Safety Information

Table 1 Adverse reactions in clinical studies

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

Neoplasm benign, malignant and unspecified (including cysts and polyps)

Rare:

Tumour lysis syndrome

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

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

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

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

Vascular disorders4

Common:

Flushing, haemorrhage

Uncommon:

Hypertension, haematoma, peripheral coldness, hypotension, Raynaud's phenomenon

Respiratory, thoracic and mediastinal disorders

Common:

Dyspnoea, epistaxis, cough

Uncommon:

Pleural effusion5, pharyngolaryngeal pain, pharyngitis

Rare:

Pleuritic pain, pulmonary fibrosis, pulmonary hypertension, pulmonary haemorrhage

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

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

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)

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

Rare:

Muscular weakness, arthritis, rhabdomyolysis/myopathy

Renal and urinary disorders

Uncommon:

Renal pain, haematuria, renal failure acute, urinary frequency increased

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

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.

The following 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.


Table 2 Adverse reactions from post-marketing reports

Infections and infestations

Not known:

Hepatitis B reactivation

Neoplasm benign, malignant and unspecified (including cysts and polyps)

Not known:

Tumour haemorrhage/tumour necrosis

Immune system disorders

Not known:

Anaphylactic shock

Nervous system disorders

Not known:

Cerebral oedema

Eye disorders

Not known:

Vitreous haemorrhage

Cardiac disorders

Not known:

Pericarditis, cardiac tamponade

Vascular disorders

Not known:

Thrombosis/embolism

Respiratory, thoracic and mediastinal disorders

Not known:

Acute respiratory failure1, interstitial lung disease

Gastrointestinal disorders

Not known:

Ileus/intestinal obstruction, gastrointestinal perforation, diverticulitis, gastric antral vascular ectasia (GAVE)

Skin and subcutaneous tissue disorders

Not known:

Palmoplantar erythrodysesthesia syndrome, lichenoid keratosis, lichen planus, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), pseudoporphyria

Musculoskeletal and connective tissue disorders

Not known:

Avascular necrosis/hip necrosis, growth retardation in children

Renal and urinary disorders

Not known:

Renal failure chronic

1 Fatal cases have been reported in patients with advanced disease, severe infections, severe neutropenia and other serious concomitant conditions.

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 < 1.0 x 109/l) and thrombocytopenias (platelet count < 50 x 109/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 < 0.5 x 109/l) and thrombocytopenia (platelet count < 10 x 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 intratumoural 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.

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 Special warnings and precautions for use).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. Listed in Appendix V of the EUSMPC.

Overdose

Experience with doses higher than the recommended therapeutic dose is limited. Isolated cases of Glivec overdose have been reported spontaneously and in the literature. In the event of overdose the patient should be observed and appropriate symptomatic treatment given. Generally the reported outcome in these cases was "improved" or "recovered". Events that have been reported at different dose ranges are as follows:

Adult population

1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.

1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine phosphokinase, increased bilirubin, gastrointestinal pain.

6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, increased transaminases.

8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.

Paediatric population

One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia and another 3-year-old male exposed to a single dose of 980 mg dose experienced decreased white blood cell count and diarrhoea.

In the event of overdose, the patient should be observed and appropriate supportive treatment given.