Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
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. Also, the combination of lenvatinib with pembrolizumab has been evaluated in 530 patients with advanced EC receiving 20 mg lenvatinib once daily and 200 mg pembrolizumab every 3 weeks.

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 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%).

DTC

The most frequently reported adverse reactions (occurring in ≥30% of patients) are hypertension (68.6%), diarrhoea (62.8%), decreased appetite (51.5%), decreased weight (49.1%), fatigue (45.8%), nausea (44.5%), proteinuria 36.9%), stomatitis (35.8%), vomiting (34.5%), dysphonia (34.1%), headache (34.1%), and palmar-plantar erythrodysaesthesia syndrome (PPE) (32.7%). Hypertension and proteinuria tend to occur early during lenvatinib treatment (see sections 4.4 and 4.8). The majority of Grade 3 to 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 important serious adverse reactions were renal failure and impairment (2.4%), arterial thromboembolisms (3.9%), cardiac failure (0.7%), intracranial tumour haemorrhage (0.7%), PRES / RPLS (0.2%), hepatic failure (0.2%), and arterial thromboembolisms (cerebrovascular accident (1.1%), transient ischaemic attack (0.7%), and myocardial infarction (0.9%).
In 452 patients with RAI-refractory DTC, dose reduction and discontinuation were the actions taken for an adverse reaction in 63.1% and 19.5% of patients, respectively. Adverse reactions that most commonly led to dose reductions (in ≥5% of patients) were hypertension, proteinuria, diarrhoea, fatigue, PPE, decreased weight, and decreased appetite. Adverse reactions that most commonly led to discontinuation of lenvatinib were proteinuria, asthenia, hypertension, cerebrovascular accident, diarrhoea, and pulmonary embolism.

HCC
The most frequently reported adverse reactions (occurring in ≥30% of patients) are hypertension (44.0%), diarrhoea (38.1%), decreased appetite (34.9%), fatigue (30.6%), and decreased weight (30.4%).

The most important serious adverse reactions were hepatic failure (2.8%), hepatic encephalopathy (4.6%), oesophageal varices haemorrhage (1.4%), cerebral haemorrhage (0.6%), arterial thromboembolic events (2.0%) including myocardial infarction (0.8%), cerebral infarction (0.4%) and cerebrovascular accident (0.4%) and renal failure/impairment events (1.4%). There was a higher incidence of decreased neutrophil count in patients with HCC (8.7% on lenvatinib than in other non- HCC tumour types (1.4%)), which was not associated with infection, sepsis or bacterial peritonitis.

In 496 patients with HCC, dose modification (interruption or reduction) and discontinuation were the actions taken for an adverse reaction in 62.3% and 20.2% of patients, respectively.
Adverse reactions that most commonly led to dose modifications (in ≥5% of patients) were decreased appetite, diarrhoea, proteinuria, hypertension, fatigue, PPE and decreased platelet count. Adverse reactions that most commonly led to discontinuation of lenvatinib were hepatic encephalopathy, fatigue, increased blood bilirubin, proteinuria and hepatic failure.

EC
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
For additional safety information when lenvatinib is administered in combination, refer to the SmPC for the respective combination therapy components.

Adverse reactions observed in clinical trials and reported from post-marketing use of lenvatinib are listed in Table 7.

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.

Table 7 Adverse reactions reported in patients treated with lenvatinib § 
System Organ      Lenvatinib                 Combination with            Combination with           Combination with Class             monotherapy                everolimus                  pembrolizumab              pembrolizumab (EC) (MedDRA                                                                  (RCC) terminology)


Infections and infestations
Very common     Urinary tract infection                                                             Urinary tract infection Common                                       Urinary tract infection     Urinary tract infection Uncommon        Perineal abscess             Perineal abscess            Perineal abscess           Perineal abscess Blood and lymphatic disorders
Very common       Thrombocytopenia‡          Thrombocytopenia‡           Thrombocytopenia‡          Thrombocytopeniaa,‡ Lymphopenia‡               Lymphopenia‡                Lymphopenia‡               Lymphopeniaa,‡ Leukopenia‡                Leukopenia‡                 Leukopenia‡                Leukopeniaa,‡ Neutropenia‡               Neutropenia‡                Neutropenia‡               Neutropeniaa,‡ Anaemia
Uncommon          Splenic infarction
System Organ        Lenvatinib                 Combination with           Combination with         Combination with Class               monotherapy                everolimus                 pembrolizumab            pembrolizumab (EC) (MedDRA                                                                   (RCC) terminology)


Endocrine disorders
Very common         Hypothyroidism*            Hypothyroidism*            Hypothyroidism*          Hypothyroidism* Increased blood thyroid    Increased blood thyroid    Increased blood          Increased blood stimulating hormone*,‡,‡   stimulating hormone*, ‡    thyroid stimulating      thyroid stimulating hormone*, ‡              hormone*
Hyperthyroidism
Common                                                                    Adrenal insufficiency    Adrenal insufficiency Uncommon            Adrenal insufficiency      Adrenal insufficiency
Metabolism and nutrition disorders
Very common         Hypocalcaemia*, ‡          Hypocalcaemia‡             Hypocalcaemia‡           Hypocalcaemia*,‡ Hypokalaemia‡              Hypokalaemia‡              Hypokalaemia‡            Hypokalaemia‡ Hypomagnesaemia‡           Hypomagnesaemia‡           Hypomagnesaemia‡         Hypercholesterolaemia Hypercholesterolaemia      Hypercholesterolaemia    b, *,‡
Hypercholesterolaemia‡
Decreased weight           *, ‡                       *, ‡                     Hypomagnesaemiab,‡ Decreased appetite         Decreased weight           Decreased weight         Decreased weight Decreased appetite         Decreased appetite       Decreased appetite Common            Dehydration                  Dehydration                Dehydration              Dehydration Psychiatric disorders
Very common         Insomnia                   Insomnia                   Insomnia Common                                                                                             Insomnia Nervous system disorders

Very common         Dizziness                  Headache                   Dizziness                Dizziness Headache                   Dysgeusia                  Headache                 Headache Dysgeusia                                             Dysgeusia                Dysgeusia Common              Cerebrovascular            Dizziness accident†
Uncommon            Posterior reversible       Cerebrovascular            Cerebrovascular          Posterior reversible encephalopathy             accident†                  accident                 encephalopathy syndrome                   Transient ischaemic        Posterior reversible     syndrome Monoparesis                attack                     encephalopathy           Cerebrovascular Transient ischaemic                                   syndrome                 accident† attack                                                Transient ischaemic      Monoparesis attack                   Transient ischaemic attack
Cardiac disorders

Common              Myocardial infarctiona,†   Myocardial infarctiona,†   Myocardial infarctiona   Prolonged Cardiac failure            Cardiac failure†           Prolonged                electrocardiogram QT Prolonged                  Prolonged                  electrocardiogram QT electrocardiogram QT       electrocardiogram QT
Decreased ejection fraction
System Organ     Lenvatinib               Combination with        Combination with       Combination with Class            monotherapy              everolimus              pembrolizumab          pembrolizumab (EC) (MedDRA                                                           (RCC) terminology)


Uncommon                                  Decreased ejection      Cardiac failure†       Myocardial fraction                Decreased ejection     infarctionc,† fraction               Cardiac failure
Decreased ejection fraction
Vascular disorders
Very common      Haemorrhageb, *, †       Haemorrhageb, *, †      Haemorrhageb, *, †     Haemorrhaged, *,† Hypertensionc,*          Hypertensionc,*         Hypertensionc,*        Hypertensione,* Hypotension
Common                                     Hypotension            Hypotension            Hypotension Not known         Aneurysms and artery     Aneurysms and artery   Aneurysms and artery dissections              dissections            dissections
Respiratory, thoracic and mediastinal disorders
Very common      Dysphonia                Dysphonia               Dysphonia              Dysphonia Common           Pulmonary embolism†      Pulmonary embolism      Pulmonary embolism     Pulmonary embolism† Pneumothorax
Uncommon          Pneumothorax                                    Pneumothorax           Pneumothorax Gastrointestinal disorders
Very common      Diarrhoea*               Diarrhoea*              Diarrhoea*             Diarrhoea* Gastrointestinal and     Gastrointestinal and    Gastrointestinal and   Gastrointestinal and abdominal painsd         abdominal painsd        abdominal painsd       abdominal painsf Vomiting                 Vomiting                Vomiting               Vomiting Nausea                   Nausea                  Nausea                 Nausea Oral inflammatione       Oral inflammatione      Oral inflammatione     Oral inflammationg Oral painf               Oral painf              Oral painf             Oral painh Constipation             Constipation            Constipation           Constipation Dyspepsia                Dyspepsia               Dyspepsia              Dry mouth Dry mouth                Increased lipase‡       Dry mouth              Increased lipase Increased lipase‡        Increased amylase‡      Increased lipase‡      Increased amylase‡ Increased amylase‡                               Increased amylase‡ 
Common           Anal fistula             Dry mouth               Pancreatitisg          Pancreatitisg Flatulence               Flatulence              Colitis                Flatulence Gastrointestinal         Gastrointestinal        Flatulence             Dyspepsia perforation              perforation             Gastrointestinal       Colitis perforation            Gastrointestinal perforation
Uncommon         Pancreatitisg            Pancreatitisg           Anal fistula           Anal fistula Colitis                  Anal fistula
Colitis
Hepatobiliary disorders
Very common      Increased blood          Hypoalbuminaemia*, ‡    Increased blood        Increased blood bilirubin*, ‡            Increased alanine       bilirubin ‡            bilirubinj,*,‡ aminotransferase‡       Hypoalbuminaemia‡
System Organ     Lenvatinib                 Combination with           Combination with        Combination with Class            monotherapy                everolimus                 pembrolizumab           pembrolizumab (EC) (MedDRA                                                                (RCC) terminology)


Hypoalbuminaemia*, ‡       Increased aspartate        Increased alanine       Hypoalbuminaemiaj,*, Increased alanine          aminotransferase‡          aminotransferase‡       ‡ Increased blood alkaline aminotransferase*, ‡                                  Increased aspartate     Increased alanine phosphatase‡               aminotransferase‡
Increased aspartate                                                           aminotransferase*, ‡ Increased blood aminotransferase*, ‡                                                          Increased aspartate alkaline phosphatase‡
Increased blood alkaline                                                      aminotransferase*, ‡ phosphatase‡                                                                  Increased blood Increased gamma-                                                              alkaline phosphatase‡ glutamyltransferase‡
Common           Hepatic failureh,†         Cholecystitis              Cholecystitis           Cholecystitis Hepatic                    Abnormal hepatic           Abnormal hepatic        Abnormal hepatic function                   function                function encephalopathyi, †
Increased gamma-           Increased gamma-        Increased gamma-
Cholecystitis glutamyltransferase        glutamyltransferase     glutamyltransferase Abnormal hepatic
Increased blood function                   bilirubin*, ‡
Uncommon         Hepatocellular             Hepatic failureh, †        Hepatic failureh,,†     Hepatic failurek,*† damage/hepatitisj          Hepatic encephalopathyi    Hepatic                 Hepatic encephalopathyi         encephalopathyl,†,*
Hepatocellular          Hepatocellular damage/hepatitisj       damage/hepatitism
Skin and subcutaneous tissue disorders
Very common      Palmar-plantar             Palmar-plantar             Palmar-plantar          Palmar-plantar erythrodysaesthesia        erythrodysaesthesia        erythrodysaesthesia     erythrodysaesthesia syndrome                   syndrome                   syndrome                syndrome Rash                       Rash                       Rash                    Rash Alopecia
Common           Hyperkeratosis             Alopecia                   Hyperkeratosis          Alopecia Alopecia
Uncommon                                   Hyperkeratosis                                      Hyperkeratosis Musculoskeletal and connective tissue disorders
Very common      Back pain                 Back pain                   Back pain               Back pain Arthralgia                Arthralgia                  Arthralgia              Arthralgia Myalgia                                               Myalgia                 Myalgia Pain in extremity                                     Pain in extremity       Pain in extremity Musculoskeletal pain                                  Musculoskeletal pain 
Common                                      Myalgia                                            Musculoskeletal pain Pain in extremity
Musculoskeletal pain
Uncommon         Osteonecrosis of the jaw   Osteonecrosis of the jaw

Renal and urinary disorders
Very common      Proteinuria*               Proteinuria*               Proteinuria*            Proteinuria* Increased blood
System Organ      Lenvatinib                      Combination with               Combination with             Combination with Class             monotherapy                     everolimus                     pembrolizumab                pembrolizumab (EC) (MedDRA                                                                          (RCC) terminology)

 creatinine‡
Increased blood                 Increased blood                Increased blood creatinine‡                     creatinine‡                    creatinine‡ Common            Renal failurek, *, †            Renal failurek, *, †           Renal failurek, * Renal impairment*               Renal impairment*              Increased blood urea         Renal failure n, *,† Increased blood urea            Increased blood urea
Uncommon          Nephrotic syndrome                                             Nephrotic syndrome           Renal impairment* Renal impairment*            Increased blood urea
General disorders and administration site conditions
Very common       Fatigue                         Fatigue                        Fatigue                      Fatigue Asthenia                        Asthenia                       Asthenia                     Asthenia Oedema peripheral               Oedema peripheral              Oedema peripheral            Oedema peripheral Common            Malaise                         Malaise                        Malaise                      Malaise Uncommon          Impaired healing                Impaired healing               Impaired healing             Impaired healing Non-gastrointestinal           Non-gastrointestinal fistulal                       fistulal
Not known         Non-gastrointestinal fistulal
§
: Adverse reaction frequencies presented in Table 3 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.
Description of selected adverse reactions

Hypertension (see section 4.4)

RCC
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.
DTC
In the pivotal Phase 3 SELECT trial (see section 5.1), hypertension (including hypertension, hypertensive crisis, increased diastolic blood pressure, and increased blood pressure) 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.

EC
In the Phase 3 Study 309 (see section 5.1), 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.

HCC
In the Phase 3 -REFLECT trial (see section 5.1), hypertension (including hypertension, increased blood pressure, increased diastolic blood pressure and orthostatic hypertension) was reported in 44.5% of lenvatinib-treated patients and Grade 3 hypertension occurred in 23.5%.
The median time to onset was 26 days. The majority of cases recovered following dose interruption or reduction, which occurred in 3.6% and 3.4% of patients respectively. One subject (0.2%) discontinued lenvatinib due to hypertension.

Proteinuria (see section 4.4)

RCC
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.

DTC
In the pivotal Phase 3 SELECT trial (see section 5.1), 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.

HCC
In the Phase 3 REFLECT trial (see section 5.1), proteinuria was reported in 26.3% of lenvatinib-treated patients and Grade 3 reactions occurred in 5.9%. The median time to onset was 6.1 weeks. The majority of cases recovered following dose interruption or reduction, which occurred in 6.9% and 2.5% of patients respectively. Proteinuria led to permanent treatment discontinuation in 0.6% of patients.

EC
In the Phase 3 Study 309 (see section 5.1), 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.


Renal failure and impairment (see section 4.4)
RCC
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.

DTC
In the pivotal Phase 3 SELECT trial (see section 5.1), 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).

HCC
In the Phase 3 REFLECT trial (see section 5.1), 7.1% of lenvatinib-treated patients developed a renal failure/impairment event. Grade 3 or greater reactions occurred in 1.9% of lenvatinib- treated patients.

EC
In the Phase 3 Study 309 (see section 5.1), 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 section 4.4)
RCC
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.

DTC
In the pivotal Phase 3 SELECT trial (see section 5.1), 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).

HCC
In the Phase 3 REFLECT trial (see section 5.1), 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.

EC
In the Phase 3 Study 309 (see section 5.1), 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 section 4.4)

RCC
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.

DTC
In the pivotal Phase 3 SELECT trial (see section 5.1), there was 1 event of PRES (Grade 2) in the lenvatinib-treated group and no reports in the placebo group.

HCC
In the Phase 3 REFLECT trial (see section 5.1), 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.

EC
In the Phase 3 Study 309 (see section 5.1), there was one event of PRES (Grade 1) in the lenvatinib plus pembrolizumab-treated group for which lenvatinib was interrupted.
Hepatotoxicity (see section 4.4)

RCC
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.
DTC
In the pivotal Phase 3 SELECT trial (see section 5.1), 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.
HCC
In the Phase 3 REFLECT trial (see section 5.1), 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%).

EC
In the Phase 3 Study 309 (see section 5.1), 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 section 4.4)

RCC
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.

DTC
In the pivotal Phase 3 SELECT trial (see section 5.1), arterial thromboembolic events were reported in 5.4% of lenvatinib-treated patients and 2.3% of patients in the placebo group.

HCC
In the Phase 3 REFLECT trial (see section 5.1), arterial thromboembolic events were reported in 2.3% of patients treated with lenvatinib.

Amongst 1,823 patients treated with lenvatinib monotherapy in clinical studies, there were 10 cases (0.5%) of arterial thromboembolisms (5 cases of myocardial infarction and 5 cases of cerebrovascular accident) with a fatal outcome.

EC
In the Phase 3 Study 309 (see section 5.1), 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.


Haemorrhage (see section 4.4)
RCC
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.

DTC
In the pivotal Phase 3 SELECT trial (see section 5.1), 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).

HCC
In the Phase 3 REFLECT trial (see section 5.1), 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.

EC
In the Phase 3 Study 309 (see section 5.1), 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 section 4.4, QT interval prolongation)

RCC
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.
DTC
In the pivotal Phase 3 SELECT trial (see section 5.1), 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.

HCC
In the Phase 3 REFLECT trial (see section 5.1), 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.

EC
In the Phase 3 Study 309 (see section 5.1), 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 section 4.4)

DTC
In the pivotal Phase 3 SELECT trial (see section 5.1), events of gastrointestinal perforation or fistula were reported in 1.9% of lenvatinib-treated patients and 0.8% of patients in the placebo group.

RCC
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.

HCC
In the Phase 3 REFLECT trial (see section 5.1), events of gastrointestinal perforation or fistula were reported in 1.9% of lenvatinib-treated patients.

EC
In the Phase 3 Study 309 (see section 5.1), 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.
Non-Gastrointestinal fistulae (see section 4.4)
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 median latency of about 3 months.

QT interval prolongation (see section 4.4)

RCC
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.

DTC
In the pivotal Phase 3 SELECT trial (see section 5.1), 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

HCC
In the Phase 3 REFLECT trial (see section 5.1), 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%.

EC
In the Phase 3 Study 309 (see section 5.1), 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.
Increased blood thyroid stimulating hormone (see section 4.4 Impairment of thyroid stimulating hormone suppression)

RCC
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% 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.

DTC
In the pivotal Phase 3 SELECT trial (see section 5.1), 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.

HCC
In the Phase 3 REFLECT trial (see section 5.1), 89.6% of patients had a baseline TSH level of less than the upper limit of normal. Elevation of TSH above the upper limit of normal was observed post baseline in 69.6% of lenvatinib-treated patients.

EC
In the Phase 3 Study 309 (see section 5.1), 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.
Diarrhoea (see section 4.4)

RCC
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.

DTC
In the pivotal Phase 3 SELECT trial (see section 5.1), 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).

HCC
In the Phase 3 REFLECT trial (see section 5.1), diarrhoea was reported in 38.7% of patients treated with lenvatinib (4.2% were Grade ≥ 3).

EC
In the Phase 3 Study 309 (see section 5.1), 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.


Paediatric population
In the paediatric Studies 207, 216, 230, and 231 (see section 5.1), the overall safety profile of lenvatinib as a single agent or in combination with either ifosfamide and etoposide or everolimus was consistent with that observed in adults treated with lenvatinib.

In patients with relapsed/refractory osteosarcoma, pneumothorax was reported at a frequency higher than that observed in adults with DTC, HCC, RCC and EC. In Study 207, pneumothorax occurred in 6 patients (10.9%) treated with single -agent lenvatinib and 7 patients (16.7%) treated with lenvatinib in combination with ifosfamide and etoposide.
Overall, 2 patients discontinued study treatment due to pneumothorax. In Study 230, pneumothorax was reported in 12 patients (11 patients [28.2%] treated with lenvatinib plus ifosfamide and etoposide, and 1 patient [2.6%] treated with ifosfamide and etoposide).

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, 230, and 231, no patient discontinued study treatment due to pneumothorax. Pneumothorax occurrence appeared to be mainly associated with pulmonary metastases and underlying disease.

In the single-agent dose-finding cohort of Study 207, the most frequently (≥40%) reported adverse drug reactions were decreased appetite, diarrhoea, hypothyroidism, vomiting, abdominal pain, pyrexia, hypertension, and weight decreased; and in the single-agent expansion cohort of patients with relapsed or refractory osteosarcoma, the most frequently (≥40%) reported adverse drug reactions were decreased appetite, headache, vomiting, hypothyroidism, and proteinuria.

In the combination dose-finding cohort of Study 207, the most frequently (≥50%) reported adverse drug reactions were vomiting, anaemia, nausea, diarrhoea, hypothyroidism, abdominal pain, arthralgia, epistaxis, neutropenia, constipation, headache, and pain in extremity; and in the combination expansion cohort, the most frequently (≥50%) reported adverse drug reactions were anaemia, nausea, white blood cell count decreased, diarrhoea, vomiting, and platelet count decreased.

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 the OLIE study (Study 230), the most frequently (≥35%) reported adverse drug reactions were hypothyroidism, anaemia, nausea, platelet count decreased, proteinuria, vomiting, back pain, febrile neutropenia, hypertension, constipation, diarrhoea, neutrophil count decreased, and pyrexia.

In Study 231, the most frequently reported (≥15%) adverse drug reactions were hypothyroidism, hypertension, proteinuria, decreased appetite, diarrhoea, and platelet count decreased.

Other special populations

Elderly
RCC
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).

DTC
Patients of age ≥75 years were more likely to experience Grade 3 or 4 hypertension, proteinuria, decreased appetite, and dehydration.

HCC
Patients of age ≥75 years were more likely to experience hypertension, proteinuria, decreased appetite, asthenia, dehydration, dizziness, malaise, peripheral oedema, pruritus and hepatic encephalopathy. Hepatic encephalopathy occurred at more than twice the incidence in patients aged ≥75 years (17.2%) than in those <75 years (7.1%). Hepatic encephalopathy tended to be associated with adverse disease characteristics at baseline or with the use of concomitant medications. Arterial thromboembolic events also occurred at an increased incidence in this age group.

EC
Patients of age ≥75 years were more likely to experience urinary tract infections and Grade ≥3 hypertension (≥ 10% increase compared to patients of age <65 years).
Gender
RCC
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.

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.

HCC
Females had a higher incidence of hypertension, fatigue, ECG QT prolongation and alopecia.
Men had a higher incidence (26.5%) of dysphonia than women (12.3%), decreased weight and decreased platelet count. Hepatic failure events were observed in male patients only.

Ethnic origin

RCC
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 hypercholesterolemia.

DTC
Asian patients had a higher (≥ 10% difference) 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. A larger proportion of Asian patients had a lenvatinib dose reduction compared to Caucasian patients. The median time to first dose reduction and the average daily dose taken were lower in Asian than in Caucasian patients.

HCC
Asian patients had a higher incidence than Caucasian patients of proteinuria, decreased neutrophil count, decreased platelet count, decreased white blood count and PPE syndrome, while Caucasian patients had a higher incidence of fatigue, hepatic encephalopathy, acute kidney injury, anxiety, asthenia, nausea, thrombocytopenia and vomiting.

EC
Asian patients had a higher (≥10% difference) incidence than Caucasian patients of anaemia, malaise, neutrophil count decrease, stomatitis, platelet count decreased, proteinuria and PPE while Caucasian patients had a higher incidence of mucosal inflammation, abdominal pain, diarrhoea, urinary tract infection, weight decreased, hypomagnesaemia, dizziness, asthenia and fatigue.

Baseline hypertension

Clear cell RCC
In CLEAR, patients with baseline hypertension had a higher incidence of proteinuria than patients without baseline hypertension.

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 GI symptoms (abdominal pain, diarrhoea, vomiting).

Baseline diabetes

Clear cell RCC
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.

Hepatic impairment

Clear cell RCC
There are limited data on patients with hepatic impairment in clear cell RCC.
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.

HCC
Patients with a baseline Child Pugh (CP) score of 6 (about 20% patients in the REFLECT study) had a higher incidence of decreased appetite, fatigue, proteinuria, hepatic encephalopathy and hepatic failure compared to patients with a baseline CP score of 5.
Hepatotoxicity events and haemorrhage events also occurred at a higher incidence in CP score 6 patients compared to CP score 5 patients.

Renal impairment

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.

DTC
Patients with baseline renal impairment had a higher incidence of Grade 3 or 4 hypertension, proteinuria, fatigue, stomatitis, oedema peripheral, thrombocytopenia, dehydration, prolonged QT, hypothyroidism, hyponatraemia, increased blood thyroid stimulating hormone, 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.
HCC
Patients with baseline renal impairment had a higher incidence of fatigue, hypothyroidism, dehydration, diarrhoea, decreased appetite, proteinuria and hepatic encephalopathy. These patients also had a higher incidence of renal reactions and arterial thromboembolic events.
Patients with body weight <60 kg

Clear cell RCC
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.

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 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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il