Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Eisai Europe Limited, European Knowledge Centre, Mosquito Way, Hatfield, AL10 9SN, United Kingdom
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, Description of selected adverse reactions). 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 subjects, 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, Description of selected 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. 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, Description of selected adverse reactions). 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, Description of selected 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.
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, Description of selected 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. 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, Description of selected 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 has been reported frequently in patients treated with lenvatinib, usually occurring early in the course of treatment (see section 4.8, Description of selected 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.
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).
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 in combination with everolimus is based on data from 62 subjects, allowing characterisation only of common adverse drug reactions in RCC patients. The adverse reactions presented in this section are based on the combined safety data of 62 RCC patients (see section 5.1) and 458 DTC patients (see Lenvima SmPC).
The most frequently reported adverse reactions in the RCC and DTC patient populations (occurring in ≥30% of patients) were diarrhoea (80.6%), hypertension (70.1%)*, fatigue (59.7%), decreased appetite (53.7%), weight decreased (52.6%)*, vomiting (48.4%), nausea (45.2%), proteinuria (38.9%)*, stomatitis (36.9%)*, headache (35.8%)*, dysphonia (35.6%)*, palmar-plantar erythrodysaesthesia syndrome (PPE) (34.1%)*, peripheral oedema (33.9%), and hypercholesterolemia (30.6%). Hypertension and proteinuria tend to occur early during lenvatinib treatment (see sections 4.4 and 4.8, Description of selected adverse reactions; the asterisked frequencies are from the DTC patient population).
The most important serious adverse reactions were renal failure and impairment (11.3%), arterial thromboembolisms (3.9%)*, cardiac failure (1.6%), cerebral haemorrhage (1.6%), intracranial tumour haemorrhage (0.7%)*, PRES/RPLS (0.2%)*, and hepatic failure (0.2%)* (the asterisked frequencies are from the DTC patient population).
In the RCC study (see section 5.1), adverse reactions led to dose reductions in 67.7% of patients and 18 (29.0%) patients discontinued the treatment. The most common adverse reactions (≥5%) resulting in dose reductions in the lenvatinib plus everolimus treated group were diarrhoea (21.0%), thrombocytopenia (6.5%), and vomiting (6.5%).
Similar adverse reactions were observed in clinical trials in RCC and DTC. Adverse reactions that occur more frequently with combination therapy compared to lenvatinib monotherapy are hypothyroidism, (including increased blood thyroid stimulating hormone), hypercholesterolaemia, and severe diarrhoea.
Adverse reactions observed in clinical trials and reported from post-marketing use of lenvatinib are listed in Table 4.
Frequencies are defined as: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Not known (cannot be estimated from the available data).
Within each frequency category, undesirable effects are presented in order of decreasing seriousness.
Table 4 Adverse reactions reported in patients treated with lenvatinib:
| System Organ Class (MedDRA terminology*) | Very Common | Common | Uncommon | Not known |
|---|---|---|---|---|
| Infections and infestation | Urinary tract infection | Perineal abscess | ||
| Blood and lymphatic disorders | Thrombocytopeniaa | Lymphopeniaa | Splenic infarction | |
| Endocrine disorders | Hypothyroidism** Blood thyroid stimulating hormone increased‡** | |||
| Metabolism and nutrition disorders | Hypocalcaemia‡ Hypercholesterolaemiab** Hypokalaemia Decreased appetite Weight decreased | Dehydration Hypomagnesaemiab | ||
| Psychiatric disorders | Insomnia | |||
| Nervous system disorders | Dizziness Headache Dysgeusia | Cerebrovascular accident | Posterior reversible encephalopathy syndrome Monoparesis Transient ischaemic attack | |
| Cardiac disorders | Myocardial infarctionc,† Cardiac failure Electrocardiogram QT prolonged Ejection fraction decreased | |||
| Vascular disorders | Haemorrhaged,†,‡ Hypertensione,‡ Hypotension | Aneurysms and artery dissections | ||
| Respiratory, thoracic and mediastinal disorders | Dysphonia | Pulmonary embolism† | Pneumothorax | |
| Gastrointestinal disorders | Diarrhoea‡** Gastrointestinal and abdominal painsf Vomiting Nausea Oral inflammationg Oral painh Constipation Dyspepsia Dry mouth | Anal fistula Flatulence Lipase increased Amylase increased | Pancreatitis | |
| Hepatobiliary disorders | Aspartate aminotransferase increased‡ Hypoalbuminaemia‡ Alanine aminotransferase increased‡ Blood alkaline phosphatase increased Hepatic function abnormal Gamma-glutamyltransferase increasedk Blood bilirubin increased‡ Cholecystitis | Hepatocellular damage/hepatitisi | ||
| Skin and subcutaneous tissue disorders | Palmar-plantar erythrodysaesthesia syndrome Palmar erythema Rash Alopecia | Hyperkeratosis | ||
| Musculoskeletal and connective tissue disorders | Back pain Arthralgia Myalgia Pain in extremity Musculoskeletal pain | Osteonecrosis of the jaw | ||
| Renal and urinary disorders | Proteinuria‡ | Renal failurej,†,‡ Renal impairment‡ Blood creatinine increased Blood urea increased | Nephrotic syndrome | |
| General disorders and administration site conditions | Fatigue Asthenia Oedema peripheral | Malaise | Impaired healing*** | Non-gastrointestinal fistulak |
* Medical Dictionary for Regulatory Activities (MedDRA) version 17.1. Preferred terms have been reassigned to the SOC most relevant to the target organ.
** These adverse reactions occur more frequently with combination therapy compared to lenvatinib monotherapy.
*** Identified from post-marketing use of lenvatinib
† Includes cases with a fatal outcome.
‡ See section 4.8 Description of selected adverse reactions for further characterisation.
The following terms have been combined:
a Thrombocytopenia includes thrombocytopenia and decreased platelet count. Lymphopenia includes lymphopenia and decreased lymphocyte count.
b Hypomagnesaemia includes hypomagnesaemia and decreased blood magnesium. Hypercholesterolaemia includes hypercholesterolaemia and increased blood cholesterol.
c Myocardial infarction includes myocardial infarction and acute myocardial infarction.
d Haemorrhage includes: epistaxis, haemoptysis, haematuria, contusion, haematochezia, gingival bleeding, petechiae, pulmonary haemorrhage, rectal haemorrhage, blood urine present, haematoma, vaginal haemorrhage, conjunctival haemorrhage, haemorrhoidal haemorrhage, intracranial tumour haemorrhage, laryngeal haemorrhage, ecchymosis, increased tendency to bruise, post procedural haemorrhage, purpura, skin haemorrhage, aneurysm ruptured, arterial haemorrhage, eye haemorrhage, gastric haemorrhage, gastroduodenitis haemorrhagic, gastrointestinal haemorrhage, haematemesis, haemorrhage, haemorrhagic stroke, melaena, metrorrhagia, nail bed bleeding, haemothorax, postmenopausal haemorrhage, proctitis haemorrhagic, renal haematoma, splenic haemorrhage, splinter haemorrhages, subarachnoid haemorrhage, tracheal haemorrhage, tumour haemorrhage.
e Hypertension includes: hypertension, hypertensive crisis, increased blood pressure diastolic, and increased blood pressure.
f Gastrointestinal and abdominal pain includes: abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, abdominal tenderness, epigastric discomfort, and gastrointestinal pain.
g Oral inflammation includes: aphthous ulcer, stomatitis, glossitis, mouth ulceration, and mucosal inflammation.
h Oral pain includes: oral pain, glossodynia, and oropharyngeal pain.
i Hepatocellular damage and hepatitis includes: drug-induced liver injury, hepatic steatosis, and cholestatic liver injury.
j Renal failure includes: acute prerenal failure, renal failure, acute kidney injury, and renal tubular necrosis.
k Non-gastrointestinal fistula includes cases of fistula occurring outside of the stomach and intestines such as tracheal, tracheo-oesophageal, oesophageal, female genital tract fistula, and cutaneous fistula.
In the RCC study (see section 5.1), hypertension was reported in 41.9% of patients in the lenvatinib plus everolimus-treated group (the incidence of Grade 3 or Grade 4 hypertension was 12.9%) and 10.0% of patients in the everolimus-treated group (the incidence of Grade 3 or Grade 4 hypertension was 2.0%). The median time to onset was 4.9 weeks (any grade) and 6.9 weeks (Grade ≥ 3) in the lenvatinib plus everolimus-treated group.
In the DTC study (see Lenvima SmPC), hypertension (including hypertension, hypertensive crisis, blood pressure diastolic increased, and blood pressure increased) was reported in 72.8% of lenvatinib-treated patients and 16.0% of patients in the placebo-treated group. The median time to onset in lenvatinib-treated patients was 16 days. Reactions of Grade 3 or higher (including 1 reaction of Grade 4) occurred in 44.4% of lenvatinib-treated patients compared with 3.8% of placebo-treated patients. The majority of cases recovered or resolved following dose interruption or reduction, which occurred in 13.0% and 13.4% of patients, respectively. In 1.1% of patients, hypertension led to permanent treatment discontinuation.
In the RCC study (see section 5.1), proteinuria was reported in 30.6% of patients in the lenvatinib plus everolimus-treated group (8.1% were Grade ≥ 3) and 14.0% of patients in the everolimus-treated group (2.0% were Grade ≥3). The median time to onset of proteinuria was 6.1 weeks (any grade) and 20.1 weeks (Grade ≥ 3) in the lenvatinib plus everolimus-treated group. Proteinuria led to permanent treatment discontinuation in 4.8% of patients.
In the DTC study (see Lenvima SmPC), proteinuria was reported in 33.7% of lenvatinib-treated patients and 3.1% of patients in the placebo-treated group. The median time to onset was 6.7 weeks. Grade 3 reactions occurred in 10.7% of lenvatinib-treated patients and none in placebo-treated patients. The majority of cases had an outcome of recovered or resolved following dose interruption or reduction, which occurred in 16.9% and 10.7% of patients, respectively. Proteinuria led to permanent treatment discontinuation in 0.8% of patients.
In the RCC study (see section 5.1), 8.1% of patients in the lenvatinib plus everolimus treated group developed renal failure and 3.2% developed renal impairment, (9.7% of patients had a Grade 3 event of renal failure or impairment). In the everolimus monotherapy group 2.0% of patients developed renal failure (2.0% were Grade 3).
In the DTC study (see Lenvima SmPC), 5.0% of patients developed renal failure and 1.9% developed renal impairment, (3.1% of patients had a Grade ≥ 3 event of renal failure or impairment). In the placebo group 0.8% of patients developed renal failure or impairment (0.8% were Grade ≥ 3).
In the RCC study (see section 5.1), decreased ejection fraction/cardiac failure was reported in 4.8% of patients (3.2% were Grade ≥ 3) in the lenvatinib plus everolimus treated group, and 4.0% in the everolimus group (2.0% were Grade ≥ 3). The median time to onset of decreased ejection fraction and cardiac failure was 15.7 weeks (any grade) and 32.8 weeks (Grade ≥ 3) in the lenvatinib plus everolimus-treated group.
In the DTC study (see Lenvima SmPC), decreased ejection fraction/cardiac failure was reported in 6.5% of patients (1.5% were Grade ≥ 3) in the lenvatinib treated group, and 2.3% in the placebo group (none were Grade ≥ 3).
In the RCC study (see section 5.1), there was 1 event of PRES (Grade 3) in the lenvatinib-treated group, occurring after 18.4 weeks of treatment. There were no reports in the lenvatinib plus everolimus or everolimus monotherapy groups.
In the DTC study (see Lenvima SmPC), there was 1 event of PRES (Grade 2) in the lenvatinib-treated group and no reports in the placebo group.
Amongst 1,166 patients treated with lenvatinib, there were 4 cases (0.3%) of PRES (0.3% were Grade 3 or 4), all of which resolved after treatment and/or dose interruption, or permanent discontinuation.
In the RCC study (see section 5.1), the most commonly reported liver-related adverse reactions in the lenvatinib plus everolimus-treated group were elevations of liver enzyme levels, including increases in alanine aminotransferase (9.7%), aspartate aminotransferase (4.8%), alkaline phosphatase (4.8%), and blood bilirubin (3.2%). The median time to onset of liver events was 6.7 weeks (any grade) and 14.2 weeks (Grade ≥ 3) in the lenvatinib plus everolimus-treated group. Grade 3 liver-related reactions occurred in 3.2% of lenvatinib plus everolimus-treated patients. Liver-related reactions led to dose interruptions and reductions in 1.6% and 1.6% of patients, respectively, and to permanent discontinuation in 3.2% of patients.
In the DTC study (see Lenvima SmPC), the most commonly reported liver-related adverse reactions were hypoalbuminaemia (9.6% lenvatinib vs. 1.5% placebo) and elevations of liver enzyme levels, including increases in alanine aminotransferase (7.7% lenvatinib vs. 0 placebo), aspartate aminotransferase (6.9% lenvatinib vs. 1.5% placebo), and blood bilirubin (1.9% lenvatinib vs. 0 placebo). The median time to onset of liver reactions in lenvatinib-treated patients was 12.1 weeks. Liver-related reactions of Grade 3 or higher (including 1 Grade 5 case of hepatic failure) occurred in 5.4% of lenvatinib-treated patients compared with 0.8% in placebo-treated patients. Liver-related reactions led to dose interruptions and reductions in 4.6% and 2.7% of patients, respectively, and to permanent discontinuation in 0.4%.
Amongst 1,166 patients treated with lenvatinib, there were 3 cases (0.3%) of hepatic failure, all with a fatal outcome. One occurred in a patient with no liver metastases. There was also a case of acute hepatitis in a patient without liver metastases.
In the RCC study (see section 5.1), 1.6% of patients in the lenvatinib plus everolimus-treated group reported arterial thromboembolic events. The time to onset was 69.6 weeks. In the everolimus group, 6.0% of patients reported an arterial thromboembolism (4.0% were Grade ≥ 3). In the DTC study (see Lenvima SmPC), arterial thromboembolic events were reported in 5.4% of lenvatinib-treated patients and 2.3% of patients in the placebo group.
Amongst 1,166 patients treated with lenvatinib, there were 5 cases (0.4%) of arterial thromboembolisms (3 cases of myocardial infarction and 2 cases of cerebrovascular accident) with a fatal outcome.
In the RCC study (see section 5.1), haemorrhage was reported in 38.7% (8.1% were Grade ≥ 3) of patients in the lenvatinib plus everolimus-treated group. Reactions that occurred at an incidence of ≥2.0% were: epistaxis (22.6%), haematuria (4.8%), haematoma (3.2%), and gastric haemorrhage (3.2%). The median time to first onset of was 10.2 weeks (any grade) and 7.6 weeks (Grade ≥ 3) in the lenvatinib plus everolimus-treated group. The incidence of serious haemorrhage was 4.8% (cerebral haemorrhage, gastric haemorrhage and haemarthrosis). Discontinuation due to haemorrhagic events occurred in 3.2% of patients in the lenvatinib plus everolimus-treated group. There was one case of fatal cerebral haemorrhage in the lenvatinib plus everolimus-treated group and one case of fatal intracranial haemorrhage in the lenvatinib-treated group.
In the DTC study (see Lenvima SmPC), haemorrhage was reported in 34.9% (1.9% were Grade ≥ 3) of lenvatinib-treated patients versus 18.3% (3.1% were Grade ≥ 3) of placebo-treated patients. Reactions that occurred at an incidence of ≥0.75% above placebo were: epistaxis (11.9%), haematuria (6.5%), contusion (4.6%), gingival bleeding (2.3%), haematochezia (2.3%), rectal haemorrhage (1.5%), haematoma (1.1%), haemorrhoidal haemorrhage (1.1%), laryngeal haemorrhage (1.1%), petechiae (1.1%), and intracranial tumour haemorrhage (0.8%). In this trial, there was 1 case of fatal intracranial haemorrhage among 16 patients who received lenvatinib and had CNS metastases at baseline.
The median time to first onset in lenvatinib-treated patients was 10.1 weeks. No differences between lenvatinib- and placebo-treated patients were observed in the incidences of serious reactions (3.4% vs. 3.8%), reactions leading to premature discontinuation (1.1% vs. 1.5%), or reactions leading to dose interruption (3.4% vs. 3.8%) or reduction (0.4% vs. 0).
Amongst 1,166 patients treated with lenvatinib, Grade 3 or greater haemorrhage was reported in 2% of patients, 3 patients (0.3%) had a Grade 4 haemorrhage and 5 patients (0.4%) had a Grade 5 reaction including arterial haemorrhage, haemorrhagic stroke, intracranial tumour haemorrhage, haemoptysis and tumour haemorrhage.
In the RCC study (see section 5.1), hypocalcaemia was reported in 8.1% of patients in the lenvatinib plus everolimus-treated group (3.2% were Grade ≥ 3) and 4.0% of patients in the everolimus-treated group (none were Grade ≥ 3). The median time to onset of hypocalcaemia was 28.3 weeks (any grade) and 45.9 weeks (Grade ≥ 3) in the lenvatinib plus everolimus-treated group. There was one Grade 4 TEAE. No events of hypocalcaemia required dose reduction or interruption, and no patients discontinued treatment due to hypocalcaemia.
In the DTC study (see Lenvima SmPC), hypocalcaemia was reported in 12.6% of lenvatinib-treated patients vs. no cases in the placebo arm. The median time to first onset in lenvatinib-treated patients was 11.1 weeks. Reactions of Grade 3 or 4 severity occurred in 5.0% of lenvatinib-treated vs 0 placebo-treated patients. Most reactions resolved following supportive treatment, without dose interruption or reduction, which occurred in 1.5% and 1.1% of patients, respectively; 1 patient with Grade 4 hypocalcaemia discontinued treatment permanently.
In the RCC study (see section 5.1), 1.6% of cases of perforated appendicitis (of Grade 3) occurred in the lenvatinib plus everolimus-treated group; there were no reports in the lenvatinib or everolimus groups.
In the DTC study, events of gastrointestinal perforation or fistula were reported in 1.9% of lenvatinib-treated patients and 0.8% of patients in the placebo group.
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 RCC study (see section 5.1), QTc interval increases greater than 60 ms were reported in 11% of patients in the lenvatinib plus everolimus-treated group. The incidence of QTc interval greater than 500 ms was 6% in the lenvatinib plus everolimus-treated group. No reports of QTc interval prolongation greater than 500 ms or increases greater than 60 ms occurred in the everolimus-treated group.
In the DTC study (see Lenvima SmPC), QT/QTc interval prolongation was reported in 8.8% of lenvatinib-treated patients and 1.5% of patients in the placebo group. The incidence of QT interval prolongation of greater than 500 ms was 2% in the lenvatinib-treated patients compared to no reports in the placebo group.
In the RCC study (see section 5.1), hypothyroidism occurred in 24% of patients in the lenvatinib plus everolimus-treated group and 2% of patients in the everolimus-treated group. All events of hypothyroidism in the lenvatinib plus everolimus-treated group were of Grade 1 or 2. In patients with a normal TSH at baseline, an elevation of TSH level was observed post baseline in 60.5% of lenvatinib plus everolimus-treated patients as compared with none in patients receiving everolimus alone.
In the DTC study (see Lenvima SmPC), 88% of all patients had a baseline TSH level less than or equal to 0.5 mU/L. In those patients with a normal TSH at baseline, elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of lenvatinib-treated patients as compared with 14% of placebo-treated patients.
In the RCC study (see section 5.1), diarrhoea was reported in 80.6% of patients in the lenvatinib plus everolimus-treated group (21.0% were Grade ≥ 3) and in 34.0% of patients in the everolimus-treated group (2.0% were Grade ≥ 3). The median time to onset was 4.1 weeks (any grade) and 8.1 weeks (Grade ≥ 3) in the lenvatinib plus everolimus-treated group. Diarrhoea was the most frequent cause of dose interruption/reduction and recurred despite dose reduction. Diarrhoea resulted in discontinuation in one patient.
In the DTC study (see Lenvima SmPC), diarrhoea was reported in 67.4% of patients in the lenvatinib-treated group (9.2% were Grade ≥ 3) and in 16.8% of patients in the placebo group (none were Grade ≥ 3).
See section 4.2 for information on paediatric use.
There are limited data on patients of age ≥75 years with RCC. However, in DTC, patients of age ≥75 years were more likely to experience Grade 3 or 4 hypertension, proteinuria, decreased appetite, and dehydration.
In patients with DTC, females had a higher incidence of hypertension (including Grade 3 or 4 hypertension), proteinuria, and PPE, while males had a higher incidence of decreased ejection fraction and gastrointestinal perforation and fistula formation.
There are limited data on Asian patients with RCC. However, in DTC Asian patients had a higher incidence than Caucasian patients of peripheral oedema, hypertension, fatigue, PPE, proteinuria, stomatitis, thrombocytopenia, and myalgia; while Caucasian patients had a higher incidence of diarrhoea, weight decreased, nausea, vomiting, constipation, asthenia, abdominal pain, pain in extremity, and dry mouth.
In DTC, patients with baseline hypertension had a higher incidence of Grade 3 or 4 hypertension, proteinuria, diarrhoea, and dehydration, and experienced more serious cases of dehydration, hypotension, pulmonary embolism, malignant pleural effusion, atrial fibrillation, and gastrointestinal (GI) symptoms (abdominal pain, diarrhoea, vomiting). In RCC, patients with baseline hypertension had a higher incidence of Grade 3 or 4 dehydration, fatigue, and hypertension.
In RCC, patients with baseline diabetes had a higher incidence of Grade 3 or 4 hypertension, hypertriglyceridemia and acute renal failure.
There are limited data on patients with hepatic impairment in RCC. However in DTC, patients with baseline hepatic impairment had a higher incidence of hypertension and PPE, and a higher incidence of Grade 3 or 4 hypertension, asthenia, fatigue, and hypocalcaemia compared with patients with normal hepatic function.
In DTC, patients with baseline renal impairment had a higher incidence of Grade 3 or 4 hypertension, proteinuria, fatigue, stomatitis, oedema peripheral, thrombocytopenia, dehydration, prolonged electrocardiogram QT, hypothyroidism, hyponatraemia, blood thyroid stimulating hormone increased, pneumonia compared with subjects with normal renal function. These patients also had a higher incidence of renal reactions and a trend towards a higher incidence of liver reactions. In RCC, patients with baseline renal impairment had a higher incidence of Grade 3 fatigue.
There are limited data on patients with body weight <60 kg in RCC. However in DTC patients with low body weight (<60 kg) had a higher incidence of PPE, proteinuria, of Grade 3 or 4 hypocalcaemia and hyponatraemia, and a trend towards a higher incidence of Grade 3 or 4 decreased appetite.
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 Yellow Card Scheme: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play and Apple App store.
Not applicable.
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