necessary

 locally recurrent or metastatic, progressive, radioactive iodine-refractory

• Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Withhold differentiated thyroid cancer (1). LENVIMA for RPLS until fully resolved

• Hemorrhagic Events: Withhold LENVIMA for Grade 3 hemorrhage. 

ADVERSE REACTIONS-

. The most common adverse reactions (incidence greater than or equal to 30%) for LENVIMA are hypertension, fatigue, diarrhea, arthralgia/myalgia

CONTRAINDICATIONS

None 

WARNINGS AND PRECAUTIONS-

 decreased appetite, weight decreased, nausea, stomatitis, headache, vomiting, • Hypertension: Control blood pressure prior to treatment with LENVIMA. proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, and Withhold LENVIMA for Grade 3 hypertension despite optimal dysphonia 

. • Cardiac Failure: Monitor for clinical symptoms or signs of cardiac failure

DOSAGE AND ADMINISTRATION-

Discontinue for Grade 4 hemorrhage 

• Recommended dose: 24 mg orally, once daily

 • Impairment of Thyroid Stimulating Hormone Suppression:                       Monitor TSH

• In patients with severe renal or hepatic impairment, the dose is 14 mg once levels monthly and adjust thyroid replacement medication as needed in daily  patients with DTC 

DOSAGE FORMS AND STRENGTHS-

• Embryofetal Toxicity: Can cause fetal harm. Advise of potential risk to a                          • Capsules: 4 mg and 10 mg . fetus and use of effective contraception

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 

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

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

Hepatotoxicity: Advise patients that they will need to undergo lab tests to monitor for liver function and to report any new symptoms indicating hepatic toxicity or failure

Proteinuria and Renal Failure/Impairment: Advise patients that they will need to undergo regular lab tests to monitor for kidney function and protein in the urine

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

Hemorrhagic Events: Advise patients that LENVIMA can increase the risk for bleeding and to contact their health care provider for bleeding or symptoms of severe bleeding 

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 

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 

Lactation: Advise nursing women to discontinue breastfeeding during treatment with LENVIMA 

Manufactured by: Patheon Inc. Mississauga, Ontario, Canada Distributed by: Eisai Inc. Woodcliff Lake, NJ 07677 LENVIMA™ is a trademark of Eisai R&D Management Co., Ltd. and is licensed to Eisai Inc. © 2015 Eisai Inc.

CLINICAL PHARMACOLOGY

1 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).

2 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 Study 1 [see Warnings and Precautions (5.8)].

.3 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.

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.

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.

Effects of Age, Sex, and Race Based on a population PK analysis, 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.

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

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.

2. 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 Reference ID: 3702309 Data].

8.3 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 Use in Specific Populations (8.1)].

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 (13.1)].

Males LENVIMA may result in damage to male reproductive tissues leading to reduced fertility of unknown duration [see Nonclinical Toxicology (13.1)].

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

8.5 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 Reference ID: 3702309 differences in safety or effectiveness were observed between these subjects and younger subjects.

8.6 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 taken once daily. Patients with end stage renal disease were not studied [see Dosage and Administration (2.1), Warnings and Precautions (5.6), Clinical Pharmacology (12.3)].

8.7 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 taken once daily [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)].

10 OVERDOSAGE 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 (12.3)]

11 DESCRIPTION