This information is about a drug called imatinib, which is also known as Glivec®. Imatinib is a man-made drug currently used for the treatment of patients with Chronic Myeloid Leukaemia(CML), and a rare type of gastrointestinal cancer known as Gastrointestinal Stromal Tumour (GIST). It may also be used to treat other types of cancers as part of a trial.
How imatinib works
Imatinib works by blocking (inhibiting) signals within cancer cells and preventing a series of chemical reactions that cause the cell to grow and divide.
The growth of cells in our bodies is controlled by a group of chemicals called growth factors. These chemicals can attach themselves to special proteins on the surface of particular cells. This starts a series of chemical reactions within the cell which trigger it to grow and multiply. In people with chronic myeloid leukaemia or GIST, cells are produced which have a damaged receptor protein called c-kit. This receptor sends out the grow-and-divide signal to the cells even when there is no growth factor present.
Imatinib identifies the faulty receptor and sticks to it, which prevents it from stimulating the cells to grow. Imatinib is known as a signal transductase inhibitor, because it blocks the ‘grow’ signal. The chemical it blocks is called tyrosine kinase, so imatinib is also known as a tyrosine kinase inhibitor.
How it is given
Imatinib is normally given once daily. It is available as 100mg and 400mg tablets or capsules. The tablets should be taken with a meal and a large glass of water. Imatinib is usually taken for as long as patients are benefiting from it.
Possible side effects
Each person’s reaction to a cancer drug is different. Some people may have very few side effects, while others may experience more. We have outlined the most common side effects. We have not included those that are very rare, and which are therefore extremely unlikely to affect you. If you notice any effects that you think may be due to the drug but are not listed here, please discuss them with your doctor or nurse.
The side effects of imatinib are generally mild or moderate. They often occur during the first month of treatment and may get better after this initial period. The most common side effects are listed below.
Feeling sick (nausea)
This is usually mild. The nausea can be relieved with anti-sickness drugs, which your doctor can prescribe. It can also be reduced by taking the tablet after food.
This can usually be controlled easily with anti-diarrhoea medication, but let your doctor know if it is severe or if it continues. It is important to drink plenty of fluids if you have diarrhoea.
Some people have headaches when taking imatinib. Let your doctor know if you get any headaches as painkillers can be given to help.
These can often be eased by taking mild painkillers, which your doctor can prescribe.
This is fairly common and is not harmful, although it can be upsetting. Many people gain weight, or notice swelling around the eyes and ankles due to the retention of fluid. Diuretics (drugs which make you pass more urine) can help to get rid of some of the fluid, but often it settles of its own accord. Let your doctor know if you put on a lot of weight very quickly.
Rarely, Imatinib can cause pain in the eyes and deterioration of vision. It may also cause more tears to be produced, which can lead to watery eyes.
If your skin becomes dry, this may be relieved with antihistamine tablets and skin lotion.
Lowered resistance to infection
Rarely, Imatinib can reduce the production of white blood cells by the bone marrow, making you more prone to infection. Your blood cells will be monitored while you are taking imatinib.
Contact your doctor or the hospital straightaway if:
- your temperature goes above 38ºC (100.5ºF)
- you suddenly feel unwell (even with a normal temperature).
You will have a blood test before having more therapy to make sure that your cells have recovered. Occasionally it may be necessary to delay your treatment if the number of blood cells (the blood count) is still low.
Bruising or bleeding
Imatinib can reduce the production of platelets (which help the blood to clot). Let your doctor know if you have any unexplained bruising or bleeding.
Anaemia (low number of red blood cells)
While having treatment with imatinib you may become anaemic. This may make you feel pale, tired, and short of breath on exertion. You may need to have a blood transfusion or iron tablets if the number of red blood cells becomes too low.
Loss of appetite
A dietitian or specialist nurse at your hospital can give advice and tips on boosting appetite, and maintaining weight.
Some medicines can be harmful to take when you are having imatinib. Always tell your doctor about any other medicine you are taking, including those bought over the counter and herbal medicines.
Little is known about the effects of imatinib on a developing foetus. Therefore, it is not advisable to become pregnant or father a child while taking this drug.
Things to remember about imatinib tablets
- It is important to take your tablets at the right times. You must take them as directed by your doctor.
- Keep the tablets in a safe place where children cannot reach them, as imatinib could harm them.
- If your doctor decides to stop the treatment, return any tablets you have to the pharmacist. Do not flush them down the toilet or throw them away.
- If you forget to take a tablet do not take a double dose. Tell your doctor and keep to your regular dose schedule.
- If you have any questions about these or any other side effects talk to your doctor or nurse. It is important to let them know if you are having any symptoms or side effects that may be related to any treatment you are having.
Additional Information For Healthcare Professionals
ADVERSE REACTIONS SIGNIFICANT
- Cardiovascular: Edema/fluid retention (33% to 86%; grades 3/4: 3% to 13%; includes aggravated edema, anasarca, pericardial effusion, peripheral edema, pulmonary edema and superficial edema); facial edema (DFSP 17%), chest pain (CML 7% to 11%)
- Central nervous system: Fatigue (29% to 75%), fever (13% to 41%), headache (20% to 37%), dizziness (10% to 19%), insomnia (10% to 19%), depression (=15%), anxiety (7% to 12%), chills (=11%)
- Dermatologic: Rash (25% to 50%; grades 3/4: 3% to 9%), pruritus (8% to 19%), alopecia (GIST 12% to 15%)
- Endocrine & metabolic: Hypokalemia (CML 6% to 13%)
- Gastrointestinal: Nausea (42% to 73%), diarrhea (25% to 58%), vomiting (23% to 58%), abdominal pain (30% to 57%), anorexia (=36%), weight gain (5% to 32%), dyspepsia (11% to 27%), constipation (9% to 16%), taste disturbance (GIST 3% to 15%), loose stools (GIST 10% to 12%)
- Hematologic: Hemorrhage (12% to 53%; grades 3/4: 2% to 19%), neutropenia (grade 3: 7% to 27%; grade 4: 3% to 48%), thrombocytopenia (grade 3: 1% to 31%; grade 4: <1% to 33%), anemia (grade 3: 3% to 42%; grade 4: 1% to 11%), leukopenia (GIST 17% to 20%)
- Hepatic: Ascites/pleural effusion (GIST 12% to 15%), hepatotoxicity (6% to 12%; grades 3/4: 3% to 8%)
- Neuromuscular & skeletal: Muscle cramps (28% to 62%), musculoskeletal pain (adults 30% to 49%; children 21%), arthralgia (=40%), joint pain (11% to 31%), myalgia (9% to 32%), back pain (GIST 23% to 26%), weakness (=21%), rigors (10% to 12%), bone pain (=11%)
- Ocular: Periorbital edema (DFSP 33%; MPD 29%), lacrimation increased (DFSP 25%; GIST 16% to 18%)
- Renal: Serum creatinine increased (=11%; grade 3: =3%; DFSP: grade 4: 8%)
- Respiratory: Nasopharyngitis (10% to 31%), cough (14% to 27%), dyspnea (=21%), upper respiratory tract infection (3% to 21%), pharyngolaryngeal pain (7% to 18%), rhinitis (DFSP 17%), pharyngitis (CML 10% to 15%), pneumonia (CML 4% to 13%), sinusitis (4% to 11%)
- Miscellaneous: Night sweats (CML 13% to 17%), infection without neutropenia (GIST 16% to 17%), influenza (1% to 14%), diaphoresis (GIST 9% to 13%)
1% to 10%:
- Cardiovascular: Flushing
- Central nervous system: CNS/cerebral hemorrhage (=9%), hypoesthesia
- Dermatologic: Dry skin, erythema, photosensitivity reaction
- Endocrine & metabolic: Albumin decreased (grade 3: =4%)
- Gastrointestinal: Flatulence (=10%), stomatitis/mucositis (=10%), gastrointestinal hemorrhage (2% to 8%), abdominal distension, gastritis, gastroesophageal reflux, mouth ulceration, weight loss, xerostomia
- Hematologic: Lymphopenia (GIST 6% to 10%), neutropenic fever, pancytopenia
- Hepatic: Alkaline phosphatase increased (grade 3: =6%; grade 4: <1%), ALT increased (grade 3: 2% to 7%; grade 4: <1%), AST increased (grade 3: 2% to 4%; grade 4: =3%), bilirubin increased (grade 3: 1% to 4%; grade 4: =3%)
- Neuromuscular & skeletal: Joint swelling, paresthesia
- Ocular: Blurred vision, conjunctival hemorrhage, conjunctivitis, dry eyes, eyelid edema
- Respiratory: Epistaxis
- Miscellaneous: Tumor hemorrhage (GIST 1% to 4%)
<1% (Limited to important or life-threatening):
cute febrile neutropenic dermatosis (Sweet’s syndrome), amylase increased, anaphylactic shock, angina, angioedema, aplastic anemia, arrhythmia, ascites, atrial fibrillation, avascular necrosis, blepharitis, breast enlargement, bullous eruption, cardiac arrest, cardiac failure, cardiac tamponade, cardiogenic shock, cataract, cellulitis, cerebral edema, cheilitis, CHF (severe), colitis, confusion, CPK increased, dehydration, diverticulitis, dysphagia, embolism, eosinophilia, erythema multiforme, esophagitis, exanthematous pustulosis (acute generalized), exfoliative dermatitis, fungal infection, gastric ulcer, gastroenteritis, gastrointestinal obstruction, gastrointestinal perforation, glaucoma, gout, hearing loss, hematoma, hematemesis, hematuria, hemolytic anemia, hepatic failure, hepatic necrosis, hepatitis, herpes simplex, herpes zoster, hip osteonecrosis, hypercalcemia, hyperglycemia, hyperkalemia, hyperuricemia, hyper-/hypotension, hypomagnesemia, hyponatremia, hypophosphatemia, ileus, inflammatory bowel disease, interstitial lung disease, interstitial pneumonitis, intracranial pressure increased, jaundice, LDH increased, left ventricular dysfunction, leukocytoclastic vasculitis, libido decreased, lichen planus, lichenoid keratosis, lymphadenopathy, macular edema, melena, memory impairment, menorrhagia, MI, migraine, optic neuritis, palpitation, pancreatitis, papilledema, pericarditis, peripheral neuropathy, petechiae, pleural effusion, pleuritic pain, pulmonary fibrosis, pulmonary hemorrhage, pulmonary hypertension, purpura, pustular rash, Raynaud’s phenomenon, renal failure, respiratory failure, respiratory tract (lower) infection, retinal hemorrhage, sciatica, scleral hemorrhage, seizure, sepsis, sexual dysfunction, skin pigment changes, somnolence, Stevens-Johnson syndrome, syncope, tachycardia, thrombocythemia, thrombosis, tinnitus, toxic epidermal necrolysis, tremor, tumor necrosis, urinary tract infection, urticaria, vertigo, vesicular rash, vitreous hemorrhage
MECHANISM OF ACTION
Inhibits Bcr-Abl tyrosine kinase, the constitutive abnormal gene product of the Philadelphia chromosome in chronic myeloid leukemia (CML). Inhibition of this enzyme blocks proliferation and induces apoptosis in Bcr-Abl positive cell lines as well as in fresh leukemic cells in Philadelphia chromosome positive CML. Also inhibits tyrosine kinase for platelet-derived growth factor (PDGF), stem cell factor (SCF), c-Kit, and cellular events mediated by PDGF and SCF.
PHARMACODYNAMICS / KINETICS
- Absorption: Rapid
- Protein binding: Parent drug and metabolite: ~95% to albumin and alpha1-acid glycoprotein
- Metabolism: Hepatic via CYP3A4 (minor metabolism via CYP1A2, CYP2D6, CYP2C9, CYP2C19); primary metabolite (active): N-demethylated piperazine derivative (CGP74588); severe hepatic impairment (bilirubin >3-10 times ULN) increases AUC by 45% to 55% for imatinib and its active metabolite, respectively
- Bioavailability: 98%
- Half-life elimination: Adults: Parent drug: ~18 hours; N-desmethyl metabolite: ~40 hours; Children: Parent drug: ~15 hours
- Time to peak: 2-4 hours
- Excretion: Faeces (68% primarily as metabolites, 20% as unchanged drug); urine (13% primarily as metabolites, 5% as unchanged drug)