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Click on icon to see table/diagram/imageAneurysms and artery dissections: The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating lenvatinib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.
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). Urine protein should be monitored 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. Lenvatinib should be discontinued in the event of nephrotic syndrome.
Renal failure and impairment/Gastrointestinal Toxicity: Renal impairment and renal failure have been reported in patients treated with lenvatinib (see Description of selected adverse reactions under 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. In RCC, caution should be taken in patients receiving agents acting on the renin-angiotensin aldosterone system given a potentially higher risk for acute renal failure with the combination treatment. 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 Description of selected adverse reactions under 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): PRES, also known as RPLS, has been reported in patients treated with lenvatinib (<1%; see Description of selected adverse reactions under 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: In DTC and RCC patients, liver-related adverse reactions most commonly reported in patients treated with lenvatinib included increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and blood bilirubin. Hepatic failure and acute hepatitis (<1%; see Description of selected adverse reactions under Adverse Reactions) have been reported in patients with DTC treated with lenvatinib. The hepatic failure cases were generally reported in patients with progressive metastatic liver metastases disease.
In HCC patients treated with lenvatinib in the REFLECT trial, liver-related adverse reactions including hepatic encephalopathy and hepatic failure (including fatal reactions) were reported at a higher frequency (see Adverse Reactions) compared to patients treated with sorafenib. Patients with worse hepatic impairment and/or greater liver tumour burden at baseline had a higher risk of developing hepatic encephalopathy and hepatic failure. Hepatic encephalopathy also occurred more frequently in patients aged 75 years and older. Approximately half of the events of hepatic failure and one third of the events of the hepatic encephalopathy were reported in patients with disease progression.
Data in HCC patients with moderate hepatic impairment (Child-Pugh B) are very limited and there are currently no data available in HCC patients with severe hepatic impairment (Child-Pugh C). Since lenvatinib is mainly eliminated by hepatic metabolism, an increase in exposure in patients with moderate to severe hepatic impairment is expected.
Close monitoring of the overall safety is recommended in patients with mild or moderate hepatic impairment (see also Dosage & Administration and Pharmacology: Pharmacokinetics under Actions). Liver function tests should be monitored before initiation of treatment, then every 2 weeks for the first 2 months and monthly thereafter during treatment. Patients with HCC should be monitored for worsening liver function including hepatic encephalopathy. In the case of hepatotoxicity, dose interruptions, adjustments, or discontinuation may be necessary (see Dosage & Administration).
Arterial thromboembolisms: Arterial thromboembolisms (cerebrovascular accident, transient ischaemic attack, and myocardial infarction) have been reported in patients treated with lenvatinib (see Description of selected adverse reactions under Adverse Reactions). Lenvatinib has not been studied in patients who have had an arterial thromboembolism 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. Lenvatinib should be discontinued following an arterial thrombotic event.
Haemorrhage: Serious tumour related bleeds, including fatal haemorrhagic events have occurred in clinical trials and have been reported in post-marketing experience (see Description of selected adverse reactions under Adverse Reactions). In post-marketing surveillance, serious and fatal carotid artery haemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than in DTC or other tumour types. The degree of tumour invasion/infiltration of major blood vessels (e.g. carotid artery) should be considered because of the potential risk of severe haemorrhage associated with tumour shrinkage/necrosis following lenvatinib therapy. Some cases of bleeding have occurred secondarily to tumour shrinkage and fistula formation, e.g. tracheooesophageal fistula. Cases of fatal intracranial haemorrhage have been reported in some patients with or without brain metastases. Bleeding in sites other than the brain (e.g. trachea, intra-abdominal, lung) has also been reported. One fatal case of hepatic tumour haemorrhage in a patient with HCC has been reported.
Screening for and subsequent treatment of oesophageal varices in patients with liver cirrhosis should be performed as per standard of care before starting treatment with lenvatinib.
In RCC, serious cases of haemorrhage have been reported in patients treated with lenvatinib (see Description of selected adverse reactions under Adverse Reactions). Cases of fatal intracranial haemorrhage have been reported in some patients with or without brain metastases.
In the case of bleeding, dose interruptions, adjustments, or discontinuation may be required (see Table 6 under Dosage & Administration).
Gastrointestinal perforation and fistulae formation: Gastrointestinal perforation or fistula has been reported in patients treated with lenvatinib (see Adverse Reactions). In most cases, gastrointestinal perforation and fistula 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 fistula when treated with lenvatinib in DTC. Cases of fistula formation or enlargement that involve other areas of the body 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. 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 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 Description of selected adverse reactions under Adverse Reactions). Electrocardiograms should be monitored at baseline and periodically during treatment in all patients with a special attention for those with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, and those taking medicinal products known to prolong the QT interval, including Class Ia and III antiarrhythmics. Lenvatinib should be withheld in the event of development of QT interval prolongation greater than 500 ms. Lenvatinib should be resumed at a reduced dose when QTc prolongation is resolved to <480 ms or baseline.
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. Blood calcium levels should be monitored at least monthly and calcium should be replaced as necessary during lenvatinib treatment. Lenvatinib dose should be interrupted or dose adjusted as necessary depending on severity, presence of ECG changes, and persistence of hypocalcaemia.
Impairment of thyroid stimulating hormone suppression/Thyroid dysfunction: Hypothyroidism has been reported in patients treated with lenvatinib (see Description of selected adverse reactions under Adverse Reactions). Thyroid function should be monitored before initiation of, and periodically throughout, treatment with lenvatinib. Hypothyroidism should be treated according to standard medical practice to maintain euthyroid state.
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.
Wound Healing Complications: No formal studies of the effect of lenvatinib on wound healing have been conducted. Impaired wound healing has been reported in patients receiving lenvatinib. Temporary interruption of lenvatinib should be considered in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of lenvatinib following a major surgical procedure. Therefore, the decision to resume lenvatinib following a major surgical procedure should be based on clinical judgment of adequate wound healing.
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.
Osteonecrosis of the jaw (ONJ): Cases of ONJ have been reported in patients treated with lenvatinib. Some cases were reported in patients 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.
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: Lenvatinib has a minor influence on the ability to drive and use machines, due to undesirable effects such as fatigue and dizziness. Patients who experience these symptoms should use caution when driving or operating machines.
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.
