Lenvima

1.1        Differentiated Thyroid Cancer 

LENVIMA is indicated for the treatment of adult patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). 

1.2        Renal Cell Carcinoma 

LENVIMA, in combination with pembrolizumab, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

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

1.3        Hepatocellular Carcinoma

LENVIMA is indicated for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC).

1.4        Endometrial Carcinoma

LENVIMA, in combination with pembrolizumab, is indicated for the treatment of patients with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H), as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation [see Dosage and Administration ( 2.1)].

2.1         Patient Selection

For the pMMR/not MSI-H advanced endometrial carcinoma indication, select patients for treatment with LENVIMA in combination with pembrolizumab based on MMR or MSI status in tumor specimens [see Clinical Studies ( 14.4)].

Information on FDA-approved tests for patient selection is available at:  http://www.fda.gov/CompanionDiagnostics.

2.2        Important Dosage Information

• Reduce the dose for certain patients with renal or hepatic impairment [see Dosage and Administration ( 2.8,  2.9)].
  
• Take LENVIMA once daily, with or without food, at the same time each day [see Clinical Pharmacology ( 12.3)]. 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.

2.3        Recommended Dosage for Differentiated Thyroid Cancer (DTC)

The recommended dosage of LENVIMA is 24 mg orally once daily until disease progression or until unacceptable toxicity.

2.4        Recommended Dosage for Renal Cell Carcinoma (RCC)

First-Line Treatment of Patients with Advanced RCC

The recommended dosage of LENVIMA is 20 mg orally once daily in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or until unacceptable toxicity or up to 2 years. After completing 2 years of combination therapy, LENVIMA may be administered as a single agent until disease progression or until unacceptable toxicity.

Refer to the pembrolizumab prescribing information for other pembrolizumab dosing information.

Previously Treated RCC

The recommended dosage of LENVIMA is 18 mg in combination with 5 mg everolimus orally once daily until disease progression or until unacceptable toxicity.

Refer to the everolimus prescribing information for recommended everolimus dosing information.

2.5        Recommended Dosage for Hepatocellular Carcinoma (HCC)

The recommended dosage of LENVIMA is based on actual body weight:

• 12 mg for patients greater than or equal to 60 kg or
  
• 8 mg for patients less than 60 kg. 

Take LENVIMA orally once daily until disease progression or until unacceptable toxicity.

2.6        Recommended Dosage for Endometrial Carcinoma (EC)

The recommended dosage of LENVIMA is 20 mg orally once daily, in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks, until unacceptable toxicity or disease progression.

Refer to the pembrolizumab prescribing information for other pembrolizumab dosing information.

2.7        Dosage Modifications for Adverse Reactions

Recommendations for LENVIMA dose interruption, reduction and discontinuation for adverse reactions are listed in Table 1. Table 2 lists the recommended dosage reductions of LENVIMA for adverse reactions.

Recommended Dose Modifications for Adverse Reactions for LENVIMA in Combination with Pembrolizumab

When administering LENVIMA in combination with pembrolizumab, modify the dosage of one or both drugs as appropriate. Withhold, dose reduce, or discontinue LENVIMA as shown in Table 1. Refer to pembrolizumab prescribing information for additional dose modification information.

Recommended Dose Modifications for Adverse Reactions for LENVIMA in Combination with Everolimus

When administering LENVIMA in combination with everolimus, withhold or reduce the LENVIMA dose first and then the everolimus dose for adverse reactions of both LENVIMA and everolimus. Refer to the everolimus prescribing information for additional dose modification information.

2.8        Dosage Modifications for Severe Renal Impairment

The recommended dosage of LENVIMA for patients with DTC, RCC, or endometrial carcinoma and severe renal impairment (creatinine clearance less than 30 mL/min calculated by Cockcroft-Gault equation using actual body weight) is [see Warnings and Precautions ( 5.5), Use in Specific Populations ( 8.6)]:

• Differentiated thyroid cancer: 14 mg orally once daily
  
• Renal cell carcinoma: 10 mg orally once daily
  
• Endometrial carcinoma: 10 mg orally once daily

2.9        Dosage Modifications for Severe Hepatic Impairment

The recommended dosage of LENVIMA for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment (Child-Pugh C) is [see Warnings and Precautions ( 5.4), Use in Specific Populations ( 8.7)]:

• Differentiated thyroid cancer: 14 mg taken orally once daily
  
• Renal cell carcinoma: 10 mg taken orally once daily
  
• Endometrial carcinoma: 10 mg orally once daily

2.10        Capsule Administration and Preparation of Suspension for Administration

Administration

Oral: Capsule or Suspension

Capsule

• Swallow LENVIMA capsules whole at the same time each day with or without food [see Clinical Pharmacology ( 12.3)]. Do not crush or chew the LENVIMA capsules.

Suspension

• Prepare [see Preparation below] oral suspension with water or apple juice and administer at the same time each day with or without food [see Clinical Pharmacology ( 12.3)].

Feeding Tube Administration

Suspension

• Prepare [see Preparation below] suspension for feeding tube administration with water and administer at the same time each day with or without food [see Clinical Pharmacology ( 12.3)].

Preparation of Suspension

• Place the required number of capsules, up to a maximum of 5, in a small container (approximately 20 mL capacity) or syringe (20 mL). Do not break or crush capsules.
  
• Add 3 mL of liquid to the container or syringe. Wait 10 minutes for the capsule shell (outer surface) to disintegrate, then stir or shake the mixture for 3 minutes until capsules are fully disintegrated and administer the entire contents.
  
• Next, add an additional 2 mL of liquid to the container or syringe using a second syringe or dropper, swirl or shake and administer. Repeat this step at least once and until there is no visible residue to ensure all of the medication is taken.
  
• If 6 capsules are required for a dose, follow these instructions using 3 capsules at a time.

If LENVIMA suspension is not used at the time of preparation, LENVIMA suspension may be stored in a refrigerator at 36ºF to 46ºF (2ºC to 8ºC) for a maximum of 24 hours in a covered container. If not administered within 24 hours, the suspension should be discarded.

Note: Compatibility has been confirmed for polypropylene syringes and for feeding tubes of at least 5 French diameter (polyvinyl chloride or polyurethane tube) and at least 6 French diameter (silicone tube).

8.1        Pregnancy

Risk Summary

Based on findings from animal studies and its mechanism of action, LENVIMA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1)]. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human doses 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.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In an embryofetal development study, daily oral administration of lenvatinib mesylate at doses ≥0.3 mg/kg [approximately 0.14 times the recommended clinical dose of 24 mg 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% post-implantation loss was observed at 1.0 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg 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 recommended clinical dose of 24 mg based on BSA). 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).

8.2        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 those in maternal plasma (see Data). Because of the potential for serious adverse reactions in breastfed children, advise women to discontinue breastfeeding during treatment with LENVIMA and for 1 week after the last dose.

Data

Animal Data

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

8.3        Females and Males of Reproductive Potential

Based on animal data and its mechanism of action, LENVIMA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating LENVIMA [see Use in Specific Populations ( 8.1)].

Contraception

Females

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with LENVIMA and for 30 days after the last dose.

Infertility

LENVIMA may impair fertility in males and females of reproductive potential [see Nonclinical Toxicology ( 13.1)].

8.4        Pediatric Use

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

The safety and efficacy of LENVIMA alone and in combination were investigated but not established in four open label studies (NCT02432274, NCT04154189, NCT04447755, NCT03245151) in 232 patients aged 2 to <17 years with relapsed or refractory solid tumors, including osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and high-grade glioma. Hypothyroidism and pneumothorax were observed at a higher rate in pediatric patients compared to that of adult patients. The pharmacokinetics (PK) of lenvatinib in pediatric patients were within range of values previously observed in adults at the approved recommended dose of 24 mg.

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 human exposure based on AUC at the recommended clinical dose of 24 mg). 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.

8.5        Geriatric Use

Of the 261 patients with differentiated thyroid cancer (DTC) who received LENVIMA in SELECT, 45% were ≥65 years of age and 11% were ≥75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Of the 352 patients with renal cell carcinoma (RCC) who received LENVIMA with pembrolizumab in CLEAR, 45% were ≥65 years of age and 13% were ≥75 years of age. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients.  

Of the 62 patients with RCC who received LENVIMA with everolimus in Study 205, 36% were ≥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. 

Of the 476 patients with hepatocellular carcinoma (HCC) who received LENVIMA in REFLECT, 44% were ≥65 years of age and 12% were ≥75 years of age. No overall differences in safety or effectiveness were observed between patients ≥65 and younger subjects. Patients ≥75 years of age showed reduced tolerability to LENVIMA.

Of 406 adult patients with endometrial carcinoma (EC) who were treated with LENVIMA in combination with pembrolizumab in Study 309, 201 (50%) were 65 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.

8.6        Renal Impairment

No dose adjustment is recommended for patients with mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. Lenvatinib concentrations may increase in patients with DTC, RCC, or endometrial carcinoma and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose of LENVIMA for patients with RCC, DTC, or endometrial carcinoma and severe renal impairment [see Dosage and Administration ( 2.7)]. There is no recommended dose of LENVIMA for patients with HCC and severe renal impairment. LENVIMA has not been studied in patients with end stage renal disease [see Warnings and Precautions ( 5.5), Clinical Pharmacology ( 12.3)].

8.7        Hepatic Impairment

No dose adjustment is recommended for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose for patients with HCC with moderate or severe hepatic impairment. 

No dose adjustment is recommended for patients with DTC, RCC, or endometrial carcinoma and mild or moderate hepatic impairment (Child-Pugh A or B). Lenvatinib concentrations may increase in patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment (Child-Pugh C). Reduce the dose of lenvatinib for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment [see Dosage and Administration ( 2.7), Clinical Pharmacology ( 12.3)].

5.1        Hypertension

Hypertension occurred in 73% of patients in SELECT (DTC) receiving LENVIMA 24 mg orally once daily and in 45% of patients in REFLECT (HCC) receiving LENVIMA 8 mg or 12 mg orally once daily. The median time to onset of new or worsening hypertension was 16 days in SELECT and 26 days in REFLECT. Grade 3 hypertension occurred in 44% of patients in SELECT and in 24% in REFLECT. Grade 4 hypertension occurred <1% in SELECT and Grade 4 hypertension was not reported in REFLECT.

In patients receiving LENVIMA 18 mg orally once daily with everolimus in Study 205 (RCC), hypertension was reported in 42% of patients and the median time to onset of new or worsening hypertension was 35 days. Grade 3 hypertension occurred in 13% of patients. Systolic blood pressure ≥160 mmHg occurred in 29% of patients and diastolic blood pressure ≥100 mmHg occurred in 21% [see Adverse Reactions ( 6.1)].

Serious complications of poorly controlled hypertension have been reported.

Control blood pressure prior to initiating LENVIMA. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at a reduced dose when hypertension is controlled or permanently discontinue LENVIMA based on severity [see Dosage and Administration ( 2.7)].

5.2        Cardiac Dysfunction

Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC or HCC, Grade 3 or higher cardiac dysfunction (including cardiomyopathy, left or right ventricular dysfunction, congestive heart failure, cardiac failure, ventricular hypokinesia, or decrease in left or right ventricular ejection fraction of more than 20% from baseline) occurred in 3% of LENVIMA-treated patients. 

Monitor patients for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA based on severity [see Dosage and Administration ( 2.7)].

5.3        Arterial Thromboembolic Events

Among patients receiving LENVIMA or LENVIMA with everolimus, arterial thromboembolic events of any severity occurred in 2% of patients in Study 205 (RCC), 2% of patients in REFLECT (HCC) and 5% of patients in SELECT (DTC). Grade 3 to 5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials [see Adverse Reactions ( 6.1)].

Among patients receiving LENVIMA with pembrolizumab, arterial thrombotic events of any severity occurred in 5% of patients in CLEAR, including myocardial infarction (3.4%) and cerebrovascular accident (2.3%).

Permanently discontinue LENVIMA following an arterial thrombotic event [see Dosage and Administration ( 2.7)]. 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.

5.4        Hepatotoxicity

Across clinical studies enrolling 1327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic failure, acute hepatitis and hepatorenal syndrome, occurred in 0.5% of patients. 

In REFLECT (HCC), hepatic encephalopathy (including hepatic encephalopathy, encephalopathy, metabolic encephalopathy, and hepatic coma) occurred in 8% of LENVIMA-treated patients and 3% of sorafenib-treated patients. Grade 3 to 5 hepatic encephalopathy occurred in 5% of LENVIMA-treated patients and 2% of sorafenib-treated patients. Grade 3 to 5 hepatic failure occurred in 3% of LENVIMA-treated patients and 3% of sorafenib-treated patients. Two percent of patients discontinued LENVIMA and 0.2% discontinued sorafenib due to hepatic encephalopathy and 1% of patients discontinued LENVIMA or sorafenib due to hepatic failure [see Adverse Reactions ( 6.1)].

Monitor liver function prior to initiating LENVIMA, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA based on severity [see Dosage and Administration ( 2.7)].

5.5        Renal Failure or Impairment

Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment occurred in 14% of patients receiving LENVIMA in SELECT (DTC) and in 7% of patients receiving LENVIMA in REFLECT (HCC). Grade 3 to 5 renal failure or impairment occurred in 3% (DTC) and 2% (HCC) of patients, including 1 fatality in each study.

In Study 205 (RCC), renal impairment or renal failure occurred in 18% of patients receiving LENVIMA with everolimus, including Grade 3 in 10% of patients [see Adverse Reactions ( 6.1)].

Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA for renal failure or impairment based on severity [see Dosage and Administration ( 2.7)]. 

5.6        Proteinuria

Proteinuria occurred in 34% of LENVIMA-treated patients in SELECT (DTC) and in 26% of LENVIMA-treated patients in REFLECT (HCC). Grade 3 proteinuria occurred in 11% and 6% in SELECT and REFLECT, respectively. In Study 205 (RCC), proteinuria occurred in 31% of patients receiving LENVIMA with everolimus and 14% of patients receiving everolimus. Grade 3 proteinuria occurred in 8% of patients receiving LENVIMA with everolimus compared to 2% of patients receiving everolimus [see Adverse Reactions ( 6.1)].

Monitor for proteinuria prior to initiating LENVIMA and periodically during treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24-hour urine protein. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA based on severity [see Dosage and Administration ( 2.7)].

5.7        Diarrhea

Of the 737 patients treated with LENVIMA in SELECT (DTC) and REFLECT (HCC), diarrhea occurred in 49% of patients, including Grade 3 in 6%.

In Study 205 (RCC), diarrhea occurred in 81% of patients receiving LENVIMA with everolimus, including Grade 3 in 19%. Diarrhea was the most frequent cause of dose interruption/reduction and diarrhea recurred despite dose reduction [see Adverse Reactions ( 6.1)].

Promptly initiate management of diarrhea. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA based on severity [see Dosage and Administration ( 2.7)].

5.8        Fistula Formation and Gastrointestinal Perforation

Of 799 patients treated with LENVIMA or LENVIMA with everolimus in SELECT (DTC), Study 205 (RCC) and REFLECT (HCC), fistula or gastrointestinal perforation occurred in 2%. 

Permanently discontinue LENVIMA in patients who develop gastrointestinal perforation of any severity or Grade 3 or 4 fistula [see Dosage and Administration ( 2.7)].

5.9        QT Interval Prolongation

In SELECT (DTC), QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%. In Study 205 (RCC), QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA with everolimus and QTc interval >500 ms occurred in 6%. In REFLECT (HCC), QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%.

Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. 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 and resume at reduced dose of LENVIMA upon recovery based on severity [see Dosage and Administration ( 2.7)].

5.10        Hypocalcemia

In SELECT (DTC), Grade 3 to 4 hypocalcemia occurred in 9% of patients receiving LENVIMA. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation, with or without dose interruption or dose reduction. 

In Study 205 (RCC), Grade 3 to 4 hypocalcemia occurred in 6% of patients treated with LENVIMA with everolimus. In REFLECT (HCC), Grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients [see Adverse Reactions ( 6.1)].

Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue LENVIMA depending on severity [see Dosage and Administration ( 2.7)].

5.11        Reversible Posterior Leukoencephalopathy Syndrome

Across clinical studies of 1823 patients who received LENVIMA as a single agent [see Adverse Reactions ( 6.1)], reversible posterior leukoencephalopathy syndrome (RPLS) occurred in 0.3%.

Confirm the diagnosis of RPLS with magnetic resonance imaging. Withhold and resume at a reduced dose upon recovery or permanently discontinue LENVIMA depending on severity and persistence of neurologic symptoms [see Dosage and Administration ( 2.7)].

5.12        Hemorrhagic Events

Serious including fatal hemorrhagic events can occur with LENVIMA. Across SELECT (DTC), Study 205 (RCC) and REFLECT (HCC), hemorrhagic events of any grade occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria. 

In SELECT, Grade 3 to 5 hemorrhage occurred in 2% of patients receiving LENVIMA, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In Study 205, Grade 3 to 5 hemorrhage occurred in 8% of patients receiving LENVIMA with everolimus, including 1 fatal cerebral hemorrhage. In REFLECT, Grade 3 to 5 hemorrhage occurred in 5% of patients receiving LENVIMA, including 7 fatal hemorrhagic events [see Adverse Reactions ( 6.1)].

Serious tumor related bleeds, including fatal hemorrhagic events, occurred in patients treated with LENVIMA in clinical trials and in the post-marketing setting. 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 or infiltration of major blood vessels (e.g. carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue LENVIMA based on the severity [see Dosage and Administration ( 2.7)].

5.13        Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction 

LENVIMA impairs exogenous thyroid suppression. In SELECT (DTC), 88% of all patients had a baseline thyroid stimulating hormone (TSH) level ≤0.5 mU/L. In those patients with a normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients.

Grade 1 or 2 hypothyroidism occurred in 24% of patients receiving LENVIMA with everolimus in Study 205 (RCC) and in 21% of patients receiving LENVIMA in REFLECT (HCC). In those patients with a normal or low TSH at baseline, an elevation of TSH was observed post baseline in 70% of patients receiving LENVIMA in REFLECT and 60% of patients receiving LENVIMA with everolimus in Study 205 [see Adverse Reactions ( 6.1)].

Monitor thyroid function prior to initiating LENVIMA and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.

5.14        Impaired Wound Healing

Impaired wound healing has been reported in patients who received LENVIMA [see Adverse Reactions ( 6.2)]. 

Withhold LENVIMA for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of LENVIMA after resolution of wound healing complications has not been established.

5.15        Osteonecrosis of the Jaw (ONJ)

Osteonecrosis of the Jaw (ONJ) has been reported in patients receiving LENVIMA [see Adverse Reactions ( 6.1)]. Concomitant exposure to other risk factors, such as bisphosphonates, denosumab, dental disease or invasive dental procedures, may increase the risk of ONJ.

Perform an oral examination prior to treatment with LENVIMA and periodically during LENVIMA treatment. Advise patients regarding good oral hygiene practices. Avoid invasive dental procedures, if possible, while on LENVIMA treatment, particularly in patients at higher risk. Withhold LENVIMA for at least 1 week prior to scheduled dental surgery or invasive dental procedures, if possible. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk of ONJ. Withhold LENVIMA if ONJ develops and restart based on clinical judgement of adequate resolution.

5.16        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 clinical doses 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 30 days after the last dose [see Use in Specific Populations ( 8.1, 8.3)].