Adult: In patients without D816V c-KIT mutational or with c-Kit mutation status unknown: 400 mg daily. In patients with eosinophilia: 100 mg daily, increase to 400 mg according to response.
Oral Accelerated phase Philadelphia chromosome positive chronic myelogenous leukaemia, Blast phase Philadelphia chromosome positive chronic myelogenous leukaemia
Adult: 600 mg daily. Increase to 400 mg bid in patients with disease progression, unsatisfactory haematological response at least 3 months of treatment, failed to achieve cytogenic response after 12 months of treatment or loss a previously achieved haematological or cytogenic response. Dose adjustment, dosing interruption, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline).
Oral Chronic phase Philadelphia chromosome positive chronic myelogenous leukaemia
Adult: 400 mg daily. Increase to 600 mg daily or 400 mg bid in patients with disease progression, unsatisfactory haematological response at least 3 months of treatment, failed to achieve cytogenic response after 12 months of treatment or loss a previously achieved haematological or cytogenic response. Dose adjustment, dosing interruption, or discontinuation may be required according to individual safety and tolerability (refer to detailed product guideline). Child: 2 years Chronic or advanced phase: 340 mg/m2 daily. Max: 800 mg. May be given once daily or divided into morning and evening doses. May be increased to 570 mg/m2 daily in children with disease progression, unsatisfactory haematological response at least 3 months of treatment, failed to achieve cytogenic response after 12 months of treatment or loss a previously achieved haematological or cytogenic response.
Adult: In patients with FIP1L1-PDGFRα rearrangement: 100 mg daily, increase to 400 mg daily according to response.
Oral Philadelphia chromosome-positive acute lymphoblastic leukaemia
Adult: As monotherapy in relapse or refractory cases, or in combination with chemotherapy for newly diagnosed cases: 600 mg daily. Continued until disease progression or unacceptable toxicity. Child: In combination with chemotherapy for newly diagnosed cases: 340 mg/m2 daily. Max: 600 mg.
Oral Myelodysplastic/myeloproliferative disease
Adult: In patients with platelet-derived growth factor receptor (PDGFR) gene rearrangement: 400 mg once daily, continued until disease progression or unacceptable toxicity.
Oral Gastrointestinal stromal tumour
Adult: In patients with Kit (CD117)-positive unresectable, metastatic malignant cases: 400 mg once daily, increase to 400 mg bid if tolerated. As adjuvant therapy following complete resection: 400 mg daily.
Oral Dermatofibrosarcoma protuberans
Adult: In patients with unresectable, recurrent, and/or metastatic cases not eligible for surgery: 400 mg bid.
Special Patient Group
Patients taking strong CYP3A4 inducers (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital): Increase dose by 50% with careful monitoring.
Pharmacogenomics:
Genetic polymorphisms may play a role in the onset of imatinib-induced ophthalmological side effects. Minor alleles of EGFR rs10258429 and SLC22A1 rs683369 has been shown to be significant determinants of conjunctival haemorrhage. The minor allele of SLC22A5 rs274558 and ABCB1 rs2235040 were found to be protective factors to periorbital oedema. Analysis of these genes may be beneficial to optimise imatinib therapy.
SLC22A5 rs274558
Patients with gastrointestinal stromal tumours treated with imatinib with genotype AA + AG may have decreased risk of periorbital oedema as compared to genotype GG.
SLC22A1 rs683369
Patients with gastrointestinal stromal tumours treated with imatinib with genotype CG + GG may have increased risk of conjunctival haemorrhage as compared to genotype CC.
EGFR rs10258429
Patients with gastrointestinal stromal tumours treated with imatinib with genotype CT + TT may have increased risk of conjunctival haemorrhage as compared to genotype CC.
ABCB1 rs2235040
Patients with gastrointestinal stromal tumours treated with imatinib with genotype CT may have decreased risk of periorbital oedema as compared to genotype CC.
Renal Impairment
Initially, 400 mg daily, reduce dose if not tolerated.
Hepatic Impairment
Initially, 400 mg daily, reduce dose if not tolerated.
Administration
Should be taken with food.
Contraindications
Lactation.
Special Precautions
Patient with pre-existing cardiac disease or risk factors for cardiac failure, or history of renal failure; pulmonary disease; risk factors for renal dysfunction (e.g. hypertension, heart failure, diabetes mellitus); high tumour burden or high proliferation rate; history of thyroidectomy; positive hepatitis B serology and active hepatitis B. Renal and hepatic impairment. Children and elderly. Pregnancy.
Adverse Reactions
Significant: Bone marrow suppression (e.g. neutropenia, thrombocytopenia, anaemia); fluid retention, weight gain; severe heart failure; oedema; gastrointestinal irritation; severe haemorrhage (e.g. gastrointestinal and/or tumour haemorrhage), gastric antral vascular ectasia; renal toxicity; thrombotic microangiopathy; growth retardation (children); severe bullous dermatologic reactions (e.g. erythema multiforme, Stevens-Johnson syndrome), drug reaction with eosinophilia and systemic symptoms (DRESS); hypothyroidism; hepatitis B reactivation; phototoxicity. Rarely, cardiogenic shock, left ventricular dysfunction. Cardiac disorders: Dyspnoea, palpitations. Eye disorders: Periorbital oedema, increased lacrimation, eyelid oedema, conjunctivitis, conjunctival haemorrhage, dry eye. Gastrointestinal disorders: Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain, flatulence, abdominal distension, constipation, gastritis, GERD, dry mouth. General disorders and admin site conditions: Night sweats, fatigue, weakness, pyrexia, chills. Investigations: Increased hepatic enzymes and bilirubin, weight increased or decreased; growth retardation (children), increased creatinine. Metabolism and nutrition disorders: Anorexia, decreased appetite, face oedema, peripheral oedema, anasarca. Musculoskeletal and connective tissue disorders: Muscle spasm and cramps, myalgia, musculoskeletal pain, arthralgia, bone pain, joint swelling. Nervous system disorders: Headache, dizziness, paraesthesia, taste disturbance, hypoaesthesia, cerebral oedema. Psychiatric disorders: Insomnia. Respiratory, thoracic and mediastinal disorders: Cough, interstitial pneumonitis. Skin and subcutaneous tissue disorders: Dermatitis, eczema, rash, pruritus, dry skin, alopecia, phototoxicity, nail disorder, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome. Vascular disorders: Flushing, epistaxis. Potentially Fatal: Hepatic necrosis, hepatic failure, tumour lysis syndrome. Rarely, gastrointestinal perforation.
This drug may cause dizziness, blurred vision or somnolence, if affected, do not drive or operate machinery.
Monitoring Parameters
CBC weekly during the 1st month, twice weekly for the 2nd month then periodically thereafter; LFT at baseline then monthly or as clinically indicated; renal function at baseline and periodically thereafter; serum electrolytes; bone marrow cytogenetics in chronic myelogenous leukaemia at 6, 12, and 18 months; echocardiogram and serum troponin levels in patient with hypereosinophilic syndrome/chronic eosinophilic leukaemia; TSH at baseline, followed by every 4 weeks for 4 months then every 2-3 months. Monitor weight; signs and symptoms of gastrointestinal perforation or irritation, dermatologic toxicities; oedema/fluid status. Monitor serum glucose, albumin and growth in children. Monitor for signs and symptoms of HBV reactivation during and several months following termination of therapy.
Decreased serum concentration and efficacy with strong CYP3A4 inducers (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital). Increased serum concentrations with strong CYP3A4 inhibitors (e.g. indinavir, ritonavir, ketoconazole, voriconazole, erythromycin, clarithromycin). May decrease the serum concentration of levothyroxine. May increase the serum concentrations of CYP3A4 substrates (e.g. simvastatin, ciclosporin, pimozide, tacrolimus, ergotamine, fentanyl, quinidine, amlodipine), and CYP2D6 substrates (e.g. metoprolol). May enhance the anticoagulant effect of warfarin.
Food Interaction
Decreased serum concentration and efficacy with St. John’s wort. Increased serum concentration with grapefruit juice.
Action
Description: Mechanism of Action: Imatinib is a tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase which is the constitutive abnormal gene product of Philadelphia chromosome thereby, blocking the proliferation and inducing apoptosis in BCR-ABL positive cell lines and Philadelphia chromosome positive leukemic cells. It also inhibits the tyrosine kinase for platelet-derived growth factor (PDGF), stem cell factor (SCF), c-KIT (CD117) and PDGF- and SCF-mediated cellular events. Pharmacokinetics: Absorption: Well absorbed from the gastrointestinal tract. Bioavailability: Approx 98%. Time to peak plasma concentration: Within 2-4 hours. Distribution: Crosses the placenta, enters breastmilk. Plasma protein binding: Approx 95%. Metabolism: Metabolised in the liver primarily by CYP3A4 and to a lesser extent by CYP1A2, CYP2D6, CYP2C9, CYP2C19 into active metabolite, N-demethylated piperazine derivative. Excretion: Via faeces (68% as primary metabolites, 20% as unchanged drug); urine (13% as primary metabolites, 5% as unchanged drug). Elimination half-life: Approx 18 hours (imatinib); approx 40 hours (N-desmethyl).
Chemical Structure
Imatinib Source: National Center for Biotechnology Information. PubChem Database. Imatinib, CID=5291, https://pubchem.ncbi.nlm.nih.gov/compound/Imatinib (accessed on Jan. 21, 2020)
Storage
Store below 30°C. Protect from moisture. This is a cytotoxic drug. Follow applicable procedures for receiving, handling, administration, and disposal.
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