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Differentiated Thyroid Cancer: The most frequently reported adverse reactions in (occurring in ≥30% of patients) are hypertension (73%), fatigue (67%), diarrhoea (67%), arthralgia/myalgia (62%), decreased appetite (54%), decreased weight (51%), nausea (47%), stomatitis (41%), headache (38%), vomiting (36%), proteinuria (34%), and palmar-plantar erythrodysaesthesia syndrome (PPE) (32%), abdominal pain (31%), and dysphonia (31%). Hypertension and proteinuria tend to occur early during lenvatinib treatment (see Description of selected adverse reactions as follows). The majority of Grade 3 or 4 adverse reactions occurred during the first 6 months of treatment except for diarrhoea, which occurred throughout treatment, and weight loss, which tended to be cumulative over time. The most common serious adverse reactions (at least 2%) were pneumonia (4%), hypertension (3%), and dehydration (3%).
In 261 patients with RAI-refractory DTC, dose reductions and discontinuations were the actions taken for an adverse reaction in 68% and 18% respectively. Adverse reactions that most commonly led to dose reductions (in ≥10% of patients) were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhoea (10%). Adverse reactions that most commonly led to discontinuation of lenvatinib were asthenia (1%), and hypertension (1%).
Renal Cell Carcinoma: Lenvatinib in combination with pembrolizumab in RCC: 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%).
Lenvatinib in combination with everolimus in RCC: The most frequently reported adverse reactions in the LENVIMA with everolimus-treated group (occurring in ≥30% of patients) are diarrhoea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, decreased weight, haemorrhagic events, and proteinuria. The most common serious adverse reactions (≥5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhoea (5%), vomiting (5%), and dyspnea (5%).
Adverse reactions led to dose reductions or interruption in 89% of patients receiving LENVIMA with everolimus. The most common adverse reactions (≥5%) in the LENVIMA with everolimus-treated group resulting in dose reductions were diarrhoea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients in the LENVIMA with everolimus-treated group.
Hepatocellular Carcinoma: The most common adverse reactions observed in the LENVIMA-treated patients (≥20%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism, and nausea. The most common serious adverse reactions (≥2%) in LENVIMA-treated patients were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%).
Adverse reactions led to dose reduction or interruption in 62% of patients receiving LENVIMA. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%). Treatment discontinuation due to adverse reactions occurred in 20% of patients in the LENVIMA-treated group. The most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%).
Endometrial Carcinoma: The safety of lenvatinib in combination with pembrolizumab has been evaluated in 530 patients with advanced EC receiving 20 mg lenvatinib once daily and 200 mg pembrolizumab every 3 weeks. The most common (occurring in ≥20% of patients) adverse reactions were hypertension (63%), diarrhoea (57%), hypothyroidism (56%), nausea (51%), decreased appetite (47%), vomiting (39%), fatigue (38%), decreased weight (35%), arthralgia (33%), proteinuria (29%), constipation (27%), headache (27%), urinary tract infection (27%), dysphonia (25%), abdominal pain (23%), asthenia (23%), palmar-plantar erythrodysaesthesia syndrome (23%), stomatitis (23%), anaemia (22%), and hypomagnesaemia (20%).
The most common (occurring in ≥5% of patients) severe (Grade ≥3) adverse reactions were hypertension (37.2%), decreased weight (9.1%), diarrhoea (8.1%), increased lipase (7.7%), decreased appetite (6.4%), asthenia (6%), fatigue (6%), hypokalaemia (5.7%), anaemia (5.3%), and proteinuria (5.1%).
Discontinuation of lenvatinib occurred in 30.6% of patients, and discontinuation of both lenvatinib and pembrolizumab occurred in 15.3% of patients due to an adverse reaction. The most common (occurring in ≥1% of patients) adverse reactions leading to discontinuation of lenvatinib were hypertension (1.9%), diarrhoea (1.3%), asthenia (1.3%), decreased appetite (1.3%), proteinuria (1.3%), and decreased weight (1.1%).
Dose interruption of lenvatinib due to an adverse reaction occurred in 63.2% of patients. Dose interruption of lenvatinib and pembrolizumab due to an adverse reaction occurred in 34.3% of patients. The most common (occurring in ≥5% of patients) adverse reactions leading to interruption of lenvatinib were hypertension (12.6%), diarrhoea (11.5%), proteinuria (7.2%), vomiting (7%), fatigue (5.7%), and decreased appetite (5.7%).
Dose reduction of lenvatinib due to adverse reactions occurred in 67.0% of patients. The most common (occurring in ≥5% of patients) adverse reactions resulting in dose reduction of lenvatinib were hypertension (16.2%), diarrhoea (12.5%), palmar-plantar erythrodysaesthesia syndrome (9.1%), fatigue (8.7%), proteinuria (7.7%), decreased appetite (6.6%), nausea (5.5%), asthenia (5.1%), and decreased weight (5.1%).
Tabulated list of adverse reactions: The safety profile of lenvatinib monotherapy and lenvatinib in combination with everolimus is based on data from 458 DTC patients, 496 HCC patients and 62 RCC patients where the most conservative frequency for each ADR is used.
The safety profile of lenvatinib as combination therapy is based on data from 530 EC and 497 RCC patients treated with lenvatinib in combination with pembrolizumab.
Similar adverse reactions were observed in clinical trials in DTC, RCC with lenvatinib in combination with everolimus, and HCC. Adverse reactions that occur more frequently with combination therapy with everolimus compared to lenvatinib monotherapy are hypothyroidism, (including increased blood thyroid stimulating hormone), hypercholesterolaemia, and severe diarrhoea. Adverse reactions that occured more frequently in RCC with lenvatinib and pembrolizumab combination therapy compared to lenvatinib monotherapy were hypothyroidism (including increased blood thyroid stimulating hormone), hypercholesterolaemia, diarrhoea, lipase increased, amylase increased, rash (including maculopapular rash), and blood creatinine increased.
Table 9 shows the frequency categories of adverse reactions observed in clinical trials for subjects taking lenvatinib monotherapy (subjects with DTC or HCC) and subjects taking lenvatinib in combination with everolimus (RCC) or pembrolizumab (RCC or EC). The adverse reaction frequency category represents the most conservative estimate of frequency from the individual populations.
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 trials with combination therapy.
For additional safety information when lenvatinib is administered in combination, refer to the product information for the respective combination therapy component (pembrolizumab or everolimus).
Frequencies are defined as: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).
Within each frequency category, undesirable effects are presented in order of decreasing seriousness. (See Table 9a and 9b.)
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Click on icon to see table/diagram/imageDescription of selected adverse reactions: Hypertension (see Precautions): Hypertension occurred in 73% of patients in SELECT (DTC) receiving LENVIMA 24 mg orally once daily and in 45% of patients in REFLECT (HCC) receiving LENVIMA 8 mg or 12 mg orally once daily. The median time to onset of new or worsening hypertension was 16 days in SELECT and 26 days in REFLECT. Grade 3 hypertension occurred in 44% of patients in SELECT and in 24% in REFLECT. Grade 4 hypertension occurred <1% in SELECT and Grade 4 hypertension was not reported in REFLECT.
In patients receiving LENVIMA 18 mg orally once daily with everolimus in Study 205 (RCC), hypertension was reported in 42% of patients and the median time to onset of new or worsening hypertension was 35 days. Grade 3 hypertension occurred in 13% of patients. Systolic blood pressure ≥160 mmHg occurred in 29% of patients and diastolic blood pressure ≥100 mmHg occurred in 21%.
In CLEAR (see Pharmacology: Pharmacodynamics under Actions), 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 Phase 3 Study 309 (see Pharmacology: Pharmacodynamics under Actions), hypertension was reported in 65% of patients in the lenvatinib plus pembrolizumab group. Reactions of Grade 3 or higher occurred in 38.4% of patients in the lenvatinib plus pembrolizumab group. The median time to onset in the lenvatinib plus pembrolizumab group was 15 days. Dose interruption, reduction and discontinuation of lenvatinib occurred in 11.6%, 17.7% and 2.0% of patients, respectively.
Proteinuria (see Precautions): Proteinuria occurred in 34% of LENVIMA-treated patients in SELECT (DTC) and in 26% of LENVIMA-treated patients in REFLECT (HCC). Grade 3 proteinuria occurred in 11% and 6% in SELECT and REFLECT, respectively. In Study 205 (RCC), proteinuria occurred in 31% of patients receiving LENVIMA with everolimus and 14% of patients receiving everolimus. Grade 3 proteinuria occurred in 8% of patients receiving LENVIMA with everolimus compared to 2% of patients receiving everolimus.
In the Phase 3 Study 309 (see Pharmacology: Pharmacodynamics under Actions), proteinuria was reported in 29.6% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 5.4% of patients. The median time to onset was 34.5 days. Dose interruption, reduction and discontinuation of lenvatinib occurred in 6.2%, 7.9% and 1.2% of patients, respectively.
Hepatotoxicity (see Precautions): In the pivotal Phase 3 SELECT trial (see Pharmacology: Pharmacodynamics under Actions), 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 events in lenvatinib-treated patients was 12.1 weeks. Liver-related events of Grade 3 or higher (including 1 Grade 5 event of hepatic failure) occurred in 5.4% of lenvatinib-treated patients compared with 0.8% in placebo-treated patients. Liver-related events led to dose interruptions and reductions in 4.6% and 2.7% of patients, respectively, and to permanent discontinuation in 0.4%.
Amongst 1108 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.
The incidence of ALT and AST elevation was similar in Study 2 in RCC. In Study 2, 3% of LENVIMA + everolimus-treated patients experienced an increase in ALT and 3% experienced an increase in AST that was Grade 3 or greater. Two percent of patients in the everolimus-treated group experienced an increase in ALT and none experienced an increase in AST that was Grade 3 or greater.
In the Phase 3 REFLECT trial (see Pharmacology: Pharmacodynamics under Actions), the most commonly reported hepatotoxicity adverse reactions were increased blood bilirubin (14.9%), increased aspartate aminotransferase (13.7%), increased alanine aminotransferase (11.1%), hypoalbuminaemia (9.2%), hepatic encephalopathy (8.0%), increased gamma-glutamyltransferase (7.8%) and increased blood alkaline phosphatase (6.7%). The median time to onset of hepatotoxocity adverse reactions was 6.4 weeks. Hepatotoxicity reactions of ≥ Grade 3 occurred in 26.1% of lenvatinib-treated patients. Hepatic failure (including fatal events in 12 patients) occurred in 3.6% of patients (all were ≥ Grade 3). Hepatic encephalopathy (including fatal events in 4 patients) occurred in 8.4% of patients (5.5% were ≥ Grade 3). There were 17 (3.6%) deaths due to hepatotoxicity events in the lenvatinib arm and 4 (0.8%) deaths in the sorafenib arm. Hepatotoxicity adverse reactions led to dose interruptions and reductions in 12.2% and 7.4% of lenvatinib-treated patients respectively, and to permanent discontinuation in 5.5%.
Across clinical studies in which 1327 patients received lenvatinib monotherapy in indications other than HCC, hepatic failure (including fatal events) was reported in 4 patients (0.3%), liver injury in 2 patients (0.2%), acute hepatitis in 2 patients (0.2%), and hepatocellular injury in 1 patient (0.1%).
In CLEAR (see Pharmacology: Pharmacodynamics under Actions), 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 pembrolizumabtreated 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 Phase 3 Study 309 (see Pharmacology: Pharmacodynamics under Actions), hepatotoxicity was reported in 33.7% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 12.1% of patients. The median time to onset was 56.0 days. Dose interruption, reduction and discontinuation of lenvatinib occurred in 5.2%, 3.0% and 1.2% of patients, respectively.
Arterial thromboembolisms (see Precautions): In CLEAR (see Pharmacology: Pharmacodynamics under Actions), 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 events 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 RCC Study 205 (see Pharmacology: Pharmacodynamics under Actions), 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 SmPC for 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 Phase 3 Study 309 (see Pharmacology: Pharmacodynamics under Actions), arterial thromboembolisms were reported in 3.7% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 2.2% of patients. The median time to onset was 59.0 days. Dose interruption and discontinuation of lenvatinib occurred in 0.2% and 2.0% of patients, respectively.
Renal Failure or Impairment (see Precautions): Renal impairment occurred in 14% of patients receiving LENVIMA in SELECT (DTC) and in 7% of patients receiving LENVIMA in REFLECT (HCC). Grade 3 to 5 renal failure or impairment occurred in 3% (DTC) and 2% (HCC) of patients, including 1 fatality in each study. In Study 205 (RCC), renal impairment or renal failure occurred in 18% of patients receiving LENVIMA with everolimus, including Grade 3 in 10% of patients.
In the Phase 3 Study 309 (see Pharmacology: Pharmacodynamics under Actions), 18.2% of lenvatinib plus pembrolizumab-treated patients developed a renal failure/impairment event. Grade ≥ 3 reactions occurred in 4.2% of patients. The median time to onset was 86.0 days. Dose interruption, reduction and discontinuation of lenvatinib occurred in 3.0%, 1.7% and 1.2% of patients, respectively.
Cardiac dysfunction (see Precautions): In the pivotal Phase 3 SELECT trial (see Pharmacology: Pharmacodynamics under Actions), 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 Phase 3 REFLECT trial (see Pharmacology: Pharmacodynamics under Actions), cardiac dysfunction (including congestive cardiac failure, cardiogenic shock, and cardiopulmonary failure) was reported in 0.6% of patients (0.4% were Grade ≥ 3) in the lenvatinib-treated group.
In the Phase 3 Study 309 (see Pharmacology: Pharmacodynamics under Actions), cardiac dysfunction was reported in 1.0% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 0.5% of patients. The median time to onset was 112.0 days. Dose reduction and discontinuation of lenvatinib both occurred in 0.2% of patients.
Posterior reversible encephalopathy syndrome (PRES)/Reversible posterior leucoencephalopathy syndrome (RPLS) (see Precautions): In the pivotal Phase 3 SELECT trial (see Pharmacology: Pharmacodynamics under Actions), there was 1 event of PRES (Grade 2) in the lenvatinib-treated group and no reports in the placebo group.
In the Phase 3 REFLECT trial (see Pharmacology: Pharmacodynamics under Actions), there was 1 event of PRES (Grade 2) in the lenvatinib-treated group.
Amongst 1,823 patients treated with lenvatinib monotherapy in clinical trials, there were 5 cases (0.3%) of PRES (0.2% were Grade 3 or 4), all of which resolved after treatment and/or dose interruption, or permanent discontinuation.
In the Phase 3 Study 309 (see Pharmacology: Pharmacodynamics under Actions), there was one event of PRES (Grade 1) in the lenvatinib plus pembrolizumab-treated group for which lenvatinib was interrupted.
Diarrhea (see Precautions): In the pivotal Phase 3 SELECT trial (see Pharmacology: Pharmacodynamics under Actions), 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).
In Study 205 (RCC), diarrhea occurred in 81% of patients receiving LENVIMA with everolimus, including Grade 3 in 19%.
In the Phase 3 REFLECT trial (see Pharmacology: Pharmacodynamics under Actions), diarrhoea was reported in 38.7% of patients treated with lenvatinib (4.2% were Grade ≥ 3).
In the Phase 3 Study 309 (see Pharmacology: Pharmacodynamics under Actions), diarrhoea was reported in 54.2% of lenvatinib plus pembrolizumab-treated patients (7.6% were Grade ≥ 3). Dose interruption, reduction and discontinuation of lenvatinib occurred in 10.6%, 11.1% and 1.2% of patients, respectively.
Haemorrhagic events (see Precautions): In the pivotal Phase 3 SELECT trial (see Pharmacology: Pharmacodynamics under Actions), haemorrhagic events were reported in 34.9% of lenvatinib-treated patients versus 18.3% of placebo-treated patients. Events 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 adverse events (3.4% vs. 3.8%), events leading to premature discontinuation (1.1% vs. 1.5%), or events leading to dose interruption (3.4% vs. 3.8%) or reduction (0.4% vs. 0).
In Study 2 in RCC, haemorrhagic events occurred in 34% of patients in the LENVIMA + everolimus-treated group and 26% of patients in the everolimus-treated group. The most frequently reported haemorrhagic event was epistaxis (LENVIMA + everolimus 23% and everolimus 24%). Grade 3 or greater events occurred in 8% of LENVIMA + everolimus-treated patients and in 2% of everolimus-treated patients. In the LENVIMA + everolimus-treated patients, this included one fatal cerebral haemorrhage. Discontinuation due to a haemorrhagic event occurred in 3% of patients in the LENVIMA + everolimus-treated group.
In the Phase 3 REFLECT trial (see Pharmacology: Pharmacodynamics under Actions), haemorrhage was reported in 24.6% of patients and 5.0% were Grade ≥ 3. Grade 3 reactions occurred in 3.4%, Grade 4 reactions in 0.2% and 7 patients (1.5%) had a grade 5 reaction including cerebral haemorrhage, upper gastrointestinal haemorrhage, intestinal haemorrhage and tumour haemorrhage. The median time to first onset was 11.9 weeks. A haemorrhage event led to dose interruption or reduction in 3.2% and 0.8% patients respectively and to treatment discontinuation in 1.7% of patients.
Across clinical studies in which 1,327 patients received lenvatinib monotherapy in indications other than HCC, Grade ≥ 3 or greater haemorrhage was reported in 2% of patients, 3 patients (0.2%) had a Grade 4 haemorrhage and 8 patients (0.6%) had a Grade 5 reaction including arterial haemorrhage, haemorrhagic stroke, intracranial haemorrhage, intracranial tumour haemorrhage, haematemesis, melaena, haemoptysis and tumour haemorrhage.
In the Phase 3 Study 309 (see Pharmacology: Pharmacodynamics under Actions), haemorrhage was reported in 24.4% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 3.0% of patients. The median time to onset was 65.0 days. Dose interruption, reduction and discontinuation of lenvatinib occurred in 1.7%, 1.2% and 1.7% of patients, respectively.
Hypocalcaemia (see QT interval prolongation under Precautions): In the pivotal Phase 3 SELECT trial (see Pharmacology: Pharmacodynamics under Actions), hypocalcaemia was reported in 12.6% of lenvatinib-treated patients vs. no events in the placebo arm. The median time to first onset in lenvatinib-treated patients was 11.1 weeks. Events of Grade 3 or 4 severity occurred in 5.0% of lenvatinib-treated vs 0 placebo-treated patients. Most events 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 Study 2 in RCC, 6% of patients in the LENVIMA + everolimus-treated group and 2% of patients in the everolimus-treated group experienced Grade 3 or greater hypocalcemia. No patients discontinued due to hypocalcemia.
In the Phase 3 REFLECT trial (see Pharmacology: Pharmacodynamics under Actions), hypocalcaemia was reported in 1.1% of patients, with grade 3 reactions occurring in 0.4%. Lenvatinib dose interruption due to hypocalcaemia occurred in one subject (0.2%) and there were no dose reductions or discontinuations.
In the Phase 3 Study 309 (see Pharmacology: Pharmacodynamics under Actions), hypocalcaemia was reported in 3.9% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 1.0% of patients. The median time to onset was 148.0 days. No lenvatinib dose modifications were reported.
Gastrointestinal perforation and fistula formation (see Precautions): In the pivotal Phase 3 SELECT trial (see Pharmacology: Pharmacodynamics under Actions), events of gastrointestinal perforation or fistula were reported in 1.9% of lenvatinib-treated patients and 0.8% of patients in the placebo group.
In the Phase 3 REFLECT trial (see Pharmacology: Pharmacodynamics under Actions), events of gastrointestinal perforation or fistula were reported in 1.9% of lenvatinib-treated patients.
In the Phase 3 Study 309 (see Pharmacology: Pharmacodynamics under Actions), events of fistula formation were reported in 2.5% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 2.5% of patients. The median time to onset was 117.0 days. Discontinuation of lenvatinib occurred in 1.0% of patients. Events of gastrointestinal perforation were reported in 3.9% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 3.0% of patients. The median time to onset was 42 days. Dose interruption and discontinuation of lenvatinib occurred in 0.5% and 3.0% of patients, respectively.
QT interval prolongation (see Precautions): In the pivotal Phase 3 SELECT trial (see Pharmacology: Pharmacodynamics under Actions), 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 Phase 3 REFLECT trial (see Pharmacology: Pharmacodynamics under Actions), QT/QTc interval prolongation was reported in 6.9% of lenvatinib-treated patients. The incidence of QTcF interval prolongation of greater than 500ms was 2.4%.
In the Phase 3 Study 309 (see Pharmacology: Pharmacodynamics under Actions), QT interval prolongation was reported in 3.9% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 0.5% of patients.
The median time to onset was 115.5 days. Dose interruption and reduction of lenvatinib occurred in 0.2% and 0.5% of patients, respectively.
Blood thyroid stimulating hormone increased/Thyroid dysfunction (see Precautions): In the pivotal Phase 3 SELECT (DTC) trial (see Pharmacology: Pharmacodynamics under Actions), 88% of all patients had a baseline TSH level ≤ 0.5 mU/L. In those patients with a normal TSH at baseline, elevation of TSH level > 0.5 mU/L was observed post baseline in 57% of lenvatinib-treated patients.
Grade 1 or 2 hypothyroidism occurred in 24% of patients receiving LENVIMA with everolimus in Study 205 (RCC) and in 21% of patients receiving LENVIMA in REFLECT (HCC). In those patients with a normal or low TSH at baseline, an elevation of TSH was observed post baseline in 70% of patients receiving LENVIMA in REFLECT and 60% of patients receiving LENVIMA with everolimus in Study 205.
In CLEAR (see Pharmacology: Pharmacodynamics under Actions), 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% 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 Phase 3 Study 309 (see Pharmacology: Pharmacodynamics under Actions), hypothyroidism was reported in 68.2% of lenvatinib plus pembrolizumab-treated patients and Grade ≥3 reactions occurred in 1.2% of patients. The median time to onset was 62.0 days. Dose interruption and reduction of lenvatinib occurred in 2.2% and 0.7% of patients, respectively.
Blood TSH increased was reported in 12.8% of lenvatinib plus pembrolizumab-treated patients with no patients reporting Grade ≥3 reactions. Dose interruption occurred in 0.2% of patients.
Paediatric population: Clinical data are not yet available in this population (see Dosage & Administration).
Other special populations: Elderly: In CLEAR, patients of age ≥75 years had a higher (≥ 10% difference) incidence of proteinuria than patients of age <65 years.
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 to 4 hypertension, proteinuria, decreased appetite, and dehydration.
Sex: In CLEAR, males had a higher (≥ 10% difference) incidence than females of diarrhoea.
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.
Race: 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.
There are limited data on Asian patients with RCC Study 205. However, in DTC, Asian patients had a higher incidence than Caucasian patients of oedema peripheral, fatigue, PPE, proteinuria, thrombocytopenia, stomatitis 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. Japanese patients had a higher incidence of Grade 3 to 4 hypertension, decreased appetite, fatigue, and thrombocytopenia compared with non-Japanese patients.
Baseline hypertension: In CLEAR, patients with baseline hypertension had a higher incidence of proteinuria than patients without baseline hypertension.
In DTC, patients with baseline hypertension had a higher incidence of Grade 3 to 4 hypertension, proteinuria, diarrhoea, and dehydration, and experienced more serious events of dehydration, hypotension, pulmonary embolism, malignant pleural effusion, atrial fibrillation, and GI symptoms (abdominal pain, diarrhoea, vomiting). In RCC Study 205, patients with baseline hypertension had a higher incidence of Grade 3 or 4 dehydration, fatigue, and hypertension.
Hepatic impairment: 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.
Renal impairment: In DTC, patients with baseline renal impairment had a higher incidence of Grade 3 to 4 hypertension, proteinuria, fatigue, stomatitis, oedema peripheral, thrombocytopenia, dehydration, prolonged electrocardiogram QT, hypothyroidism, hyponatraemia, and blood thyroid stimulating hormone increased, pneumonia compared with patients with normal renal function. These patients also had a higher incidence of renal events and a trend towards a higher incidence of liver events. In RCC Study 205, patients with baseline renal impairment had a higher incidence of Grade 3 fatigue.
Patients with body weight <60 kg: 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 3-4 hypocalcaemia and hyponatraemia, and a trend towards a higher incidence of grade 3-4 decreased appetite.
Reporting of suspected adverse reactions: 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.
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