2.1 Recommended Dose

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 (12.3)]. Continue LENVIMA until disease progression or until unacceptable toxicity occurs.

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.

Severe Renal or Hepatic Impairment

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 Cockroft-Gault equation) or severe hepatic impairment (Child-Pugh C) [see Warning and Precaution (5.3), Use in Specific Populations (8.6, 8.7)].

2.2 Dose Modifications

Hypertension

• Assess blood pressure prior to and periodically during treatment. Initiate or adjust medical management to control blood pressure prior to and during treatment.
• Withhold LENVIMA for Grade 3 hypertension that persists despite optimal antihypertensive therapy; resume at a reduced dose (see Table 1) when hypertension is controlled at less than or equal to Grade 2.
• Discontinue LENVIMA for life-threatening hypertension.

Cardiac dysfunction or hemorrhage

• Discontinue for a Grade 4 event.
• Withhold LENVIMA for development of Grade 3 event until improved to Grade 0 or 1 or baseline.
• Either resume at a reduced dose (see Table 1) or discontinue LENVIMA depending on the severity and persistence of the adverse event.

Arterial thrombotic event

• Discontinue LENVIMA following an arterial thrombotic event.

Renal failure and impairment or hepatotoxicity

• Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment or hepatotoxicity until resolved to Grade 0 to 1 or baseline.
• Either resume at a reduced dose (see Table 1) or discontinue LENVIMA depending on the severity and persistence of renal impairment or hepatotoxicity.
• Discontinue LENVIMA for hepatic failure.

Proteinuria

• Withhold LENVIMA for ≥2 grams of proteinuria/24 hours.
• Resume at a reduced dose (see Table 1) when proteinuria is <2 gm/24 hours.
• Discontinue LENVIMA for nephrotic syndrome.

Gastrointestinal perforation or fistula formation

• Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula.

QT prolongation

• Withhold LENVIMA for the development of Grade 3 or greater QT interval prolongation. 
• Resume LENVIMA at a reduced dose (see Table 1) when QT prolongation resolves to Grade 0 or 1 or baseline.

Reversible posterior leukoencephalopathy syndrome (RPLS)

• 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.

Manage other adverse reactions according to the instructions in Table 1.  Based on the absence of clinical experience, there are no recommendations on resumption of dosing in patients with Grade 4 clinical adverse reactions that resolve.

5.1 Hypertension

In Study 1 hypertension was reported in 73% of LENVIMA-treated patients and 16% of patients in the placebo group [see Adverse Reactions (6.1)]. 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.

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 (2.2)].

5.2 Cardiac Dysfunction

In Study 1, 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. 

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 (2.2)].

5.3 Arterial Thromboembolic Events

In Study 1, 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. 

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 (2.2)].

5.4 Hepatotoxicity

In Study 1, 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. Across clinical studies in which 1108 patients received LENVIMA, hepatic failure (including fatal events) was reported in 3 patients and acute hepatitis was reported in 1 patient. 

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 (2.2)].

5.5 Proteinuria

In Study 1, proteinuria was reported in 34% of LENVIMA-treated patients and 3% of patients in the placebo group [see Adverse Reactions (6.1)]. The incidence of Grade 3 proteinuria in LENVIMA-treated patients was 11% compared to none in the placebo group.

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 (2.2)]. 

5.6 Renal Failure and Impairment

In Study 1, 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. The primary risk factor for severe renal impairment in LENVIMA-treated patients was dehydration/hypovolemia due to diarrhea and vomiting.  

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 (2.2)].

5.7 Gastrointestinal Perforation and Fistula Formation

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

Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula [see Dosage and Administration (2.2)].

5.8 QT Interval Prolongation

In Study 1, 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 Grade 3 or greater was 2% in LENVIMA-treated patients compared to no reports in the placebo group. 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.

Monitor and correct electrolyte abnormalities in all patients. Withhold LENVIMA for the development of Grade 3 or greater QT interval prolongation. Resume LENVIMA at a reduced dose when QT prolongation resolves to Grade 0 or 1 or baseline [see Dosage and Administration (2.2), Clinical Pharmacology (12.2)].

5.9 Hypocalcemia

In study 1, 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 [see Adverse Reactions (6.1)]. 

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 (2.2)].

5.10 Reversible Posterior Leukoencephalopathy Syndrome

Across clinical studies in which 1108 patients received LENVIMA, there were 3 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 (2.2)].

5.11 Hemorrhagic Events

In Study 1, hemorrhagic events occurred in 35% of LENVIMA-treated patients and in 18% of the placebo group. However, the incidence of Grade 3-5 hemorrhage was similar between arms at 2% and 3%, respectively. 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.

Across clinical studies in which 1108 patients received LENVIMA, Grade 3 or greater hemorrhage was reported in 2% of patients. In Study 1, there was 1 case of fatal intracranial hemorrhage among 16 patients who received lenvatinib and had CNS metastases at baseline.

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 (2.2)].

5.12 Impairment of Thyroid Stimulating Hormone Suppression

LENVIMA impairs exogenous thyroid suppression. In Study 1, 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.

Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC.

5.13 Embryofetal 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 (8.1, 8.3)].