Imatinib information from DrugsUpdate  

Pharmacodynamics

Pharmacokinetics

Imatinib, a tyrosine kinase inhibitor, inhibits the Bcr-Abl tyrosine kinase which is created by the Philadelphia chromosome abnormality in chronic myeloid leukaemia (CML). It blocks proliferation and induces apoptosis in BCR-ABL positive cell lines, as well as fresh leukaemic cells from Philadelphia chromosome positive CML.

Absorption Mean bioavailability: approx 98%; peak blood concentrations reached after 2-4 hr.

Distribution Protein-binding: Approx 95%.

Metabolism Major isoenzyme responsible for metabolism is CYP3A4; isoenzymes CYP1A2, CYP2D6, CYP2C9 and CYP2C19 also play a minor role.

Excretion Elimination half-life: 18 hr (imatinib), 40 hr (N-demethylated piperazine derivative). About 81% is eliminated within 7 days in the faeces (68%) and urine (13%). Excreted mostly as metabolites, with only 25% as unchanged drug.

Imatinib Indications / Imatinib Uses

Information Not Available

Imatinib Adverse Reactions / Imatinib Side Effects

Fluid retention/oedema, nausea and vomiting, muscle cramps, musculoskeletal pain, diarrhoea, rash. Fatigue, asthenia, headache, dizziness, insomnia, depression, anxiety, joint pain, arthralgia, myalgia, back pain, abdominal pain, flatulence, dyspepsia, loose stools, anorexia, constipation, taste disturbance, nasopharyngitis, cough, pharyngolaryngeal pain, pharyngitis, sinusitis, upper respiratory tract infection, pneumonia, influenza, dyspnoea, haemorrhage, pyrexia, increased wt, night sweats, rigors, hepatotoxicity, hypokalaemia, pruritus, chest pain, increased lacrimation.

Precautions

Monitor Carefully investigate unexpected rapid weight gain and provide appropriate treatment. Perform CBC and platelet counts weekly for first month, biweekly for second month, and periodically thereafter as clinically indicated. Monitor liver function (alkaline phosphatase, bilirubin, transaminases) prior to therapy, then monthly or as clinically indicated during treatment. Monitor TSH levels in thyroidectomy patients receiving levothyroxine replacement therapy.

Special Precautions

Cardiac disease or increased risk for CHF. Monitor for signs of severe fluid retention. Monitor CBC regularly. Renal and hepatic impairment. Monitor LFTs. Pregnancy.

Other Drug Interactions

Increased blood levels with CYP3A4 inhibitors (azole antifungals, macrolide antibiotics). Reduced blood levels with CYP3A4 inducers (carbamazepine, dexamethasone, St John's wort, phenobarbital, phenytoin, rifampicin). May increase blood levels of substrates of CYP3A4 (ciclosporin, pimozide, triazolo-benzodiazepines, dihydropyridine calcium-channel blockers, certain statins), CYP2C9 (warfarin) and CYP2D6.

Other Interactions

Information Not Available

Dosage

Oral Chronic myeloid leukaemia Adult: Chronic phase: 400 mg daily, increased to 600 mg daily or 400 mg bid. Blast crisis or accelerated phase: 600 mg daily, increased to 400 mg bid as required. Child: Chronic or advanced phase: 340 mg/m2 daily. Max Dose: 600 mg. May be given once daily ordivided into morning and evening doses. Hepatic impairment: Severe: Reduce dose by 25%. Oral Acute lymphoblastic leukaemia Adult: 600 mg daily with induction, consolidation or maintenance chemotherapy. Hepatic impairment: Severe: Reduce dose by 25%. Oral As monotherapy in relapsed or refractory acute lymphoblastic leukaemia Adult: 600 mg daily with induction, consolidation or maintenance chemotherapy. Hepatic impairment: Severe: Reduce dose by 25%. Oral Myelodysplastic disease Adult: 400 mg daily. For eosinophilic syndrome: Start with 100 mg daily in patients with FIP1L1-platelet-derived growth factor receptor-a fusion kinase, may increase to 400 mg if response is insufficient. Hepatic impairment: Severe: Reduce dose by 25%. Oral Hypereosinophilic syndrome Adult: 400 mg daily. For eosinophilic syndrome: Start with 100 mg daily in patients with FIP1L1-platelet-derived growth factor receptor-a fusion kinase, may increase to 400 mg if response is insufficient. Hepatic impairment: Severe: Reduce dose by 25%. Oral Unresectable, metastatic malignant gastrointestinal stromal tumours Adult: 400 or 600 mg daily. Hepatic impairment: Severe: Reduce dose by 25%. Oral Mastocytosis Adult: 400 mg daily. Start with 100 mg daily if there is associated eosinophilia. Hepatic impairment: Severe: Reduce dose by 25%. Oral Dermatofibrosarcoma protuberans Adult: 400 mg bid. Hepatic impairment: Severe: Reduce dose by 25%. Special Populations Recommended dose in patients on potent CYP3A4 inducers: Increase dose by 50%; careful monitoring is recommended.

Food(before/after)

Should be taken with food.

Imatinib and Pregnancy

Caution when used during pregnancy. Category D: There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Imatinib and Lactation

Contraindicated in lactation

Imatinib and Children

The safety and efficacy of imatinib in children are not established, except in children with newly diagnosed Ph+ chronic-phase CML and in children with Ph+ chronic-phase CML whose disease recurred after stem cell transplantation or who are resistant to interferon-alpha therapy. No data are available in children younger than 2 yr of age.

Imatinib and Geriatic

Higher frequency of edema

Imatinib and Other Contraindications

Lactation

Storage

Information Not Available

Lab interference

Information Not Available