Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
Pooled data from the pivotal RCC study (VEG105192, n=290), the extension study (VEG107769, n=71), the 
VOT SPI Jan22 V3                                                          EU SmPC 12-Nov-2021 supportive Phase II study (VEG102616, n=225) and the randomised, open-label, parallel group Phase III non-inferiority study (VEG108844, n=557) were evaluated in the overall evaluation of safety and tolerability of pazopanib (total n=1149) in subjects with RCC (see section 5.1).

Pooled data from the pivotal STS study (VEG110727, n=369) and the supportive Phase II study (VEG20002, n=142) was evaluated in the overall evaluation of safety and tolerability of pazopanib (total safety population n=382) in subjects with STS (see section 5.1).

The most important serious adverse reactions identified in the RCC or STS studies were transient ischaemic attack, ischaemic stroke, myocardial ischaemia, myocardial and cerebral infarction, cardiac dysfunction, gastrointestinal perforation and fistula, QT prolongation, Torsade de Pointes and pulmonary, gastrointestinal and cerebral haemorrhage, all adverse reactions being reported in <1% of treated patients. Other important serious adverse reactions identified in STS studies included venous thromboembolic events, left ventricular dysfunction and pneumothorax.

Fatal events that were considered possibly related to pazopanib included gastrointestinal haemorrhage, pulmonary haemorrhage/haemoptysis, abnormal hepatic function, intestinal perforation and ischaemic stroke.

The most common adverse reactions (experienced by at least 10% of the patients) of any grade in the RCC and STS trials included: diarrhoea, hair colour change, skin hypopigmentation, exfoliative rash, hypertension, nausea, headache, fatigue, anorexia, vomiting, dysgeusia, stomatitis, weight decreased, pain, elevated alanine aminotransferase and elevated aspartate aminotransferase.

Adverse drug reactions, all grades, which were reported in RCC and STS subjects or during the post marketing period are listed below by MedDRA body system organ class, frequency and grade of severity.
The following convention has been utilised for the classification of frequency: 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); and not known (cannot be estimated from the available data).

Categories have been assigned based on absolute frequencies in the clinical trial data. Post-marketing data on safety and tolerability across all pazopanib clinical studies and from spontaneous reports have also been evaluated. Within each system organ class, adverse reactions with the same frequency are presented in order of decreasing seriousness.

Tabulated list of adverse reactions

Table 2      Treatment-related adverse reactions reported in RCC studies (n = 1149) or during post- marketing period

System Organ          Frequency         Adverse reactions         All grades      Grade 3         Grade 4 Class                 (all grades)                                n (%)           n (%)           n (%) Common            Infections (with or       not known       not known       not known Infections and                          without neutropenia)†
Infestations          Uncommon          Gingival infection        1 (<1%)         0               0 Infectious peritonitis    1 (<1%)         0               0
Neoplasms             Uncommon          Tumour pain               1 (<1%)         1 (<1%)         0 benign, malignant and unspecified
(incl cysts and polyps)
Common            Thrombocytopenia          80 (7%)         10 (<1%)        5 (<1%) Blood and                               Neutropenia               79 (7%)         20 (2%)         4 (<1%) lymphatic system disorders                               Leukopenia                63 (5%)         5 (<1%)         0 Uncommon          Polycythaemia             6 (0.03%)       1               0 

VOT SPI Jan22 V3                                                            EU SmPC 12-Nov-2021 Rare          Thrombotic               not known       not known       not known microangiopathy
(including thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome)†
Endocrine           Common        Hypothyroidism           83 (7%)         1 (<1%)         0 disorders
Very common   Decreased appetitee      317 (28%)       14 (1%)         0 Common        Hypophosphataemia        21 (2%)         7 (<1%)         0 Metabolism and                    Dehydration              16 (1%)         5 (<1%)         0 nutrition disorders           Uncommon      Hypomagnesaemia          10 (<1%)        0               0 Tumour lysis             not known       not known       not known
Not known syndrome*
Psychiatric         Common        Insomnia                 30 (3%)         0               0 disorders
Very common   Dysgeusiac               254 (22%)       1 (<1%)         0 Headache                 122 (11%)       11 (<1%)        0
Common        Dizziness                55 (5%)         3 (<1%)         1 (<1%) Lethargy                 30 (3%)         3 (<1%)         0
Paraesthesia             20 (2%)         2 (<1%)         0
Peripheral sensory       17 (1%)         0               0 neuropathy
Uncommon      Hypoaesthesia            8 (<1%)         0               0 Nervous system                    Transient ischaemic      7 (<1%)         4 (<1%)         0 attack disorders
Somnolence               3 (<1%)         1 (<1%)         0
Cerebrovascular          2 (<1%)         1 (<1%)         1 (<1%) accident
Ischaemic stroke         2 (<1%)         0               1 (<1%)
Rare          Posterior reversible     not known       not known       not known encephalopathy/ reversible posterior leukoencephalopathy syndrome†
Common        Vision blurred           19 (2%)         1 (<1%)         0 Uncommon      Retinal detachment†      1 (<1%)         1 (<1%)         0 Eye disorders
Retinal tear†            1 (<1%)         1 (<1%)         0
Eyelash discolouration   4 (<1%)         0               0
Uncommon      Bradycardia              6 (<1%)         0               0 Myocardial infarction    5 (<1%)         1 (<1%)         4 (<1%)
Cardiac disorders
Cardiac dysfunctionf     4 (<1%)         1 (<1%)         0
Myocardial ischaemia     3 (<1%)         1 (<1%)         0
Very common   Hypertension             473 (41%)       115 (10%)       1 (<1%) Common        Hot flush                16 (1%)         0               0 Venous                   13 (1%)         6 (<1%)         7 (<1%)
Vascular                          thromboembolic disorders                         event g
Flushing                 12 (1%)         0               0
Uncommon      Hypertensive crisis      6 (<1%)         0               2 (<1%) Haemorrhage              1 (<1%)         0               0

VOT SPI Jan22 V3                                                     EU SmPC 12-Nov-2021 Rare          Aneurysms and artery     not known       not known       not known dissections
Common        Epistaxis                50 (4%)         1 (<1%)         0 Dysphonia                48 (4%)         0               0
Dyspnoea                 42 (4%)         8 (<1%)         1 (<1%)
Respiratory,                     Haemoptysis              15 (1%)         1 (<1%)         0 thoracic and       Uncommon      Rhinorrhoea              8 (<1%)         0               0 mediastinal                      Pulmonary                2 (<1%)         0               0 disorders                        haemorrhage
Pneumothorax             1 (<1%)         0               0
Rare          Interstitial lung        not known       not known       not known disease/pneumonitis†
Very common   Diarrhoea                614 (53%)       65 (6%)         2 (<1%) Nausea                   386 (34%)       14 (1%)         0
Vomiting                 225 (20%)       18 (2%)         1 (<1%)
Abdominal paina          139 (12%)       15 (1%)         0
Common        Stomatitis               96 (8%)         4 (<1%)         0 Dyspepsia                83 (7%)         2 (<1%)         0
Flatulence               43 (4%)         0               0
Abdominal distension     36 (3%)         2 (<1%)         0
Mouth ulceration         28 (2%)         3 (<1%)         0
Dry mouth                27 (2%)         0               0
Uncommon      Pancreatitis             8 (<1%)         4 (<1%)         0 Rectal haemorrhage       8 (<1%)         2 (<1%)         0
Haematochezia            6 (<1%)         0               0
Gastrointestinal         4 (<1%)         2 (<1%)         0 haemorrhage
Melaena                  4 (<1%)         1(<1%)          0
Gastrointestinal                 Frequent bowel           3 (<1%)         0               0 disorders                        movements
Anal haemorrhage         2 (<1%)         0               0
Large intestine          2 (<1%)         1 (<1%)         0 perforation
Mouth haemorrhage        2 (<1%)         0               0
Upper gastrointestinal   2 (<1%)         1 (<1%)         0 haemorrhage
Enterocutaneous          1 (<1%)         0               0 fistula
Haematemesis             1 (<1%)         0               0
Haemorrhoidal            1 (<1%)         0               0 haemorrhage
Ileal perforation        1 (<1%)         0               1 (<1%)
Oesophageal              1 (<1%)         0               0 haemorrhage
Retroperitoneal          1 (<1%)         0               0 haemorrhage
Common        Hyperbilirubinaemia      38 (3%)         2 (<1%)         1 (<1%) Hepatic function         29 (3%)         13 (1%)         2 (<1%) abnormal
Hepatobiliary                    Hepatotoxicity           18 (2%)         11(<1%)         2 (<1%) disorders          Uncommon      Jaundice                 3 (<1%)         1 (<1%)         0 Drug induced liver       2 (<1%)         2 (<1%)         0 injury
Hepatic failure†         1 (<1%)         0               1 (<1%)


VOT SPI Jan22 V3                                                    EU SmPC 12-Nov-2021 Very common   Hair colour change     404 (35%)       1 (<1%)         0 Palmar-plantar         206 (18%)       39 (3%)         0 erythrodysaesthesia syndrome
Alopecia               130 (11%)       0               0
Rash                   129 (11%)       7 (<1%)         0
Common        Skin                   52 (5%)         0               0 hypopigmentation
Dry skin               50 (4%)         0               0
Pruritus               29 (3%)         0               0
Erythema               25 (2%)         0               0
Skin depigmentation    20 (2%)         0               0
Skin and                          Hyperhidrosis          17 (1%)         0               0 subcutaneous        Uncommon      Nail disorders         11 (<1%)        0               0 disorders                         Skin exfoliation       10 (<1%)        0               0 Photosensitivity       7 (<1%)         0               0 reaction
Rash erythematous      6 (<1%)         0               0
Skin disorder          5 (<1%)         0               0
Rash macular           4 (<1%)         0               0
Rash pruritic          3 (<1%)         0               0
Rash vesicular         3 (<1%)         0               0
Pruritus generalised   2 (<1%)         1 (<1%)         0
Rash generalised       2 (<1%)         0               0
Rash papular           2 (<1%)         0               0
Plantar erythema       1 (<1%)         0               0
Skin ulcer†            Not known       Not known       Not Known
Common        Arthralgia             48 (4%)         8 (<1%)         0 Musculoskeletal
Myalgia                35 (3%)         2 (<1%)         0 and connective
Muscle spasms          25 (2%)         0               0 tissue disorders
Uncommon      Musculoskeletal pain   9 (<1%)         1 (<1%)         0 Very Common   Proteinuria            135 (12%)       32 (3%)         0 Renal and urinary disorders   Uncommon      Haemorrhage urinary    1 (<1%)         0               0 tract
Reproductive        Uncommon      Menorrhagia            3 (<1%)         0               0 system and breast                 Vaginal haemorrhage    3 (<1%)         0               0 disorders                         Metrorrhagia           1 (<1%)         0               0 Very common   Fatigue                415 (36%)       65 (6%)         1 (<1%) Common        Mucosal inflammation   86 (7%)         5 (< 1%)        0 Asthenia               82 (7%)         20 (2%)         1 (<1%)
General disorders
Oedemab                72 (6%)         1 (<1%)         0 and administration                    Chest pain             18 (2%)         2 (<1%)         0 site conditions     Uncommon      Chills                 4 (<1%)         0               0 Mucous membrane        1 (<1%)         0               0 disorder
Very common   Alanine                246 (21%)       84 (7%)         14 (1%) aminotransferase increased
Investigations                    Aspartate              211 (18%)       51 (4%)         10 (<1%) aminotransferase increased
Common        Weight decreased       96 (8%)         7 (<1%)         0 

VOT SPI Jan22 V3                                                   EU SmPC 12-Nov-2021 Blood bilirubin             61 (5%)         6 (<1%)         1 (<1%) increased
Blood creatinine            55 (5%)         3 (<1%)         0 increased
Lipase increased            51 (4%)         21 (2%)         7 (<1%)
White blood cell count      51 (4%)         3 (<1%)         0 decreasedd
Blood thyroid               36 (3%)         0               0 stimulating hormone increased
Amylase increased           35 (3%)         7 (<1%)         0
Gamma-                      31 (3%)         9 (<1%)         4 (<1%) glutamyltransferase increased
Blood pressure              15 (1%)         2 (<1%)         0 increased
Blood urea increased        12 (1%)         1 (<1%)         0
Liver function test         12 (1%)         6 (<1%)         1 (<1%) abnormal
Uncommon           Hepatic enzyme              11 (<1%)        4 (<1%)         3 (<1%) increased
Blood glucose               7 (<1%)         0               1 (<1%) decreased
Electrocardiogram QT        7 (<1%)         2 (<1%)         0 prolonged
Transaminase                7 (<1%)         1 (<1%)         0 increased
Thyroid function test       3 (<1%)         0               0 abnormal
Blood pressure              2 (<1%)         0               0 diastolic increased
Blood pressure              1 (<1%)         0               0 systolic increased
†Treatment-related adverse reaction reported during post-marketing period (spontaneous case reports and serious adverse reactions from all pazopanib clinical studies).
*Treatment-related adverse reaction reported only during the post-marketing period. Frequency cannot be estimated from the available data.
The following terms have been combined: a
Abdominal pain, abdominal pain upper and abdominal pain lower b
Oedema, oedema peripheral, eye oedema, localised oedema and face oedema c
Dysgeusia, ageusia and hypogeusia d
White cell count decreased, neutrophil count decreased and leukocyte count decreased e
Decreased appetite and anorexia f
Cardiac dysfunction, left ventricular dysfunction, cardiac failure and restrictive cardiomyopathy g
Venous thromboembolic event, deep vein thrombosis, pulmonary embolism and thrombosis 
Neutropenia, thrombocytopenia and palmar-plantar erythrodysaethesia syndrome were observed more frequently in patients of East Asian descent.



VOT SPI Jan22 V3                                                                EU SmPC 12-Nov-2021 Table 3    Treatment-related adverse reactions reported in STS studies (n=382) or during post- marketing period

System Organ          Frequency      Adverse reactions       All grades   Grade 3        Grade 4 Class                 (all grades)                           n (%)        n (%)          n (%) Infections and        Common         Gingival infection      4 (1%)       0              0 infestations
Neoplasms benign,     Very common    Tumour pain             121 (32%)    32 (8%)        0 malignant and unspecified (incl cysts and polyps)
Very common    Leukopenia              106 (44%)    3 (1%)         0
Thrombocytopenia        86 (36%)     7 (3%)         2 (<1%)
Neutropenia             79 (33%)     10 (4%)        0
Blood and             Uncommon       Thrombotic              1 (<1%)      1 (<1%)        0 lymphatic system                     microangiopathy disordersf                           (including thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome)
Endocrine             Common         Hypothyroidism          18 (5%)      0              0 disorders
Very common    Decreased appetite      108 (28%)    12 (3%)        0
Hypoalbuminemiaf        81 (34%)     2 (<1%)        0
Metabolism and        Common         Dehydration             4 (1%)       2 (1%)         0 nutrition disorders   Uncommon       Hypomagnesaemia         1 (<1%)      0              0 Not known      Tumour lysis            not known    not known      not known syndrome*
Psychiatric           Common         Insomnia                5 (1%)       1 (<1%)        0 disorders
Very common    Dysgeusiac              79 (21%)     0              0
Headache                54 (14%)     2 (<1%)        0
Common         Peripheral sensory      30 (8%)      1 (<1%)        0
Nervous system                       neuropathy disorders                            Dizziness               15 (4%)      0              0 Uncommon       Somnolence              3 (<1%)      0              0
Paresthesia             1 (<1%)      0              0
Cerebral infarction     1 (<1%)      0              1 (<1%)
Eye disorders         Common         Vision blurred          15 (4%)      0              0 Common         Cardiac dysfunctiong    21 (5%)      3 (<1%)        1 (<1%) Left ventricular        13 (3%)      3 (<1%)        0
Cardiac disorders                    dysfunction
Bradycardia             4 (1%)       0              0
Uncommon       Myocardial infarction   1 (<1%)      0              0
Very common    Hypertension            152 (40%)    26 (7%)        0
Common         Venous                  13 (3%)      4 (1%)         5 (1%) thromboembolic eventd
Hot flush               12 (3%)      0              0
Vascular disorders                   Flushing                4 (1%)       0              0 Uncommon       Haemorrhage             2 (<1%)      1 (<1%)        0
Rare           Aneurysms and artery    not known    not known      not known dissections

VOT SPI Jan22 V3                                                   EU SmPC 12-Nov-2021 Common        Epistaxis                22 (6%)     0              0
Dysphonia                20 (5%)     0              0
Dyspnoea                 14 (4%)     3 (<1%)        0
Cough                    12 (3%)     0              0
Pneumothorax             7 (2%)      2 (<1%)        1 (<1%)
Hiccups                  4 (1%)      0              0
Respiratory,                     Pulmonary                4 (1%)      1 (<1%)        0 thoracic and                     haemorrhage mediastinal        Uncommon      Oropharyngeal pain       3 (<1%)     0              0 disorders
Bronchial                2 (<1%)     0              0 haemorrhage
Rhinorrhoea              1 (<1%)     0              0
Haemoptysis              1 (<1%)     0              0
Rare          Interstitial lung        not known   not known      not known disease/pneumonitis†
Very common   Diarrhoea                174 (46%)   17 (4%)        0
Nausea                   167 (44%)   8 (2%)         0
Vomiting                 96 (25%)    7 (2%)         0
Abdominal paina          55 (14%)    4 (1%)         0
Stomatitis               41 (11%)    1 (<1%)        0
Common        Abdominal distension     16 (4%)     2 (1%)         0
Dry mouth                14 (4%)     0              0
Dyspepsia                12 (3%)     0              0
Mouth haemorrhage        5 (1%)      0              0
Flatulence               5 (1%)      0              0
Anal haemorrhage         4 (1%)      0              0
Uncommon      Gastrointestinal         2 (<1%)     0              0
Gastrointestinal                 haemorrhage disorders                        Rectal haemorrhage       2 (<1%)     0              0 Enterocutaneous          1 (<1%)     1 (<1%)        0 fistula
Gastric haemorrhage      1 (<1%)     0              0
Melaena                  2 (<1%)     0              0
Oesophageal              1 (<1%)     0              1 (<1%) haemorrhage
Peritonitis              1 (<1%)     0              0
Retroperitoneal          1 (<1%)     0              0 haemorrhage
Upper gastrointestinal   1 (<1%)     1 (<1%)        0 haemorrhage
Ileal perforation        1 (<1%)     0              1 (<1%)
Uncommon      Hepatic function         2 (<1%)     0              1 (<1%) Hepatobiliary abnormal disorders
Not known     Hepatic failure*         not known   not known      not known Very common   Hair colour change       93 (24%)    0              0
Skin                     80 (21%)    0              0 hypopigmentation
Exfoliative rash         52 (14%)    2 (<1%)        0
Skin and           Common        Alopecia                 30 (8%)     0              0 subcutaneous                     Skin disorderc           26 (7%)     4 (1%)         0 disorders                        Dry skin                 21 (5%)     0              0 Hyperhydrosis            18 (5%)     0              0
Nail disorder            13 (3%)     0              0
Pruritus                 11 (3%)     0              0
Erythema                 4 (1%)      0              0

VOT SPI Jan22 V3                                               EU SmPC 12-Nov-2021 Uncommon      Skin ulcer              3 (<1%)     1 (<1%)        0
Rash                    1 (<1%)     0              0
Rash papular            1 (<1%)     0              0
Photosensitivity        1 (<1%)     0              0 reaction
Palmar-plantar          2 (<1%)     0              0 erythrodysaesthesia syndrome
Common        Musculoskeletal pain    35 (9%)     2 (<1%)        0
Musculoskeletal
Myalgia                 28 (7%)     2 (<1%)        0 and connective
Muscle spasms           8 (2%)      0              0 tissue disorders
Uncommon      Arthralgia              2 (<1%)     0              0
Renal and urinary    Uncommon      Proteinuria             2 (<1%)     0              0 disorders
Reproductive         Uncommon      Vaginal haemorrhage     3 (<1%)     0              0 system and breast                  Menorrhagia             1 (<1%)     0              0 disorder
Very common   Fatigue                 178 (47%)   34 (9%)        1 (<1%) Common        Oedemab                 18 (5%)     1 (<1%)        0
General disorders                  Chest pain              12 (3%)     4 (1%)         0 and administration                 Chills                  10 (3%)     0              0 site conditions      Uncommon      Mucosal                 1 (<1%)     0              0 inflammatione
Asthenia                1 (<1%)     0              0
Very common   Weight decreased        86 (23%)    5 (1%)         0
Common        Ear, nose and throat    29 (8%)     4 (1%)         0 examination abnormale
Alanine                 8 (2%)      4 (1%)         2 (<1%) aminotransferase increased
Blood cholesterol       6 (2%)      0              0 abnormal
Aspartate               5 (1%)      2 (<1%)        2 (<1%) aminotransferase increased
Gamma                   4 (1%)      0              3 (<1%)
Investigationsh glutamyltransferase increased
Uncommon      Blood bilirubin         2 (<1%)     0              0 increased
Aspartate               2 (<1%)     0              2 (<1%) aminotransferase
Alanine                 1 (<1%)     0              1 (<1%) aminotransferase
Platelet count          1 (<1%)     0              1 (<1%) decreased
Electrocardiogram QT    2 (<1%)     1 (<1%)        0 prolonged



VOT SPI Jan22 V3                                                EU SmPC 12-Nov-2021 †Treatment-related adverse reaction reported during post-marketing period (spontaneous case reports and serious adverse reactions from all pazopanib clinical studies).
*Treatment-related adverse reaction reported only during the post-marketing period. Frequency cannot be estimated from the available data.
The following terms have been combined: a
Abdominal pain, abdominal pain upper and gastrointestinal pain b
Oedema, oedema peripheral and eyelid oedema c
The majority of these cases were Palmar-plantar erythrodysaesthesia syndrome d
Venous thromboembolic events – includes Deep vein thrombosis, Pulmonary embolism and Thrombosis terms e
The majority of these cases describe mucositis f
Frequency is based on laboratory value tables from VEG110727 (N=240). These were reported as adverse events less frequently by investigators than as indicated by laboratory value tables.
g
Cardiac dysfunction events – includes Left ventricular dysfunction, Cardiac failure and Restrictive cardiomyopathy h
Frequency is based on adverse events reported by investigators. Laboratory abnormalities were reported as adverse events less frequently by investigators than as indicated by laboratory value tables.

Neutropenia, thrombocytopenia and palmar-plantar erythrodysaethesia syndrome were observed more frequently in patients of East Asian descent.

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/