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Click on icon to see table/diagram/imageSerious cases of artery dissection, some with a fatal outcome, have been reported in patients using vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs), with or without hypertension.
Women of childbearing potential: Women of childbearing potential must use highly effective contraception while taking lenvatinib and for one month after stopping treatment (see Use in Pregnancy & Lactation). It is currently unknown if lenvatinib increases the risk of thromboembolic events when combined with oral contraceptives.
Proteinuria: Proteinuria has been reported in patients treated with lenvatinib, usually occurring early in the course of treatment (see Description of selected adverse reactions under Adverse Reactions). Monitor urine protein regularly. If urine dipstick proteinuria ≥2+ is detected, dose interruptions, adjustments, or discontinuation may be necessary (see Dosage & Administration). Cases of nephrotic syndrome have been reported in patients using lenvatinib. LENVIMA should be discontinued in the event of nephrotic syndrome.
Renal failure and impairment: Events of renal impairment (including renal failure) have been reported in patients treated with lenvatinib (see Adverse Reactions). The primary risk factor identified was dehydration and/or hypovolemia due to gastrointestinal toxicity. Gastrointestinal toxicity should be actively managed in order to reduce the risk of development of renal impairment or renal failure. Dose interruptions, adjustments, or discontinuation may be necessary (see Dosage & Administration).
If patients have severe renal impairment, the initial dose of lenvatinib should be adjusted (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Cardiac dysfunction: Cardiac failure (<1%) and decreased left ventricular ejection fraction have been reported in patients treated with lenvatinib (see Adverse Reactions). Patients should be monitored for clinical symptoms or signs of cardiac decompensation, as dose interruptions, adjustments, or discontinuation may be necessary (see Dosage & Administration).
Posterior reversible encephalopathy syndrome (PRES)/Reversible Posterior Leucoencephalopathy Syndrome (RPLS): Events of posterior reversible encephalopathy syndrome (PRES, also known as RPLS) have been reported in patients treated with lenvatinib (<1%; see Adverse Reactions). PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, altered mental function, blindness, and other visual or neurological disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of PRES. Appropriate measures should be taken to control blood pressure (see Hypertension as previously mentioned). In patients with signs or symptoms of PRES, dose interruptions, adjustments, or discontinuation may be necessary (see Dosage & Administration).
Hepatotoxicity: Liver-related adverse reactions most commonly reported in patients treated with lenvatinib included increases in alanine aminotransferase, increases in aspartate aminotransferase, and increases in blood bilirubin. Hepatic failure and acute hepatitis (<1%; see Description of selected adverse reactions under Adverse Reactions) have been reported in patients treated with lenvatinib. The hepatic failure events were generally reported in patients with progressive liver metastases. Liver function tests should be monitored before initiation of treatment, then every 2 weeks for the first 2 months and monthly thereafter during treatment. In the case of hepatotoxicity, dose interruptions, adjustments, or discontinuation may be necessary (see Dosage & Administration).
If patients have severe hepatic impairment, the initial dose of lenvatinib should be adjusted (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
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.
Haemorrhagic events: Serious haemorrhagic events have been reported in patients treated with lenvatinib (see Description of selected adverse reactions under Adverse Reactions). Fatal intracranial haemorrhagic events have been reported in some patients with brain metastases. Serious tumour related bleeds, including fatal haemorrhagic events in LENVIMA-treated patients, have occurred in clinical trials and been reported in post-marketing experience. In post-marketing surveillance, serious and fatal carotid artery haemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than in other tumour types. The safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials. In the case of bleeding, dose interruptions, adjustments, or discontinuation may be necessary (see Dosage & Administration).
Arterial thromboembolic events: Arterial thromboembolic events (cerebrovascular accident, transient ischaemic attack, and myocardial infarction) have been reported in patients treated with lenvatinib (see Adverse Reactions). Lenvatinib has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months, and therefore should be used with caution in such patients. A treatment decision should be made based upon an assessment of the individual patient's benefit/risk. LENVIMA should be discontinued following an arterial thrombotic event.
Gastrointestinal perforation and fistula formation: Events of gastrointestinal perforation or fistulae have been reported in patients treated with lenvatinib (see Adverse Reactions). In most cases, gastrointestinal perforation and fistulae occurred in patients with risk factors such as prior surgery or radiotherapy. In the case of a gastrointestinal perforation or fistula, dose interruptions, adjustments, or discontinuation may be necessary (see Dosage & Administration).
Non-Gastrointestinal fistula: Patients may be at increased risk for the development of fistulae when treated with lenvatinib. Cases of fistula formation or enlargement that involve areas of the body other than stomach or intestines were observed in clinical trials and in post-marketing experience (e.g. tracheal, tracheo-oesophageal, oesophageal, cutaneous, female genital tract fistulae). In addition, pneumothorax has been reported with and without clear evidence of a bronchopleural fistula. Some reports of fistula and pneumothorax occurred in association with tumour regression or necrosis. Prior surgery and radiotherapy may be contributing risk factors. Lung metastases may also increase the risk of pneumothorax. Lenvatinib should not be started in patients with fistula to avoid worsening and lenvatinib should be permanently discontinued in patients with oesophageal or tracheobronchial tract involvement and any Grade 4 fistula (see Dosage & Administration); limited information is available on the use of dose interruption or reduction in management of other events, but worsening was observed in some cases and caution should be taken. Lenvatinib may adversely affect the wound healing process as for other agents of the same class.
QT interval prolongation: QT/QTc interval prolongation has been reported at a higher incidence in patients treated with lenvatinib than in patients treated with placebo (see Adverse Reactions). Electrocardiograms should be monitored in all patients with a special attention for those with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, and those taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Electrolyte disturbances such as hypokalaemia, hypocalcaemia, or hypomagnesaemia increase the risk of QT prolongation, therefore electrolyte abnormalities should be monitored and corrected in all patients before starting treatment. Periodic monitoring of ECG and electrolytes (magnesium, potassium and calcium) should be considered during treatment.
Impairment of thyroid stimulating hormone suppression/Thyroid dysfunction: Lenvatinib impairs exogenous thyroid suppression (see Description of selected adverse reactions under Adverse Reactions). Thyroid stimulating hormone (TSH) levels should be monitored on a regular basis and thyroid hormone administration should be adjusted to reach appropriate TSH levels, according to the patient's therapeutic target.
Diarrhoea: Diarrhoea has been reported frequently in patients treated with lenvatinib, usually occurring early in the course of treatment (see Description of selected adverse reactions under Adverse Reactions). Prompt medical management of diarrhoea should be instituted in order to prevent dehydration. Lenvatinib should be discontinued in the event of persistence of Grade 4 diarrhoea despite medical management.
Impaired wound healing: No formal studies of the effect of lenvatinib on wound healing have been conducted. Impaired wound healing has been reported in patients receiving lenvatinib. Withhold lenvatinib 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 lenvatinib after resolution of wound healing complications has not been established.
Osteonecrosis of the jaw (ONJ): Cases of ONJ have been reported in patients treated with lenvatinib. Some cases were reported inpatients who had received prior or concomitant treatment with antiresorptive bone therapy, and/or other angiogenesis inhibitors, e.g. bevacizumab, TKI, mTOR inhibitors. Caution should therefore be exercised when lenvatinib is used either simultaneously or sequentially with antiresorptive therapy and/or other angiogenesis inhibitors.
Invasive dental procedures are an identified risk factor. Prior to treatment with lenvatinib, a dental examination and appropriate preventive dentistry should be considered. In patients who have previously received or are receiving intravenous bisphosphonates, invasive dental procedures should be avoided if possible (see Adverse Reactions).
Special populations: Limited data are available for patients of ethnic origin other than Caucasian or Asian, and in patients aged ≥75 years. Lenvatinib should be used with caution in such patients, given the reduced tolerability of lenvatinib in Asian and elderly patients (see Other special populations under Adverse Reactions).
There are no data on the use of lenvatinib immediately following sorafenib or other anticancer treatments and there may be a potential risk for additive toxicities unless there is an adequate washout period between treatments. The minimal washout period in clinical trials was of 4 weeks.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. Lenvatinib may cause side effects such as fatigue and dizziness. Patients who experience these symptoms should use caution when driving or operating machines.
