U.S. ResidentsSafety 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 myalgia, arthralgia, bone pain9 |
| 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 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 | |
|---|---|
| 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 |
| Skin and subcutaneous tissue disorders | |
| Not known: | Palmoplantar erythrodysesthesia syndrome |
| Not known: | Lichenoid keratosis, lichen planus |
| Not known: | Toxic epidermal necrolysis |
| Musculoskeletal and connective tissue disorders | |
| Not known: | Avascular necrosis/hip necrosis |
| Not known: | Growth retardation in children |
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.
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.
