Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Eisai GmbH, Edmund-Rumpler-Straße 3, 60549 Frankfurt am Main, Germany, E-mail: medinfo_de@eisai.net
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Breast-feeding (see section 4.6).
Hypertension has been reported in patients treated with lenvatinib, usually occurring early in the course of treatment (see section 4.8). Blood pressure (BP) should be well controlled prior to treatment with lenvatinib and, if patients are known to be hypertensive, they should be on a stable dose of antihypertensive therapy for at least 1 week prior to treatment with lenvatinib. Serious complications of poorly controlled hypertension, including aortic dissection, have been reported. The early detection and effective management of hypertension are important to minimise the need for lenvatinib dose interruptions and reductions. Antihypertensive agents should be started as soon as elevated BP is confirmed. BP should be monitored after 1 week of treatment with lenvatinib, then every 2 weeks for the first 2 months, and monthly thereafter. The choice of antihypertensive treatment should be individualised to the patient’s clinical circumstances and follow standard medical practice. For previously normotensive patients, monotherapy with one of the classes of antihypertensive should be started when elevated BP is observed. For those patients already on an antihypertensive medicinal product, the dose of the current agent may be increased, if appropriate, or one or more agents of a different class of antihypertensive should be added. When necessary, manage hypertension as recommended in Table 3.
Table 3. Recommended management of hypertension:
| Blood pressure (BP) level | Recommended action |
|---|---|
| Systolic BP ≥140 mmHg up to <160 mmHg or diastolic BP ≥90 mmHg up to <100 mmHg | Continue lenvatinib and initiate antihypertensive therapy, if not already receiving OR Continue lenvatinib and increase the dose of the current antihypertensive therapy or initiate additional antihypertensive therapy |
| Systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg despite optimal antihypertensive therapy | 1. Withhold lenvatinib 2. When systolic BP ≤150 mmHg, diastolic BP ≤95 mmHg, and patient has been on a stable dose of antihypertensive therapy for at least 48 hours, resume lenvatinib at a reduced dose (see section 4.2) |
| Life-threatening consequences (malignant hypertension, neurological deficit, or hypertensive crisis) | Urgent intervention is indicated. Discontinue lenvatinib and institute appropriate medical management. |
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.
Women of childbearing potential must use highly effective contraception while taking lenvatinib and for one month after stopping treatment (see section 4.6). It is currently unknown if lenvatinib increases the risk of thromboembolic events when combined with oral contraceptives.
Proteinuria has been reported in patients treated with lenvatinib, usually occurring early in the course of treatment (see section 4.8, Description of selected adverse reactions). Urine protein should be monitored regularly. If urine dipstick proteinuria ≥2+ is detected, dose interruptions, adjustments, or discontinuation may be necessary (see section 4.2). Cases of nephrotic syndrome have been reported in patients using lenvatinib. Lenvatinib should be discontinued in the event of nephrotic syndrome.
Renal impairment and renal failure have been reported in patients treated with lenvatinib (see section 4.8). 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. 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 section 4.2).
If patients have severe renal impairment, the initial dose of lenvatinib should be adjusted (see sections 4.2 and 5.2).
Cardiac failure (<1%) and decreased left ventricular ejection fraction have been reported in patients treated with lenvatinib (see section 4.8). Patients should be monitored for clinical symptoms or signs of cardiac decompensation, as dose interruptions, adjustments, or discontinuation may be necessary (see section 4.2).
PRES, also known as RPLS, has been reported in patients treated with lenvatinib (<1%; see section 4.8, Description of selected 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 section 4.4, Hypertension). In patients with signs or symptoms of PRES, dose interruptions, adjustments, or discontinuation may be necessary (see section 4.2).
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 section 4.8, Description of selected adverse reactions) have been reported in patients treated with lenvatinib. The hepatic failure cases 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 section 4.2).
If patients have severe hepatic impairment, the initial dose of lenvatinib should be adjusted (see sections 4.2 and 5.2).
Arterial thromboembolisms (cerebrovascular accident, transient ischaemic attack, and myocardial infarction) have been reported in patients treated with lenvatinib (see section 4.8). 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.
Serious tumour related bleeds, including fatal haemorrhagic events have occurred in clinical trials and have been reported in post-marketing experience (see section 4.8). 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. tracheo-oesophageal fistulae. 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.
In the case of bleeding, dose interruptions, adjustments, or discontinuation may be required (see section 4.2, Table 2).
Gastrointestinal perforation or fistulae have been reported in patients treated with lenvatinib (see section 4.8). 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 section 4.2).
Patients may be at increased risk for the development of fistulae when treated with lenvatinib. 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. Lung metastases may also increase the risk of pneumothorax. Lenvatinib should not be started in patients with fistulae to avoid worsening and lenvatinib should be permanently discontinued in patients with oesophageal or tracheobronchial tract involvement and any Grade 4 fistula (see section 4.2); 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 do other agents of the same class.
QT/QTc interval prolongation has been reported at a higher incidence in patients treated with lenvatinib than in patients treated with placebo (see section 4.8, Description of selected adverse reactions). Electrocardiograms should be monitored in all patients with a special attention for those with congenital long QT syndrome, congestive heart failure, bradyarrhythmics, 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.
Hypothyroidism has been reported in patients treated with lenvatinib (see section 4.8, Description of selected 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 section 4.8). 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 has been reported frequently in patients treated with lenvatinib, usually occurring early in the course of treatment (see section 4.8). 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.
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.
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 (see section 4.8).
Lenvatinib can cause TLS which can be fatal. Risk factors for TLS include but are not limited to high tumour burden, pre-existing renal impairment and dehydration. These patients should be monitored closely and treated as clinically indicated, and prophylactic hydration should be considered.
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 section 4.8, Other special populations).
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.
Concomitant administration of lenvatinib, carboplatin, and paclitaxel has no significant impact on the pharmacokinetics of any of these 3 substances. Additionally, in patients with RCC the pharmacokinetics of lenvatinib was not significantly affected by concomitant everolimus.
A clinical drug-drug interaction (DDI) study in cancer patients showed that plasma concentrations of midazolam (a sensitive CYP3A and Pgp substrate) were not altered in the presence of lenvatinib. Additionally, in patients with RCC the pharmacokinetics of everolimus was not significantly affected by concomitant Lenvatinib. No significant drug-drug interaction is therefore expected between lenvatinib and other CYP3A4/Pgp substrates.
It is currently unknown whether lenvatinib may reduce the effectiveness of hormonal contraceptives, and therefore women using oral hormonal contraceptives should add a barrier method (see section 4.6).
Women of childbearing potential should avoid becoming pregnant and use highly effective contraception while on treatment with lenvatinib and for at least one month after finishing treatment. It is currently unknown whether lenvatinib may reduce the effectiveness of hormonal contraceptives, and therefore women using oral hormonal contraceptives should add a barrier method.
There are no data on the use of lenvatinib in pregnant women. Lenvatinib was embryotoxic and teratogenic when administered to rats and rabbits (see section 5.3).
Lenvatinib should not be used during pregnancy unless clearly necessary and after a careful consideration of the needs of the mother and the risk to the foetus.
It is not known whether lenvatinib is excreted in human milk. Lenvatinib and its metabolites are excreted in rat milk (see section 5.3).
A risk to newborns or infants cannot be excluded and, therefore, lenvatinib is contraindicated during breast-feeding (see section 4.3).
Effects in humans are unknown. However, testicular and ovarian toxicity has been observed in rats, dogs, and monkeys (see section 5.3).
Lenvatinib has 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.
The safety profile of lenvatinib is based on pooled data from 497 RCC patients treated with lenvatinib in combination with pembrolizumab, including Study 307 (CLEAR); pooled data from 623 RCC patients treated with lenvatinib in combination with everolimus: 458 DTC patients and 496 HCC patients treated with lenvatinib as monotherapy.
The safety profile of lenvatinib in combination with pembrolizumab is based on data from 497 RCC patients. The most frequently reported adverse reactions (occurring in ≥30% of patients) were diarrhoea (61.8%), hypertension (51.5%) fatigue (47.1%), hypothyroidism (45.1%), decreased appetite (42.1%), nausea (39.6%), stomatitis (36.6%), proteinuria (33.0%), dysphonia (32.8%), and arthralgia (32.4%).
The most common severe (Grade ≥3) adverse reactions (≥5%) were hypertension (26.2%), lipase increased (12.9%), diarrhoea (9.5%), proteinuria (8.0%), amylase increased (7.6%), weight decreased (7.2%), and fatigue (5.2%).
Discontinuation of lenvatinib, pembrolizumab, or both due to an adverse reaction occurred in 33.4% of patients; 23.7% lenvatinib, and 12.9 % both drugs. The most common adverse reactions (≥1%) leading to discontinuation of lenvatinib, pembrolizumab, or both were myocardial infarction (2.4%), diarrhoea (2.0%), proteinuria (1.8%), and rash (1.4%). Adverse reactions that most commonly led to discontinuation of lenvatinib (≥1%) were myocardial infarction (2.2%), proteinuria (1.8%), and diarrhoea (1.0%).
Dose interruptions of lenvatinib, pembrolizumab, or both due to an adverse reaction occurred in 80.1% of patients; lenvatinib was interrupted in 75.3%, and both drugs in 38.6% of patients. Lenvatinib was dose reduced in 68.4% of patients. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of lenvatinib were diarrhoea (25.6%), hypertension (16.1%), proteinuria (13.7%), fatigue (13.1%), appetite decreased (10.9%), palmar-plantar erythrodysaesthesia syndrome (PPE) (10.7%), nausea (9.7%), asthenia (6.6%), stomatitis (6.2%), lipase increased (5.6%), and vomiting (5.6%).
The safety profile of lenvatinib in combination with everolimus is based on data from 623 patients. The most frequently reported adverse reactions(occurring in ≥30% of patients) were diarrhoea (69.0%), fatigue (41.9%), hypertension (41.7%), decreased appetite (41.6%), stomatitis (40.6%), nausea (38.8%), proteinuria (34.2%), vomiting (32.7%) and weight decreased (31.3%). The most common severe (Grade ≥3) adverse reactions (≥5%) were hypertension (19.3%), diarrhoea (13.8%), proteinuria (8.8%), fatigue (7.1%), decreased appetite (6.3%) and weight decreased (5.8%).
Discontinuation of lenvatinib, everolimus, or both due to an adverse reaction occurred in 27.0% of patients; 21.7% lenvatinib, and 18.7% both drugs. The most common adverse reactions (≥1%) leading to discontinuation of lenvatinib, everolimus, or both were proteinuria (2.7%), diarrhoea (1.0%) and decreased appetite (1.0%). Adverse reaction that most commonly led to discontinuation of lenvatinib (≥1%) was proteinuria (2.1%).
Dose interruptions of lenvatinib, everolimus, or both due to an adverse reaction occurred in 82.2% of patients; in patients where data on individual drug modifications were collected, lenvatinib was interrupted in 74.3%, and both drugs in 71.9% of patients. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of lenvatinib were diarrhoea (30.4%), fatigue (15.3%), proteinuria (14.7%), appetite decreased (13.4%), stomatitis (13.2%), nausea (10.9%), vomiting (10.2%), hypertension (9.2%), asthenia (7.9%), platelet count decreased (5.7%), and weight decreased (5.1%).
Adverse reactions observed in clinical trials and reported from post-marketing use of lenvatinib are listed in Table 4. Adverse reactions known to occur with lenvatinib or combination therapy components given alone may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical studies with combination therapy.
For additional safety information when lenvatinib is administered in combination, refer to the SmPC for the respective combination therapy components.
Frequencies are defined as:
Within each frequency category, adverse reactions are presented in order of decreasing seriousness.
Table 4. Adverse reactions reported in patients treated with lenvatinib§:
| System Organ Class (MedDRA terminology) | Lenvatinib monotherapy | Combination with everolimus | Combination with pembrolizumab |
|---|---|---|---|
| Infections and infestations | |||
| Very common | Urinary tract infection | ||
| Common | Urinary tract infection | Urinary tract infection | |
| Uncommon | Perineal abscess | Perineal abscess | Perineal abscess |
| Blood and lymphatic disorders | |||
| Very common | Thrombocytopenia‡ Lymphopenia‡ Leukopenia‡ Neutropenia‡ | Thrombocytopenia‡ Lymphopenia‡ Leukopenia‡ Neutropenia‡ | Thrombocytopenia‡ Lymphopenia‡ Leukopenia‡ Neutropenia‡ |
| Uncommon | Splenic infarction | ||
| Endocrine disorders | |||
| Very common | Hypothyroidism* Increased blood thyroid stimulating hormone*‡ | Hypothyroidism* Increased blood thyroid stimulating hormone*‡ | Hypothyroidism* Increased blood thyroid stimulating hormone*‡ |
| Common | Adrenal insufficiency | ||
| Uncommon | Adrenal insufficiency | Adrenal insufficiency | |
| Metabolism and nutrition disorders | |||
| Very common | Hypocalcaemia*‡ Hypokalaemia‡ Hypomagnesaemia‡ Hypercholesterolaemia‡ Decreased weight Decreased appetite | Hypocalcaemia‡ Hypokalaemia‡ Hypomagnesaemia‡ Hypercholesterolaemia*‡ Decreased weight Decreased appetite | Hypocalcaemia‡ Hypokalaemia‡ Hypomagnesaemia‡ Hypercholesterolaemia*‡ Decreased weight Decreased appetite |
| Common | Dehydration | Dehydration | Dehydration |
| Rare | Tumour lysis syndrome† | Tumour lysis syndrome† | Tumour lysis syndrome† |
| Psychiatric disorders | |||
| Very common | Insomnia | Insomnia | Insomnia |
| Nervous system disorders | |||
| Very common | Dizziness Headache Dysgeusia | Headache Dysgeusia | Dizziness Headache Dysgeusia |
| Common | Cerebrovascular accident† | Dizziness | |
| Uncommon | Posterior reversible encephalopathy syndrome Monoparesis Transient ischaemic attack | Cerebrovascular accident† Transient ischaemic attack | Cerebrovascular accident Posterior reversible encephalopathy syndrome Transient ischaemic attack |
| Cardiac disorders | |||
| Common | Myocardial infarctiona,† Cardiac failure Prolonged electrocardiogram QT Decreased ejection fraction | Myocardial infarctiona,† Cardiac failure† Prolonged electrocardiogram QT | Myocardial infarctiona Prolonged electrocardiogram QT |
| Uncommon | Decreased ejection fraction | Cardiac failure† Decreased ejection fraction | |
| Vascular disorders | |||
| Very common | Haemorrhage*b,† Hypertension*c Hypotension | Haemorrhage*b,† Hypertension*c | Haemorrhage*b,† Hypertension*c |
| Common | Hypotension | Hypotension | |
| Not known | Aneurysms and artery dissections | Aneurysms and artery dissections | Aneurysms and artery dissections |
| Respiratory, thoracic and mediastinal disorders | |||
| Very common | Dysphonia | Dysphonia | Dysphonia |
| Common | Pulmonary embolism† | Pulmonary embolism Pneumothorax | Pulmonary embolism |
| Uncommon | Pneumothorax | Pneumothorax | |
| Gastrointestinal disorders | |||
| Very common | Diarrhoea* Gastrointestinal and abdominal painsd Vomiting Nausea Oral inflammatione Oral painf Constipation Dyspepsia Dry mouth Increased lipase‡ Increased amylase‡ | Diarrhoea* Gastrointestinal and abdominal painsd Vomiting Nausea Oral inflammatione Oral painf Constipation Dyspepsia Increased lipase‡ Increased amylase‡ | Diarrhoea* Gastrointestinal and abdominal painsd Vomiting Nausea Oral inflammatione Oral painf Constipation Dyspepsia Dry mouth Increased lipase‡ Increased amylase‡ |
| Common | Anal fistula Flatulence Gastrointestinal perforation | Dry mouth Flatulence Gastrointestinal perforation | Pancreatitisg Colitis Flatulence Gastrointestinal perforation |
| Uncommon | Pancreatitisg Colitis | Pancreatitisg Anal fistula Colitis | Anal fistula |
| Hepatobiliary disorders | |||
| Very common | Increased blood bilirubin*‡ Hypoalbuminaemia*‡ Increased alanine aminotransferase*‡ Increased aspartate aminotransferase*‡ Increased blood alkaline phosphatase‡ Increased gamma- glutamyltransferase‡ | Hypoalbuminaemia*‡ Increased alanine aminotransferase‡ Increased aspartate aminotransferase‡ Increased blood alkaline phosphatase‡ | Increased blood bilirubin‡ Hypoalbuminaemia‡ Increased alanine aminotransferase‡ Increased aspartate aminotransferase‡ Increased blood alkaline phosphatase‡ |
| Common | Hepatic failureh,† Hepatic encephalopathyi,† Cholecystitis Abnormal hepatic function | Cholecystitis Abnormal hepatic function Increased gamma- glutamyltransferase Increased blood bilirubin*‡ | Cholecystitis Abnormal hepatic function Increased gamma- glutamyltransferase |
| Uncommon | Hepatocellular damage/hepatitisj | Hepatic failureh,† Hepatic encephalopathyi | Hepatic failureh,† Hepatic encephalopathyi Hepatocellular damage/hepatitisj |
| Skin and subcutaneous tissue disorders | |||
| Very common | Palmar-plantar erythrodysaesthesia syndrome Rash Alopecia | Palmar-plantar erythrodysaesthesia syndrome Rash | Palmar-plantar erythrodysaesthesia syndrome Rash |
| Common | Hyperkeratosis | Alopecia | Hyperkeratosis Alopecia |
| Uncommon | Hyperkeratosis | ||
| Musculoskeletal and connective tissue disorders | |||
| Very common | Back pain Arthralgia Myalgia Pain in extremity Musculoskeletal pain | Back pain Arthralgia | Back pain Arthralgia Myalgia Pain in extremity Musculoskeletal pain |
| Common | Myalgia Pain in extremity Musculoskeletal pain | ||
| Uncommon | Osteonecrosis of the jaw | Osteonecrosis of the jaw | |
| Renal and urinary disorders | |||
| Very common | Proteinuria* Increased blood creatinine‡ | Proteinuria* Increased blood creatinine‡ | Proteinuria* Increased blood creatinine‡ |
| Common | Renal failure*k,† Renal impairment* Increased blood urea | Renal failure*k,† Renal impairment* Increased blood urea | Renal failure*k Increased blood urea |
| Uncommon | Nephrotic syndrome | Nephrotic syndrome Renal impairment* | |
| General disorders and administration site conditions | |||
| Very common | Fatigue Asthenia Oedema peripheral | Fatigue Asthenia Oedema peripheral | Fatigue Asthenia Oedema peripheral |
| Common | Malaise | Malaise | Malaise |
| Uncommon | Impaired healing | Impaired healing Non-gastrointestinal fistulal | Impaired healing Non-gastrointestinal fistulal |
| Not known | Non-gastrointestinal fistulal | ||
§ Adverse reaction frequencies presented in Table 4 may not be fully attributable to lenvatinib alone but may contain contributions from the underlying disease or from other medicinal products used in a combination.
* See section 4.8 Description of selected adverse reactions for further characterisation.
† Includes cases with a fatal outcome.
‡ Frequency based on laboratory data.
The following terms have been combined:
a Myocardial infarction includes myocardial infarction and acute myocardial infarction.
b Includes all haemorrhage terms: Haemorrhage terms that occurred in 5 or more patients with RCC in lenvatinib plus pembrolizumab were: epistaxis, haematuria, contusion, gingival bleeding, rectal haemorrhage, haemoptysis, ecchymosis, and haematochezia.
c Hypertension includes: hypertension, hypertensive crisis, increased blood pressure diastolic, orthostatic hypertension and increased blood pressure.
d Gastrointestinal and abdominal pain includes: abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, abdominal tenderness, epigastric discomfort, and gastrointestinal pain.
e Oral inflammation includes: aphthous stomatitis, aphthous ulcer, gingival erosion, gingival ulceration, oral mucosal blistering, stomatitis, glossitis, mouth ulceration, and mucosal inflammation.
f Oral pain includes: oral pain, glossodynia, gingival pain, oropharyngeal discomfort, oropharyngeal pain and tongue discomfort.
g Pancreatitis includes: pancreatitis and acute pancreatitis.
h Hepatic failure includes: hepatic failure, acute hepatic failure and chronic hepatic failure.
i Hepatic encephalopathy includes: hepatic encephalopathy, coma hepatic, metabolic encephalopathy and encephalopathy.
j Hepatocellular damage and hepatitis includes: drug-induced liver injury, hepatic steatosis, and cholestatic liver injury.
k Renal failure includes: acute prerenal failure, renal failure, renal failure acute, acute kidney injury, and renal tubular necrosis.
l Non-gastrointestinal fistula includes cases of fistula occurring outside of the stomach and intestines such as tracheal, tracheo-oesophageal, oesophageal, cutaneous fistula and female genital tract fistula.
In CLEAR (see section 5.1), hypertension was reported in 56.3% of patients in the lenvatinib plus pembrolizumab-treated group and 42.6% of patients in the sunitinib-treated group. The exposure-adjusted frequency of hypertension was 0.65 episodes per patient year in the lenvatinib plus pembrolizumab-treated group and 0.73 episodes per patient year in the sunitinib-treated group. The median time to onset in lenvatinib plus pembrolizumab-treated patients was 0.7 months. Reactions of Grade 3 or higher occurred in 28.7% of lenvatinib plus pembrolizumab-treated group compared with 19.4% of the sunitinib-treated group. 16.8% of patients with hypertension had dose modifications of lenvatinib (9.1% dose interruption and 11.9% dose reduction). In 0.9% of patients, hypertension led to permanent treatment discontinuation of lenvatinib.
In the pooled RCC population treated with lenvatinib and everolimus, hypertension was reported in 42.5% of patients (the incidence of Grade 3 or Grade 4 hypertension was 19.7%). In patients where data on individual drug modifications were collected, 9.8% of patients with hypertension had dose modifications of lenvatinib (5.3% dose reduction and 6.2% dose interruption) and led to permanent treatment discontinuation in 0.9% of patients. The median time to onset of hypertension events in lenvatinib plus everolimus treated patients was 0.5 months.
In the pooled RCC population treated with lenvatinib and everolimus, proteinuria was reported in 34.8% of patients (9.0% were Grade ≥3). In patients where data on individual drug modifications were collected, 15.1% of patients with proteinuria had dose modifications of lenvatinib (9.6% reduction and 9.8% interruption) and led to permanent treatment discontinuation in 2.1% of patients. The median time to onset of proteinuria events in lenvatinib plus everolimus treated patients was 1.4 months.
In the pooled RCC population treated with lenvatinib and everolimus, 1.3% of patients developed renal failure (0.6% were Grade ≥3) and 5.3% developed acute kidney injury (2.7% were Grade ≥3). Renal events were reported in 17.2% of patients (4.3% were Grade ≥3). In patients where data on individual drug modifications were collected, 5.5% of patients with renal events had dose modifications of lenvatinib (2.3% reduction and 4.0% interruption) and led to permanent treatment discontinuation in 1.9% of patients. The median time to onset of renal events in lenvatinib plus everolimus treated patients was 3.5 months.
In the pooled RCC population treated with lenvatinib and everolimus, cardiac dysfunction events were reported in 3.5% of patients (1.8% were Grade ≥3). In patients where data on individual drug modifications were collected, 0.9% of patients with cardiac dysfunction events had dose modifications of lenvatinib (0.4% reduction and 0.8% interruption) and led to permanent treatment discontinuation in 0.6% of patients. The median time to onset of cardiac dysfunction events in lenvatinib plus everolimus treated patients was 3.6 months.
In the pooled RCC population treated with lenvatinib and everolimus, there was 1 event of PRES reported (Grade 2), occurring after 1.3 months of treatment for which no dose modifications or discontinuation were required.
In CLEAR (see section 5.1), the most commonly reported liver-related adverse reactions in the lenvatinib plus pembrolizumab-treated group were elevations of liver enzyme levels, including increases in alanine aminotransferase (11.9%), aspartate aminotransferase (11.1%) and blood bilirubin (4.0%). Similar events occurred in the sunitinib-treated group at rates of 10.3%, 10.9% and 4.4% respectively. The median time to onset of liver events was 3.0 months (any grade) in the lenvatinib plus pembrolizumab-treated group and 0.7 months in the sunitinib-treated group. The exposure-adjusted frequency of hepatoxicity events was 0.39 episodes per patient year in the lenvatinib plus pembrolizumab-treated group and 0.46 episodes per patient year in the sunitinib-treated group. Grade 3 liver-related reactions occurred in 9.9% of lenvatinib plus pembrolizumab-treated patients and 5.3% of sunitinib-treated patients. Liver-related reactions led to dose interruptions and reductions of lenvatinib in 8.5% and 4.3% of patients, respectively, and to permanent discontinuation of lenvatinib in 1.1% of patients.
In the pooled RCC population treated with lenvatinib and everolimus, the most commonly reported liver-related adverse reactions were elevations of liver enzyme levels, including increases in alanine aminotransferase (11.9%), aspartate aminotransferase (11.4%) and gamma-glutamyltransferase increased (2.7%). Grade 3 liver related reactions occurred in 6.1% of lenvatinib plus everolimus treated patients. In patients where data on individual drug modifications were collected, 6.0% of patients with hepatotoxicity events had dose modifications of lenvatinib (2.8% reduction and 4.2% interruption) and led to permanent treatment discontinuation in 0.9% of patients. The median time to onset of liver-related reactions in lenvatinib plus everolimus treated patients was 1.8 months.
In CLEAR (see section 5.1), 5.4% of patients in the lenvatinib plus pembrolizumab-treated group reported arterial thromboembolic events (of which 3.7% were Grade ≥ 3) compared with 2.1% of patients in the sunitinib-treated group (of which 0.6% were Grade ≥ 3). No events were fatal. The exposure-adjusted frequency of arterial thromboembolic event episodes was 0.04 episodes per patient year in the lenvatinib plus pembrolizumab-treated group and 0.02 episodes per patient year in the sunitinib-treated group. The most commonly reported arterial thromboembolic event in the lenvatinib plus pembrolizumab-treated group was myocardial infarction (3.4%). One event of myocardial infarction (0.3%) occurred in the sunitinib-treated group. The median time to onset of arterial thromboembolic events was 10.4 months in the lenvatinib plus pembrolizumab-treated group.
In the pooled RCC population treated with lenvatinib and everolimus, arterial thromboembolic events were reported in 2.7% of patients (2.2% were Grade ≥3). In patients where data on individual drug modifications were collected, 0.6% of patients with arterial thromboembolic events had dose modifications of lenvatinib (0.6% interruption) and led to permanent treatment discontinuation in 1.5% of patients. The most commonly reported arterial thromboembolic event in the lenvatinib plus everolimus-treated group was myocardial infarction (1.3%). The median time to onset of arterial thromboembolic events in lenvatinib plus everolimus treated patients was 6.8 months.
In the pooled RCC population treated with lenvatinib and everolimus, haemorrhage events were reported in 28.6% of patients (3.2% were Grade ≥3). In patients where data on individual drug modifications were collected, 4.9% of patients with haemorrhage events had dose modifications of lenvatinib (4.2% interruption and 0.8% reduction) and led to permanent treatment discontinuation in 0.6% of patients. The most commonly reported haemorrhage events in the lenvatinib plus everolimus-treated group were epistaxis (19.4%) and haematuria (4.2%). The median time to onset of haemorrhage events in lenvatinib plus everolimus treated patients was 1.9 months.
In the pooled RCC population treated with lenvatinib and everolimus, hypocalcaemia was reported in 4.8% of patients (1.1% were Grade ≥3). In patients where data on individual drug modifications were collected, 0.8% of patients with hypocalcaemia had dose modifications of lenvatinib (0.6% dose interruption and 0.4% dose reduction) and led to permanent treatment discontinuation in no patients. The median time to onset of hypocalcaemia events in lenvatinib plus everolimus-treated patients was 2.9 months.
In the pooled RCC population treated with lenvatinib and everolimus, GI perforation events were reported in 3.7% of patients (2.9% were Grade ≥3). In patients where data on individual drug modifications were collected, 2.1% of patients with GI perforations had dose modifications of lenvatinib (1.5% interruption and 0.6% reduction) and led to permanent treatment discontinuation in 1.1% of patients. The median time to onset of GI perforation events in lenvatinib plus everolimus-treated patients was 3.6 months.
In the pooled RCC population treated with lenvatinib and everolimus, fistula formation events were reported in 1.0% of patients (0.5% were Grade ≥3). In patients where data on individual drug modifications were collected, 0.8% of patients with GI perforations had dose modifications of lenvatinib (0.8% interruption) and led to permanent treatment discontinuation in 0.4% of patients. The median time to onset of fistula formation events in lenvatinib plus everolimus-treated patients was 3.7 months.
Lenvatinib use has been associated with cases of fistulae including reactions resulting in death. Reports of fistulae that involve areas of the body other than stomach or intestines were observed across various indications. Reactions were reported at various time points during treatment ranging from two weeks to greater than 1 year from initiation of lenvatinib, with a median latency of about 3 months.
In the pooled RCC population treated with lenvatinib and everolimus, QTcF interval increases greater than 60 ms were reported in 9.8% of patients in the lenvatinib plus everolimus-treated group. The incidence of QTc interval greater than 500 ms was 3.3% in the lenvatinib plus everolimus-treated group. The median time to onset of QT prolongation events in lenvatinib plus everolimus-treated patients was 3.0 months.
In CLEAR (see section 5.1), hypothyroidism occurred in 47.2% of patients in the lenvatinib plus pembrolizumab-treated group and 26.5% of patients in the sunitinib-treated group. The exposure- adjusted frequency of hypothyroidism was 0.39 episodes per patient year in the lenvatinib plus pembrolizumab-treated group and 0.33 episodes per patient year in the sunitinib-treated group. In general, the majority of hypothyroidism events in the lenvatinib plus pembrolizumab-treated group were of Grade 1 or 2. Grade 3 hypothyroidism was reported in 1.4% of patients in the lenvatinib plus pembrolizumab-treated group versus none in the sunitinib-treated group. At baseline, 90.0% of patients in the lenvatinib plus pembrolizumab-treated group and 93.1% of patients in the sunitinib-treated group had baseline TSH levels ≤ upper limit of normal. Elevations of TSH > upper limit of normal were observed post baseline in 85.0% of lenvatinib plus pembrolizumab-treated patients versus 65.6% of sunitinib-treated patients. In lenvatinib plus pembrolizumab-treated patients, hypothyroidism events resulted in dose modification of lenvatinib (reduction or interruption) in 2.6% patients and discontinuation of lenvatinib in 1 patient.
In the pooled RCC population treated with lenvatinib and everolimus, hypothyroidism occurred in 24.1% of patients. In general, the majority of hypothyroidism events were of Grade 1 or 2. Grade 3 hypothyroidism was reported in 0.3% of patients in the lenvatinib plus everolimus-treated patients. The median time to onset of hypothyroidism events in lenvatinib plus everolimus-treated patients was 2.7 months. At baseline, 83.0% of patients in the lenvatinib plus everolimus-treated group had TSH levels ≤ upper limit of normal. Elevations of TSH > upper limit of normal were observed post-baseline in 71.3% of lenvatinib plus everolimus-treated patients. In patients where data on individual drug modifications were collected, hypothyroidism events resulted in dose modification of lenvatinib (0.4% dose reduction or 0.9% dose interruption) in 1.3% of patients. No discontinuations were reported.
In the pooled RCC population treated with lenvatinib and everolimus, diarrhoea was reported in 69.0% of patients (13.8% were Grade ≥3). In patients where data on individual drug modifications were collected, 30.4% of patients had dose modifications of lenvatinib (17.7% interruptions and 19.6% reductions) and led to permanent treatment discontinuation in 0.6% of patients.
In the paediatric Studies 216 and 231 (see section 5.1), the overall safety profile of lenvatinib as a single agent or in combination with everolimus was consistent with that observed in adults treated with lenvatinib.
In Study 216, pneumothorax was reported in 3 patients (4.7%) with Ewing sarcoma, rhabdomyosarcoma (RMS) and Wilms tumour; all 3 patients had lung metastases at baseline. In
Study 231, pneumothorax was reported in 7 patients (5.5%) with spindle cell sarcoma, undifferentiated sarcoma, RMS, malignant peripheral nerve sheath tumour, synovial sarcoma, spindle cell carcinoma, and malignant fibromyxoid ossifying tumour; all 7 patients had lung metastases or primary disease in the chest wall or pleural cavity at baseline. For Studies 216 and 231, no patient discontinued study treatment due to pneumothorax (for additional paediatric information see also Lenvima SmPC section 4.8). In Phase 1 (combination dose-finding cohort) of Study 216, the most frequently (≥40%) reported adverse drug reactions were hypertension, hypothyroidism, hypertriglyceridemia, abdominal pain, and diarrhoea; and in Phase 2 (combination expansion cohort), the most frequently reported (≥35%) adverse drug reactions were hypertriglyceridemia, proteinuria, diarrhoea, lymphocyte count decreased, white blood cell count decreased, blood cholesterol increased, fatigue, and platelet count decreased. In Study 231, the most frequently reported (≥15%) adverse drug reactions were hypothyroidism, hypertension, proteinuria, decreased appetite, diarrhoea, and platelet count decreased.
In CLEAR, elderly patients (≥75 years) had a higher (≥10% difference) incidence of proteinuria than younger patients (<65 years).
In the pooled RCC population treated with lenvatinib and everolimus, elderly patients (≥75 years) had a higher (≥10% difference) incidence of platelet count decreased, weight decreased, proteinuria and hypertension than younger patients (<65 years).
In CLEAR, males had a higher (≥10% difference) incidence than females of diarrhoea.
In the pooled RCC population treated with lenvatinib and everolimus, females had a higher (≥10% difference) incidence than males of nausea, vomiting, asthenia and hypertension.
In CLEAR, Asian patients had a higher (≥10% difference) incidence than Caucasian patients of palmar-plantar erythrodysaesthesia syndrome, proteinuria and hypothyroidism (including blood thyroid hormone increased) while Caucasian patients had a higher incidence of fatigue, nausea, arthralgia, vomiting, and asthenia.
In the pooled RCC population treated with lenvatinib and everolimus, Asian patients had a higher (≥10% difference) incidence than Caucasian patients of hypothyroidism, stomatitis, platelet count decreased, proteinuria, dysphonia, PPE and hypertension while Caucasian patients had a higher incidence of nausea, asthenia, fatigue and hypercholesterolaemia.
In CLEAR, patients with baseline hypertension had a higher incidence of proteinuria than patients without baseline hypertension.
In the pooled RCC population treated with lenvatinib and everolimus, patients with baseline diabetes had a higher incidence (≥10% difference) of proteinuria than those without baseline diabetes.
There are limited data on patients with hepatic impairment in RCC.
In RCC patients treated with lenvatinib and everolimus, patients with baseline renal impairment had higher incidence of thrombocytopenia or platelet count decreased compared with patients with normal renal function.
In RCC patients treated with lenvatinib and everolimus, those with low body weight (<60 kg) had a higher incidence (≥10% difference) of platelet count decreased and hypertension.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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