Lenvatinib

Hypertension, including grade 3 and 4 toxicity, occurred in patients treated with lenvatinib in clinical trials; the median time to onset of new or worsening hypertension was 16 to 35 days. Blood pressure should be controlled prior to initiating therapy; monitor frequently throughout treatment. Other cardiac events, such as decreased left or right ventricular function, decreased ejection fraction (EF), cardiac failure, or pulmonary edema, were also reported, including grades 2, 3, and 4 events. In patients with thyroid cancer, decreased ejection fraction was the most commonly reported of these events; some patients experienced greater than 20% EF reduction. Monitor for signs/symptoms of cardiac decompensation. QT/QTc prolongation was also observed in lenvatinib-treated patients, including prolongation >500 msec and increases >60 msec from baseline. Monitor and correct electrolyte abnormalities in all patients; obtain electrocardiograms in patients with congenital long QT syndrome, heart failure, bradyarrhythmias, or in those on concomitant medications known to prolong the QT interval. Cardiac effects may require therapy interruption, dosage reduction, or discontinuation.

Lenvatinib impairs exogenous thyroid suppression. In patients with differentiated thyroid cancer and a normal thyroid stimulating hormone (TSH) level at baseline, TSH elevations were observed in over half of lenvatinib-treated patients. Grades 1 and 2 hypothyroidism occurred in renal cell cancer patients receiving lenvatinib and everolimus; TSH elevations occurred in over half of in patients with a normal or low TSH at baseline. Monitor TSH levels at baseline and at least monthly; adjust thyroid hormone therapy or manage hypothyroidism as clinically necessary.

Gastrointestinal perforation, fistula formation, or abscess were reported in a small percentage of patients in clinical trials. Discontinue use in patients who develop perforation or life-threatening fistula.

Lenvatinib is associated with a moderate emetic potential; antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017). Nausea, vomiting, and diarrhea were commonly observed. Initiate appropriate management prior to therapy interruption or dosage reduction; initiate active management of diarrhea and other gastrointestinal symptoms for grade 1 or higher events. Monitor closely for dehydration; dehydration or hypovolemia due to diarrhea and vomiting are risk factors for renal toxicity. Diarrhea may require treatment interruption, dose reduction, and or discontinuation. The incidence of diarrhea is higher in when lenvatinib is used in combination with everolimus; recurrent diarrhea occurred despite dose reduction. Diarrhea was the most common reason for dose reduction or treatment interruption in patients with renal cell cancer.

Hemorrhagic events (most frequently epistaxis) occurred in over one-third of lenvatinib-treated patients. Serious tumor-related bleeding events (including cases of fatal hemorrhage) have been observed in clinical trials and postmarketing surveillance. Serious and fatal carotid artery hemorrhages were reported more frequently in patients with anaplastic thyroid carcinoma (ATC) than with other tumor types. Safety and efficacy of lenvatinib have not been established in the treatment of ATC. Consider the risk of hemorrhage associated with tumor infiltration/invasion of major blood vessels. Monitor for bleeding; may require therapy interruption, dosage reduction, or discontinuation.

Elevations in transaminases (including grade 3 or greater events) were observed. There have been case reports of hepatic failure (some fatal) and acute hepatitis with single-agent lenvatinib. Monitor liver function tests at baseline and throughout therapy. May require therapy interruption, dosage reduction, or discontinuation. If hepatic failure occurs, discontinue treatment.

An increased incidence of hypocalcemia (including grade 3 events) was observed in lenvatinib-treated patients compared to the control group in clinical trials. Calcium replacement therapy and dosage interruption or reduction generally corrected hypocalcemia. Monitor serum calcium levels at least monthly; replace calcium as necessary. May require therapy interruption or dosage reduction.

Palmar-plantar erythrodysesthesia (usually grades 1 to 2) was observed in nearly one-third of patients receiving lenvatinib.

Proteinuria (including grade 3 toxicity) was commonly observed. Monitor for proteinuria at baseline and periodically throughout therapy. If urine dipstick for proteinuria is 2+, obtain a 24-hour urine protein. Withhold treatment for proteinuria ≥2 g/24 hours; resume at a reduced dose when proteinuria is • Reversible posterior leukoencephalopathy syndrome: Reversible posterior leukoencephalopathy syndrome (RPLS) has occurred (rarely). If RPLS diagnosis is confirmed through MRI, interrupt treatment until fully resolved. Therapy may resume at a reduced dose or be discontinued, depending on the severity and persistence of neurologic symptoms.

Arterial thromboembolic events, including grade 3 or greater events, have been reported. Discontinue treatment if arterial thrombosis occurs; the safety of resuming therapy after such an event has not been established. Lenvatinib has not been studied in patients who have had an arterial thromboembolic event within the preceding 6 months. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.