Imitab

Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy. Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy. Adult patients with myelodysplastic or myeloproliferative diseases associated with PDGFR (platelet-derived growth factor receptor) gene re-arrangements as determined with an FDA-approved test Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation as determined with an FDA approved test Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFR? fusion kinase (mutational analysis or FISHdemonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFR? fusion kinase negative or unknown. Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans. Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors. Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.

Tyrosine kinase inhibitor

Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor (SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR-beta). Imatinib can also inhibit cellular events mediated by activation of these receptor kinases. Absorption and Distribution: Imatinib is well absorbed after oral administration with Cmax achieved within 2-4 hours post-dose. Mean absolute bioavailability is 98%. Mean Imatinib AUC increases proportionally with increasing doses ranging from 25 mg to 1,000 mg. There is no significant change in the pharmacokinetics of Imatinib on repeated dosing, and accumulation is 1.5- to 2.5- fold at steady state when Imatinib is dosed once-daily. At clinically relevant concentrations of Imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and 1-acid glycoprotein. Metabolism: CYP3A4 is the major enzyme responsible for metabolism of Imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent Imatinib. The plasma AUC for this metabolite is about 15% of the AUC for Imatinib. The plasma protein binding of N-demethylated metabolite CGP74588 is similar to that of the parent compound. Excretion: Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of Imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged Imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites. Following oral administration in healthy volunteers, the elimination half-lives of Imatinib and its major active metabolite, the N-demethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively.

Oral (Adult)- Dermatofibrosarcoma protuberans: 400 mg bid. Chronic myeloid leukaemia: 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. Mastocytosis: 400 mg daily. Start with 100 mg daily if there is associated eosinophilia, may increase to 400 mg if response is insufficient. Unresectable, metastatic malignant gastrointestinal stromal tumours: 400 mg daily, may increase up to 400 mg bid. Myelodysplastic disease: 400 mg daily. Acute lymphoblastic leukaemia, Monotherapy in relapsed or refractory acute lymphoblastic leukaemia: 600 mg daily with induction, consolidation or maintenance chemotherapy. Hypereosinophilic syndrome: 400 mg daily. Start with 100 mg daily in patients with FIP1L1-PDGF receptor-? fusion kinase, may increase to 400 mg if response is inadequate. Oral (Child)- Chronic myeloid leukaemia: 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 childn w/ disease progression, unsatisfactory haematological response at least 3 mth of treatment, failed to achieve cytogenic response after 12 mth of treatment or loss a previously achieved haematological or cytogenic response. Acute lymphoblastic leukaemia, Monotherapy in relapsed or refractory acute lymphoblastic leukaemia: 340 mg/m2 daily. Max: 600 mg.

Agents Inducing CYP3A Metabolism: Concomitant administration of Imatinib and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents. Agents Inhibiting CYP3A Metabolism: Concomitant administration of Imatinib and strong CYP3A4 inhibitors may result in a significant imatinib exposure increase. Grapefruit juice may also increase plasma concentrations of imatinib; avoid grapefruit juice). Interactions with Drugs Metabolized by CYP3A4: Imatinib will increase plasma concentration of CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.). Use caution when administering Imatinib with CYP3A4 substrates that have a narrow therapeutic window. Because warfarin is metabolized by CYP2C9 and CYP3A4, use low-molecular weight or standard heparin instead of warfarin in patients who require anticoagulation. Interactions with Drugs Metabolized by CYP2D6: Use caution when administering Imatinib with CYP2D6 substrates that have a narrow therapeutic window.

Hypersensitivity. Lactation. Patient with cardiac disease or increased risk for CHF. Renal and hepatic impairment. Pregnancy.

GI disturbances and bleeding, myelosuppression, superficial oedema, myalgia, arthralgia, muscle cramps, fatigue, rhabdomyolysis, rashes, pruritus, headache, dizziness, taste disturbances, anorexia, paraesthesia, insomnia, eye disorders or visual disturbances, epistaxis, cough, dyspnoea, dry skin, alopecia, night sweats, pyrexia, weakness, rigors, haemorrhages, growth retardation in childn, CHF, palpitations, tachycardia, arrhythmias, angina pectoris and MI. Rarely, serious and severe skin disorders (e.g. erythema multiforme, Stevens-Johnson syndrome, acute generalised exanthematous pustulosis, exfoliative dermatitis and bullous eruptions); aseptic necrosis of bone, ulceration.

There is positive evidence of human fetal 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).

Experience with doses higher than the recommended therapeutic dose is limited. In the event of overdose the patient should be observed and an 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, and increased transaminases. 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported. Pediatric population: One 3-year-old male exposed to a single dose: 400 mg experienced vomiting, diarrhoea and anorexia and another 3-year-old male exposed to a single dose: 980 mg experienced decreased white blood cell count and diarrhoea. In the event of overdose, the patient should be observed and appropriate supportive treatment given.

Store below 30°C, in a cool and dry place. Keep away from light. Keep out of the reach of children.

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