Adverse reactions : תופעות לוואי

4.8 Undesirable effects
Patients with advanced stages of malignancies may have numerous confounding medical conditions that make causality of adverse reactions difficult to assess due to the variety of symptoms related to the underlying disease, its progression, and the co-administration of numerous medicinal products.
In clinical trials in CML, drug discontinuation for drug-related adverse reactions was observed in 2.4% of newly diagnosed patients, 4% of patients in late chronic phase after failure of interferon therapy, 4% of patients in accelerated phase after failure of interferon therapy and 5% of blast crisis patients after failure of interferon therapy. In GIST the study drug was discontinued for drug-related adverse reactions in 4% of patients.
The adverse reactions were similar in all indications, with two exceptions. There was more myelosuppression seen in CML patients than in GIST, which is probably due to the underlying disease.
In the study in patients with unresectable and/or metastatic GIST, 7 (5%) patients experienced CTC grade 3/4 GI bleeds (3 patients), intra-tumoural bleeds (3 patients) or both (1 patient). GI tumour sites may have been the source of the GI bleeds (see section 4.4). GI and tumoural bleeding may be serious and sometimes fatal. The most commonly reported (≥ 10%) drug-related adverse reactions in both settings were mild nausea, vomiting, diarrhoea, abdominal pain, fatigue, myalgia, muscle cramps and rash. Superficial oedemas were a common finding in all studies and were described primarily as periorbital or lower limb oedemas. However, these oedemas were rarely severe and may be managed with diuretics, other supportive measures, or by reducing the dose of Glivec.
When imatinib was combined with high dose chemotherapy in Ph+ ALL patients, transient liver toxicity in the form of transaminase elevation and hyperbilirubinaemia were observed.
Miscellaneous adverse reactions such as pleural effusion, ascites, pulmonary oedema and rapid weight GLI FCT API May23 V17                                                                       EU SmPC March 2022

gain with or without superficial oedema may be collectively described as “fluid retention”. These reactions can usually be managed by withholding Glivec temporarily and with diuretics and other appropriate supportive care measures. However, some of these reactions may be serious or life- threatening and several patients with blast crisis died with a complex clinical history of pleural effusion, congestive heart failure and renal failure. There were no special safety findings in paediatric clinical trials.
Adverse reactions
Adverse reactions reported as more than an isolated case are listed below, by system organ class and by frequency. Frequency categories are defined using the following convention: 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 grouping, undesirable effects are presented in order of frequency, the most frequent first.

Adverse reactions and their frequencies are reported in Table 1.

Table 1          Tabulated summary of adverse reactions
Infections and infestations
Uncommon:                 Herpes zoster, herpes simplex, nasopharyngitis, pneumonia1, sinusitis, cellulitis, upper respiratory tract infection, influenza, urinary tract infection, gastroenteritis, sepsis
Rare:                     Fungal infection
Not known:                Hepatitis B reactivation*
Neoplasm benign, malignant and unspecified (including cysts and polyps) 
Rare:                     Tumour lysis syndrome
Not known:                Tumour haemorrhage/tumour necrosis*
Immune system disorders
Not known:                Anaphylactic shock*

Blood and lymphatic system disorders
Very common:              Neutropenia, thrombocytopenia, anaemia
Common:                   Pancytopenia, febrile neutropenia
Uncommon:                 Thrombocythaemia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy

Rare:                     Haemolytic anaemia, thrombotic microangiopathy 


GLI FCT API May23 V17                                                                                        EU SmPC March 2022

Metabolism and nutrition disorders
Common:                    Anorexia
Uncommon:                  Hypokalaemia, increased appetite, hypophosphataemia, decreased appetite, dehydration, gout, hyperuricaemia, hypercalcaemia, hyperglycaemia, hyponatraemia Rare:                      Hyperkalaemia, hypomagnesaemia
Psychiatric disorders
Common:                    Insomnia
Uncommon:                  Depression, libido decreased, anxiety
Rare:                      Confusional state
Nervous system disorders
Very common:               Headache2
Common:                    Dizziness, paraesthesia, taste disturbance, hypoaesthesia 
Uncommon:                  Migraine, somnolence, syncope, peripheral neuropathy, memory impairment, sciatica, restless leg syndrome, tremor, cerebral haemorrhage

Rare:                      Increased intracranial pressure, convulsions, optic neuritis Not known:                 Cerebral oedema*
Eye disorders
Common:                    Eyelid oedema, lacrimation increased, conjunctival haemorrhage, conjunctivitis, dry eye, blurred vision
Uncommon:                  Eye irritation, eye pain, orbital oedema, scleral haemorrhage, retinal haemorrhage, blepharitis, macular oedema
Rare:                      Cataract, glaucoma, papilloedema
Not known:                 Vitreous haemorrhage*
Ear and labyrinth disorders
Uncommon:                  Vertigo, tinnitus, hearing loss
Cardiac disorders
Uncommon:                  Palpitations, tachycardia, cardiac failure congestive3, pulmonary oedema Rare:                      Arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion
Not known:                 Pericarditis*, cardiac tamponade*



GLI FCT API May23 V17                                                                                       EU SmPC March 2022

Vascular disorders4
Common:                      Flushing, haemorrhage
Uncommon:                    Hypertension, haematoma, subdural haematoma, peripheral coldness, hypotension, Raynaud’s phenomenon
Not known:                   Thrombosis/embolism*
Respiratory, thoracic and mediastinal disorders
Common:                      Dyspnoea, epistaxis, cough
Uncommon:                    Pleural effusion5, pharyngolaryngeal pain, pharyngitis Rare:                        Pleuritic pain, pulmonary fibrosis, pulmonary hypertension, pulmonary haemorrhage Not known:                   Acute respiratory failure11*, interstitial lung disease* Gastrointestinal disorders
Very common:                 Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain6 
Common:                      Flatulence, abdominal distension, gastro-oesophageal reflux, constipation, dry mouth, gastritis

Uncommon:                    Stomatitis, mouth ulceration, gastrointestinal haemorrhage7, eructation, melaena, oesophagitis, ascites, gastric ulcer, haematemesis, cheilitis, dysphagia, pancreatitis 
Rare:                        Colitis, ileus, inflammatory bowel disease Not known:                   Ileus/intestinal obstruction*, gastrointestinal perforation*, diverticulitis*, gastric antral vascular ectasia (GAVE)*
Hepatobiliary disorders
Common:                      Increased hepatic enzymes
Uncommon:                    Hyperbilirubinaemia, hepatitis, jaundice Rare:                        Hepatic failure8, hepatic necrosis
Skin and subcutaneous tissue disorders
Very common:                 Periorbital oedema, dermatitis/eczema/rash Common:                      Pruritus, face oedema, dry skin, erythema, alopecia, night sweats, photosensitivity reaction
Uncommon:                    Rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, dermatitis exfoliative, onychoclasis, folliculitis, petechiae, psoriasis, purpura, skin hyperpigmentation, bullous eruptions, panniculittis12
Rare:                        Acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discolouration, angioneurotic oedema, rash vesicular, erythema multiforme, leucocytoclastic vasculitis, Stevens-Johnson syndrome, acute generalised exanthematous pustulosis (AGEP), pemphigus*
Not known:                   Palmoplantar erythrodysesthesia syndrome*, lichenoid keratosis*, lichen planus*, toxic epidermal necrolysis*, drug rash with eosinophilia and systemic symptoms (DRESS)*, pseudoporphyria*



GLI FCT API May23 V17                                                                                           EU SmPC March 2022

Musculoskeletal and connective tissue disorders
Very common:                Muscle spasm and cramps, musculoskeletal pain including myalgia9, arthralgia, bone pain10
Common:                     Joint swelling
Uncommon:                   Joint and muscle stiffness, osteonecrosis* Rare:                       Muscular weakness, arthritis, rhabdomyolysis/myopathy Not known:                  , growth retardation in children*
Renal and urinary disorders
Uncommon:                   Renal pain, haematuria, renal failure acute, urinary frequency increased Not known:                  Renal failure chronic
Reproductive system and breast disorders
Uncommon:                   Gynaecomastia, erectile dysfunction, menorrhagia, menstruation irregular, sexual dysfunction, nipple pain, breast enlargement, scrotal oedema
Rare:                       Haemorrhagic corpus luteum/haemorrhagic ovarian cyst 
General disorders and administration site conditions
Very common:                Fluid retention and oedema, fatigue
Common:                     Weakness, pyrexia, anasarca, chills, rigors Uncommon:                   Chest pain, malaise
Investigations
Very common:                Weight increased
Common:                     Weight decreased
Uncommon:                   Blood creatinine increased, blood creatine phosphokinase increased, blood lactate dehydrogenase increased, blood alkaline phosphatase increased
Rare:                       Blood amylase increased
*        These types of reactions have been reported mainly from post-marketing experience with Glivec. This includes spontaneous case reports as well as serious adverse events from ongoing studies, the expanded access programmes, clinical pharmacology studies and exploratory studies in unapproved indications. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to imatinib exposure.
1        Pneumonia was reported most commonly in patients with transformed CML and in patients with GIST.
2        Headache was the most common in GIST patients.
3        On a patient-year basis, cardiac events including congestive heart failure were more commonly observed in patients with transformed CML than in patients with chronic CML.
4        Flushing was most common in GIST patients and bleeding (haematoma, haemorrhage) was most common in patients with GIST and with transformed CML (CML-AP and CML-BC).
5        Pleural effusion was reported more commonly in patients with GIST and in patients with transformed CML (CML- AP and CML-BC) than in patients with chronic CML.
6+7      Abdominal pain and gastrointestinal haemorrhage were most commonly observed in GIST patients.
8        Some fatal cases of hepatic failure and of hepatic necrosis have been reported.
9      Musculoskeletal pain during treatment with imatinib or after discontinuation has been observed in post-marketing.
10       Musculoskeletal pain and related events were more commonly observed in patients with CML than in GIST patients.
11   Fatal cases have been reported in patients with advanced disease, severe infections, severe neutropenia and other GLI FCT API May23 V17                                                                                    EU SmPC March 2022

serious concomitant conditions.
12    Including erythema nodosum.



Aggressive Systemic Mastocytosis
All aggressive systemic mastocytosis (ASM) patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were diarrhea, nausea, ascites, muscle cramps, dyspnea, fatigue, peripheral edema, anemia, pruritus, rash, and lower respiratory tract infection. None of the 5 patients in the Phase 2 study with ASM discontinued Glivec due to drug-related adverse reactions or abnormal laboratory values.

Laboratory test abnormalities
Haematology
In CML, cytopenias, particularly neutropenia and thrombocytopenia, have been a consistent finding in all studies, with the suggestion of a higher frequency at high doses ≥ 750 mg (phase I study). However, the occurrence of cytopenias was also clearly dependent on the stage of the disease, the frequency of grade 3 or 4 neutropenias (ANC < 1.0x109/l) and thrombocytopenias (platelet count < 50 x109/l) being between 4 and 6 times higher in blast crisis and accelerated phase (59 - 64% and 44 - 63% for neutropenia and thrombocytopenia, respectively) as compared to newly diagnosed patients in chronic phase CML (16.7% neutropenia and 8.9% thrombocytopenia). In newly diagnosed chronic phase CML grade 4 neutropenia (ANC < 0.5x109/l) and thrombocytopenia (platelet count < 10x 109/l) were observed in 3.6% and <1% of patients, respectively. The median duration of the neutropenic and thrombocytopenic episodes usually ranged from 2 to 3 weeks, and from 3 to 4 weeks, respectively. These events can usually be managed with either a reduction of the dose or an interruption of treatment with Glivec, but can in rare cases lead to permanent discontinuation of treatment. In paediatric CML patients the most frequent toxicities observed were grade 3 or 4 cytopenias involving neutropenia, thrombocytopenia and anaemia.
These generally occur within the first several months of therapy.
In the study in patients with unresectable and/or metastatic GIST, grade 3 and 4 anaemia was reported in 5.4% and 0.7% of patients, respectively, and may have been related to gastrointestinal or intra-tumoural bleeding in at least some of these patients. Grade 3 and 4 neutropenia was seen in 7.5% and 2.7% of patients, respectively, and grade 3 thrombocytopenia in 0.7% of patients. No patient developed grade 4 thrombocytopenia. The decreases in white blood cell (WBC) and neutrophil counts occurred mainly during the first six weeks of therapy, with values remaining relatively stable thereafter.
Biochemistry
Severe elevation of transaminases (<5%) or bilirubin (<1%) was seen in CML patients and was usually managed with dose reduction or interruption (the median duration of these episodes was approximately one week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1% of CML patients. In GIST patients (study B2222), 6.8% of grade 3 or 4 ALT (alanine aminotransferase) elevations and 4.8% of grade 3 or 4 AST (aspartate aminotransferase) elevations were observed. Bilirubin elevation was below 3%.
There have been cases of cytolytic and cholestatic hepatitis and hepatic failure; in some of them outcome was fatal, including one patient on high dose paracetamol.

GLI FCT API May23 V17                                                                     EU SmPC March 2022

Description of selected adverse reactions
Hepatitis B reactivation
Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see section 4.4).

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