Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of safety profile
The most serious observed adverse reactions in patients receiving Lonsurf are bone marrow suppression and gastrointestinal toxicity (see section 4.4).

Lonsurf as monotherapy
The safety profile of Lonsurf as monotherapy is based on the pooled data from 1114 patients with metastatic colorectal or gastric cancer in controlled phase III clinical studies.
The most common adverse reactions (≥ 30%) are neutropenia (53% [34% ≥ Grade 3]), nausea (31% [1% ≥ Grade 3]), fatigue (31% [4% ≥ Grade 3]), and anaemia (30% [11% ≥ Grade 3]).

The most common adverse reactions (≥ 2%) that resulted in treatment discontinuation, dose reduction, dose delay, or dose interruption were neutropenia, anaemia, fatigue, leukopenia, thrombocytopenia, diarrhoea, and nausea.

Lonsurf in combination with bevacizumab
The safety profile of Lonsurf in combination with bevacizumab is based on the data from 246 patients with metastatic colorectal cancer in the controlled phase III clinical study (SUNLIGHT).
The most common adverse reactions (≥ 30%) are neutropenia (69% [48% ≥ Grade 3]), fatigue (35% [3% ≥ Grade 3]), and nausea (33% [1% ≥ Grade 3]).
LONS-SPC-1024-V1                   Page 8 of 27
The most common adverse reactions (≥ 2%) that resulted in treatment discontinuation, dose reduction, dose delay, or dose interruption of Lonsurf when used in combination with bevacizumab were neutropenia, fatigue, thrombocytopenia, nausea and anaemia.
When Lonsurf is used in combination with bevacizumab, the frequency of the following adverse reactions was increased compared to Lonsurf as monotherapy: neutropenia (69% vs 53%), severe neutropenia (48% vs 34%), thrombocytopenia (24% vs 16%), stomatitis (11% vs 6%).


Tabulated list of adverse reactions
The adverse reactions observed from the 533 treated patients with metastatic colorectal cancer in the placebo-controlled Phase III (RECOURSE) clinical study, the 335 treated patients with metastatic gastric cancer in the placebo-controlled Phase III (TAGS) clinical study, the 246 patients treated with Lonsurf in monotherapy and the 246 patients treated with Lonsurf in combination with bevacizumab for metastatic colorectal cancer in the controlled Phase III (SUNLIGHT) clinical study are shown in Table 5.
They are classified according to System Organ Class (SOC) and the appropriate Medical Dictionary for Regulatory (MedDRA) term is used to describe a certain drug reaction and its synonyms and related conditions.

Adverse reactions known to occur with Lonsurf given alone or with bevacizumab may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical trials with combination therapy.
Adverse reactions are grouped according to their frequencies. Frequency groups are defined by the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥1/1,000 to < 1/100) and rare (≥ 1/10,000 to < 1/1,000) 
Within each frequency group, adverse reactions are presented in order of decreasing seriousness.



LONS-SPC-1024-V1                  Page 9 of 27
Table 5 - Adverse reactions reported in clinical studies in patients treated with Lonsurf 
System Organ Class
(MedDRA)a                        Adverse reactions                Frequency Monotherapy Combination with bevacizumab
Infections and infestations   Lower respiratory tract      Common             - infection
Neutropenic sepsis          Uncommon              -
Biliary tract infection     Uncommon              -
Infection                   Uncommon           Common
Urinary tract infection     Uncommon          Uncommon
Bacterial infection         Uncommon              -
Candida infection           Uncommon              -
Conjunctivitis              Uncommon              -
Herpes zoster               Uncommon              -
Influenza                   Uncommon              -
Upper respiratory tract     Uncommon              - infection
Enteritis infectious          Rare                -
Septic shockb                 Rare                -
Gingivitis                    Rare            Uncommon
Tinea pedis                   Rare                -
Neoplasms benign,             Cancer pain                 Uncommon              - malignant and unspecified
(incl cysts and polyps)
Blood and lymphatic system Anaemia                           Very         Very common disorders                                                  common
Neutropenia                       Very         Very common common
Leukopenia                     Very            Common common
Thrombocytopenia               Very            Very common common
Febrile neutropenia          Common            Uncommon
Lymphopenia                  Common            Common
Pancytopenia                Uncommon           Uncommon
Erythropenia                Uncommon           -
Leukocytosis                Uncommon           -
Monocytopenia               Uncommon           -
Monocytosis                 Uncommon           -
Granulocytopenia               Rare            -
Metabolism and nutrition      Decreased appetite             Very            Very common disorders                                                  common
Hypoalbuminaemia             Common            Uncommon
Dehydration                 Uncommon           -
Hyperglycaemia              Uncommon           Uncommon
Hyperkalaemia               Uncommon           -
Hypocalcaemia               Uncommon           -
Hypokalaemia                Uncommon           -
Hyponatraemia               Uncommon           -
Hypophosphataemia           Uncommon           -
Gout                           Rare            -
Hypernatraemia                 Rare            -
Psychiatric disorders         Anxiety                     Uncommon           - Insomnia                    Uncommon           -
LONS-SPC-1024-V1                  Page 10 of 27
System Organ Class
(MedDRA)a                       Adverse reactions               Frequency Monotherapy Combination with bevacizumab
Nervous system disorders      Dysgeusia                  Common          Common Dizziness                 Uncommon         Common
Headache                  Uncommon         Common
Neuropathy peripheral     Uncommon         Uncommon
Paraesthesia              Uncommon         Uncommon
Lethargy                  Uncommon         -
Neurotoxicity             Uncommon         -
Burning sensation            Rare          -
Dysaesthesia                 Rare          -
Hyperaesthesia               Rare          -
Hypoaesthesia                Rare          -
Syncope                      Rare          -
Eye disorders                 Cataract                     Rare          - Diplopia                     Rare          -
Dry eye                      Rare          -
Vision blurred               Rare          -
Visual acuity reduced        Rare          -
Ear and labyrinth disorders   Vertigo                   Uncommon         - Ear discomfort               Rare          -
Cardiac disorders             Angina pectoris           Uncommon         - Arrhythmia                Uncommon         -
Palpitations              Uncommon         -
Vascular disorders            Hypertension              Uncommon         Common Flushing                  Uncommon         -
Hypotension               Uncommon         -
Embolism                     Rare          -
Respiratory, thoracic and     Dyspnoea                   Common          Common mediastinal disorders
Pulmonary embolismb       Uncommon        -
Dysphonia                 Uncommon        Uncommon
Cough                     Uncommon        -
Epistaxis                 Uncommon        -
Rhinorrhoea                  Rare         Uncommon
Oropharyngeal pain           Rare         -
Pleural effusion             Rare         -
Gastrointestinal disorders    Diarrhoea                    Very         Very common common
Vomiting                     Very         Very common common
Nausea                       Very         Very common common
Abdominal pain             Common         Common
Stomatitis                 Common         Very common
Constipation               Common         Common
Ileus                     Uncommon        -
Gastrointestinal          Uncommon        - haemorrhage
Colitis                   Uncommon        Uncommon
Mouth ulceration          Uncommon        Common
Oral disorder             Uncommon        Common
Abdominal distension      Uncommon        Uncommon
Anal inflammation         Uncommon        Uncommon
Dyspepsia                 Uncommon        Uncommon
LONS-SPC-1024-V1                 Page 11 of 27
System Organ Class
(MedDRA)a                        Adverse reactions                  Frequency Monotherapy Combination with bevacizumab
Flatulence                    Uncommon         Uncommon
Gastritis                     Uncommon         -
Gastrooesophageal reflux      Uncommon         - disease
Glossitis                     Uncommon        -
Impaired gastric emptying     Uncommon        -
Retching                      Uncommon        -
Tooth disorder                Uncommon        -
Ascites                         Rare          -
Pancreatitis acute              Rare          -
Subileus                        Rare          -
Breath odour                    Rare          -
Buccal polyp                    Rare          -
Enterocolitis                   Rare          - haemorrhagic
Gingival bleeding               Rare          -
Oesophagitis                    Rare          -
Periodontal disease             Rare          -
Proctalgia                      Rare          -
Reflux gastritis                Rare          -
Hepatobiliary disorders       Hyperbilirubinaemia            Common         Common Hepatotoxicity                Uncommon        -
Biliary dilatation              Rare          -
Skin and subcutaneous         Alopecia                       Common         Common tissue disorders
Dry skin                       Common         Common
Pruritus                       Common         Uncommon
Rash                           Common         Uncommon
Nail disorder                 Uncommon        Uncommon
Palmar-plantar                Uncommon        Uncommon erythrodysaesthesia syndromec
Acne                          Uncommon        -
Hyperhidrosis                 Uncommon        -
Urticaria                     Uncommon        -
Blister                         Rare          -
Erythema                        Rare          -
Photosensitivity reaction       Rare          -
Skin exfoliation                Rare          -
Musculoskeletal and           Arthralgia                    Uncommon        Common connective tissue disorders
Myalgia                       Uncommon        Common
Muscular weakness             Uncommon        Uncommon
Pain in extremity             Uncommon        Uncommon
Bone pain                     Uncommon        -
Limb discomfort               Uncommon        -
Muscle spasms                 Uncommon        -
Joint swelling                  Rare          -
Renal and urinary disorders   Proteinuria                    Common         Uncommon Renal failure                 Uncommon        -
Haematuria                    Uncommon        -
Micturition disorder          Uncommon        -
Cystitis noninfective           Rare          -
LONS-SPC-1024-V1                 Page 12 of 27
System Organ Class
(MedDRA)a                        Adverse reactions                   Frequency Monotherapy Combination with bevacizumab
Leukocyturia                     Rare          -
Reproductive system and        Menstrual disorder               Rare          Uncommon breast disorders
General disorders and          Fatigue                           Very             Very common administration site conditions                                 common Pyrexia                         Common             Uncommon
Mucosal inflammation            Common             Uncommon
Malaise                         Common             -
Oedema                          Common             -
General physical health        Uncommon            - deterioration
Pain                           Uncommon            Uncommon
Feeling of body                Uncommon            - temperature change
Xerosis                          Rare              -
Investigations                 Weight decreased                Common             Common Hepatic enzyme                  Common             Common increased
Blood alkaline                  Common             Uncommon phosphatase increased
Blood lactate                  Uncommon            - dehydrogenase increased
C-reactive protein             Uncommon            - increased
Blood creatinine               Uncommon            - increased
Blood urea increased           Uncommon            -
Haematocrit decreased          Uncommon            -
International normalised       Uncommon            - ratio increased
Activated partial                 Rare             - thromboplastin time prolonged
Electrocardiogram QT              Rare             - prolonged
Protein total decreased           Rare             -
 a. Different MedDRA preferred terms that were considered clinically similar have been grouped into a single term.
b. Fatal cases have been reported.
c. Hand-foot skin reaction.

Elderly

Patients 65 years of age or older who received Lonsurf as monotherapy had a higher incidence (≥ 5%) of the following treatment-related adverse events compared to patients younger than 65 years: neutropenia (58.9% vs 48.2%), severe neutropenia (41.3% vs 27.9%), anaemia (36.5% vs 25.2%), severe anaemia (14.1% vs 8.9%), decreased appetite (22.6% vs 17.4%), and thrombocytopenia (21.4% vs 12.1%). When Lonsurf is used in combination with bevacizumab, patients 65 years of age or older had a higher incidence (≥ 5%) of the following treatment-related adverse events compared to patients younger than 65 years: neutropenia (75.0% vs 65.1%), severe neutropenia (57.0% vs 41.8%), fatigue (39.0% vs 32.2%), thrombocytopenia (28.0% vs 20.5%), and stomatitis (14.0% vs 8.9%).
LONS-SPC-1024-V1                  Page 13 of 27
Infections

In the Phase III placebo-controlled clinical studies, treatment-related infections occurred more frequently in Lonsurf-treated patients (5.8%) compared to those receiving placebo (1.8%).
In the clinical study in combination with bevacizumab, treatment-related infections occurred similarly in patients who received Lonsurf with bevacizumab (2.8%) compared to Lonsurf-treated patients (2.4%).

Proteinuria

In the phase III placebo-controlled clinical studies, treatment-related proteinuria occurred more frequently in Lonsurf-treated patients (1.8%) compared to those receiving placebo (0.9%), all of which were Grade 1 or 2 in severity (see section 4.4).
In the clinical study in combination with bevacizumab, one patient who received Lonsurf with bevacizumab (0.4%) reported a treatment-related proteinuria which was Grade 2 and none among the Lonsurf-treated patients (see section 4.4).


Radiotherapy
There was a slightly higher incidence of overall haematological and myelosuppression-related adverse reactions for patients who received prior radiotherapy compared to patients without prior radiotherapy in RECOURSE (54.6% versus 49.2%, respectively), of note febrile neutropenia was higher in Lonsurf-treated patients who received prior radiotherapy vs. those that did not.
In the clinical study in combination with bevacizumab, no increase of incidence of overall haematological and myelosuppression-related adverse reactions was observed for patients who received prior radiotherapy compared to patients without prior radiotherapy in both arms in SUNLIGHT: Lonsurf with bevacizumab (73.7% versus 77.4%) and in Lonsurf-treated patients (64.7% versus 67.7%).

Post-marketing experience in patients with unresectable advanced or recurrent colorectal cancer There have been reports of interstitial lung disease in patients receiving Lonsurf post approval.

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/