Hepatocellular carcinoma, unresectableRenal cell carcinoma, advancedThyroid cancer, differentiated

Lenvatinib is a multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), VEGFR3 (FLT4), fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4, platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. Inhibition of these receptor tyrosine kinases leads to decreased tumor growth and slowing of cancer progression. In hepatocellular carcinoma cell lines dependent on activated FGFR signaling (with a concurrent inhibition of FGF-receptor substrate 2α phosphorylation), lenvatinib exhibited antiproliferative activity. Combining lenvatinib with everolimus has demonstrated increased antiangiogenic and antitumor activity by decreasing human endothelial cell proliferation, tube formation, and VEGF signaling (in vitro) compared to either drug alone.

Absorption：Tmax, oral: 1 to 4 hours Effects of food: Delayed Tmax by 2 hours; delayed the rate but not the extent of absorption Distribution：Protein binding, plasma proteins: 98% to 99% Metabolism：Liver，Substrate of CYP3A, P-gp, and BCRPExcretion：Renal: 25% Fecal: 64% Elimination Half Life：28 hours

Based on the mechanism of action and findings from animal reproduction studies, lenvatinib may cause fetal harm if administered in pregnancy. Verify pregnancy status prior to initiating lenvatinib in females of reproductive potential. Females of reproductive potential should use effective contraception during lenvatinib treatment and for at least 30 days after completion of therapy. Lenvatinib may impair fertility in males and females of reproductive potential.

It is not known if lenvatinib is present in breast milk. Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends discontinuing breastfeeding during lenvatinib treatment and for at least 1 week after the last lenvatinib dose.

CommonCardiovascular: Hypertension (42% to 73% ), Peripheral edema (14% to 42% )Dermatologic: Hand-foot syndrome due to cytotoxic therapy (27% to 32% ), Impaired wound healing, Rash (14% to 35% )Gastrointestinal: Abdominal pain (31% to 37% ), Decrease in appetite (34% to 54% ), Nausea (20% to 47% ), Stomatitis (41% to 44% ), Weight decreased (31% to 51% )Musculoskeletal: Arthralgia, MyalgiaNeurologic: Headache (10% to 38% )Renal: Proteinuria (26% to 34% )Respiratory: Cough (24% to 37% )Other: Difficulty speaking (18% to 31% ), Fatigue (44% to 73% )SeriousCardiovascular: Myocardial dysfunction (7% to 10% ), Prolonged QT interval (2% to 11% )Gastrointestinal: Diarrhea (Renal cell carcinoma, 81%; thyroid cancer, 67% ; hepatocellular carcinoma, 39% ), Vomiting (16% to 48% )Hematologic: Anemia (Renal cell carcinoma, 6% ), Arterial thrombosis (2% to 5%), Thrombocytopenia (Renal cell carcinoma, 5% )Hepatic: Hepatic encephalopathy (Hepatocellular carcinoma, 8% ), Hepatitis, Hepatorenal syndrome, Liver failureRenal: Renal failure (Renal cell carcinoma, 18% ), Renal impairment (7% to 18% )Respiratory: Dyspnea (35% )Other: Dehydration (9% to 10% )

Hepatocellular carcinoma, unresectable: Oral: 12 mg once daily (patients ?60 kg [actual body weight]) or 8 mg once daily (patients <60 kg [actual body weight]) continue until disease progression or unacceptable toxicityRenal cell carcinoma, advanced: Oral: 18 mg once daily (in combination with everolimus), continue until disease progression or unacceptable toxicity Thyroid cancer, differentiated: Oral: 24 mg once daily until disease progression or unacceptable toxicity

Preexisting renal impairment:CrCl ?30 mL/minute: No dosage adjustment necessary.CrCl <30 mL/minute:Hepatocellular carcinoma, unresectable: There are no dosage adjustments provided in the manufacturer's labeling.Renal cell cancer, advanced: 10 mg once dailyThyroid cancer, differentiated: 14 mg once dailyESRD: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).Hemodialysis: Lenvatinib is not expected to be dialyzable (due to high protein binding).Renal toxicity during treatment:Nephrotic syndrome: Permanently discontinue therapy.Proteinuria ?2 g proteinuria/24 hours: Withhold therapy; resume therapy at a reduced dose when improved to <2 g proteinuria/24 hours.Renal failure or impairment (grade 3 or 4): Withhold therapy; if improves to ? grade 1 or baseline, depending on the severity and persistence, resume at a reduced dose or permanently discontinue therapy.

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.Moderate impairment (Child-Pugh class B):There are no dosage adjustments provided in the manufacturer's labeling.Severe impairment (Child-Pugh class C):Hepatocellular carcinoma, unresectable: There are no dosage adjustments provided in the manufacturer's labeling.Renal cell cancer, advanced: 10 mg once dailyThyroid cancer, differentiated: 14 mg once dailyHepatotoxicity during treatment (grade 3 or 4): Withhold therapy; if improves to ? grade 1 or baseline, depending on the severity and persistence, resume at a reduced dose or permanently discontinue therapy. Permanently discontinue for hepatic failure.

Store at controlled room temperature, 25 degrees C , with excursions permitted between 15 and 30 degrees C