Imatinib mesylate

589.70800

589.24700

606-892-3

8A1O1M485B

716051

DTXSID9040502

C1687

White to off white to brownish or yellowish tinged crystalline powder

L01XE01

2933990090

149.03000

5.19690

white crystalline powder .

0.858 g/mL at 25 °C(lit.)

146-148 °C

754.9ºC at 760 mmHg

410.3ºC

n20/D 1.401(lit.)

In water, >100 g/l @ pH 4.2; 49 mg/l @ pH 7.4

Lipophilic at pH 7.4|Molecular weight: 493.60; melting point: 211-213 °C; pKa1: 8.07; pKa2: 3.73; pKa3: 2.56; pKa 4: 1.52 /Imatinib/

II

3

UN 1993 3/PG 2

3

22

S16-S26-S36/37/39

Xn

P301 + P312 + P330

H302

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl imatinib mesylate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.|Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

The purpose of this report is to summarize ... /a drug/ recently approved by the U.S. Food and Drug Administration. ... Gleevec (imatinib mesylate) ... for the treatment of malignant unresectable and/or metastatic gastrointestinal stromal tumors ... . Gleevec /was/ an accelerated approval and supplemental new drug application (NDA); ... .[Cohen MH et al; US FDA Drug Approval Summaries: Imetinib Mesylate, Mesna Tablets, and Zoledronic Acid; Oncologist 7 (5): 393-400 (2002).]|Imatinib is ... a new drug being developed using the principle of molecular targeting. Imatinib is able to kill the cancer cells and not the body's healthy cells. Imatinib mesylate is indicated for the treatment of patients with Kit (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors and patients with Philadelphia chromosome-positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alfa.[Baker DE; Imatinib mesylate; Rev Gastroenterol Disord 2 (2): 75-86 (2002).]

|Danger|H302 (83.33%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P264, P270, P281, P301+P312, P308+P313, P330, P405, and P501|Aggregated GHS information provided by 115 companies from 17 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

In this study /an investigation was conducted to study/ the effect of concomitant administration of imatinib and idarubicin, an anthracycline with haematosuppressive activity, in nu/nu mice and murine bone marrow cells. Double-treated animals showed significantly increased mortality compared to mice that received imatinib or idarubicin alone only when idarubicin and imatinib were given simultaneously. The combined treatment induced a more severe neutropenia with a slower recovery when compared to mice treated with idarubicin alone. The myeloid metaplasia usually observed in the spleen after idarubicin treatment was absent in mice co-treated with imatinib. Bone marrow from double-treated animals also showed decreased numbers of megakaryocytes and myeloid precursor cells. In vitro culture of murine bone marrow cells in the presence of imatinib inhibited SCF-induced proliferation and recovery from treatment with idarubicin. ... Results indicate that the simultaneous administration of imatinib enhances idarubicin-induced hematopoietic toxicity in vivo and in vitro.|Caution is recommended when administering Gleevec /imatinib/ with inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin). Substances that inhibit the cytochrome P450 isoenzyme (CYP3A4) activity may decrease metabolism and increase imatinib concetrations.|Substances that are inducers of CYP3A4 activity may increase metabolism and decrease imatinib plasma concentrations. Co-medications that induce CYP3A4 (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, or St. John's Wort) may reduce exposure to Gleevec /imatinib/. ...A patient on chronic therapy with phenytoin... given 350 mg daily dose of Gleevec had an AUC0-24 about one-fifth of the typical AUC0-24 of 20 ug/hr/mL. This probably reflects the induction of CYP3A4 by phenytoin.|Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by imatinib. Particular caution is recommended when administering Gleevec /imatinib/ with CYP3A4 substrates that have a narrow therapeutic window (e.g., cyclosporine or pimozide). Gleevec will increase plasma concentration of other CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.).|For more Interactions (Complete) data for IMATINIB MESYLATE (6 total), please visit the HSDB record page.

In lactating female rats administered 100 mg/kg ... imatinib and/or its metabolites were extensively excreted in milk. It is estimated that approximately 1.% of a maternal dose is excreted into milk, which is equivalent to a dose to the infant of 30% the maternal dose per unit body weight.

Glivec is indicated for the treatment ofadult and paediatric patients with newly diagnosed Philadelphia-chromosome (bcr-abl)-positive (Ph+) chronic myeloid leukaemia (CML) for whom bone-marrow transplantation is not considered as the first line of treatment;adult and paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or in accelerated phase or blast crisis;adult and paediatric patients with newly diagnosed Philadelphia-chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy;adult patients with relapsed or refractory Ph+ ALL as monotherapy;adult patients with myelodysplastic / myeloproliferative diseases (MDS / MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements;adult patients with advanced hypereosinophilic syndrome (HES) and / or chronic eosinophilic leukaemia (CEL) with FIP1L1-PDGFRa rearrangement.The effect of Glivec on the outcome of bone-marrow transplantation has not been determined.Glivec is indicated for:the treatment of adult patients with Kit (CD 117)-positive unresectable and / or metastatic malignant gastrointestinal stromal tumours (GIST);the adjuvant treatment of adult patients who are at significant risk of relapse following resection of Kit (CD117)-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment;the treatment of adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with recurrent and / or metastatic DFSP who are not eligible for surgery.In adult and paediatric patients, the effectiveness of Glivec is based on overall haematological and cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic response rates in Ph+ ALL, MDS / MPD, on haematological response rates in HES / CEL and on objective response rates in adult patients with unresectable and / or metastatic GIST and DFSP and on recurrence-free survival in adjuvant GIST. The experience with Glivec in patients with MDS / MPD associated with PDGFR gene re-arrangements is very limited (see section 5.1). Except in newly diagnosed chronic phase CML, there are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.|Imatinib Teva B.V. is indicated for the treatment of:, , , Paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+) chronic myeloid leukaemia (CML) for whom bone marrow transplantation is not considered as the first line of treatment., Paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or in accelerated phase or blast crisis., Adult patients with Ph+ CML in blast crisis., Adult and paediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy., Adult patients with relapsed or refractory Ph+ ALL as monotherapy.,  Adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements., Adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL) with FIP1L1-PDGFRα rearrangement., , , The effect of imatinib on the outcome of bone marrow transplantation has not been determined., , Imatinib Teva B.V. is indicated for:, , , The treatment of adult patients with Kit (CD 117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumours (GIST)., The adjuvant treatment of adult patients who are at significant risk of relapse following resection of Kit (CD117)-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment., The treatment of adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with recurrent and/or metastatic DFSP who are not eligible for surgery., , , In adult and paediatric patients, the effectiveness of imatinib is based on overall haematological and cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic response rates in Ph+ ALL, MDS/MPD, on haematological response rates in HES/CEL and on objective response rates in adult patients with unresectable and/or metastatic GIST and DFSP and on recurrence-free survival in adjuvant GIST. The experience with imatinib in patients with MDS/MPD associated with PDGFR gene re-arrangements is very limited. There are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.,|Dermatofibrosarcoma protuberans, Hypereosinophilic syndrome and/or chronic eosinophilic leukaemia with FIP1L1-platelet-derived growth factor receptor alpha gene re-arrangement, Kit (CD 117)-positive gastrointestinal stromal tumours, Myelodysplastic / myeloproliferative diseases associated with platelet-derived growth factor receptor gene re-arrangements, Philadelphia chromosome (BCR-ABL translocation)-positive acute lymphoblastic leukaemia, Philadelphia chromosome (BCR-ABL translocation)-positive chronic myeloid leukaemia|Treatment of pulmonary arterial hypertension|Imatinib Koanaa is indicated for the treatment ofadult and paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+) chronic myeloid leukaemia (CML) for whom bone marrow transplantation is not considered as the first line of treatment.adult and paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or in accelerated phase or blast crisis.adult and paediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy.adult patients with relapsed or refractory Ph+ ALL as monotherapy.adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL) with FIP1L1-PDGFRα rearrangement.The effect of Imatinib on the outcome of bone marrow transplantation has not been determined.Imatinib Koanaa is indicated forthe treatment of adult patients with Kit (CD 117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumours (GIST).the adjuvant treatment of adult patients who are at significant risk of relapse following resection of Kit (CD117)-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.the treatment of adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with recurrent and/or metastatic DFSP who are not eligible for surgery.In adult and paediatric patients, the effectiveness of Imatinib is based on overall haematological and cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic response rates in Ph+ ALL, MDS/MPD, on haematological response rates in HES/CEL and on objective response rates in adult patients with unresectable and/or metastatic GIST and DFSP and on recurrence-free survival in adjuvant GIST. The experience with Imatinib in patients with MDS/MPD associated with PDGFR gene re-arrangements is very limited (see section 5.1). Except in newly diagnosed chronic phase CML, there are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.|Drug: Imatinibmesylate

Imatinib mesylate (Gleevec), ... /an/ inhibitor of abl, kit, and platelet-derived growth factor receptor (PDGFR) tyrosine kinases, has been reported to be effective in the treatment of hypereosinophilic syndrome (HES) and a rare eosinophilia-associated chronic myeloid disorder (eos-CMD) characterized by the t(5;12)(q33;p13) cytogenetic abnormality. In the current study, we sought to confirm the preliminary observations in HES as well as evaluate the therapeutic value of imatinib in eos-CMD that is not associated with t(5;12)(q33;p13). Five patients with HES (all men, median age = 46 years) and 2 with eos-CMD (both men, aged 45 and 58 years) were treated with imatinib at a starting dose of 100 to 400 mg/day. Cytogenetic studies showed no evidence of either the bcr-abl translocation or t(5;12)(q33;p13) in any patient. Screening of exons encoding the intracellular catalytic domains and extracellular ligand binding domains of PDGFR beta (exons 2-23) and c-kit (exons 1-21) in six patients demonstrated mostly previously known polymorphisms. At a median follow-up of 17 weeks (range, 10-33 weeks), 2 patients with HES and 1 with eos-CMD have achieved complete clinical remission and 1 additional patient with HES has achieved a partial remission. In contrast to previous observations, all four responding patients had elevated serum interleukin-5 levels.|/A study was conducted to include/ 28 patients with accelerated phase chronic myelogenous leukemia (CML) ... . Diagnosis of accelerated phase CML was based on karyotypic evolution (n = 9) and hematologic criteria (n = 18). All patients were begun on 600 mg/day of imatinib mesylate. Dose reductions to 400 mg/day and then 300 mg/day were prescribed for an absolute neutrophil count (ANC) of <0.5/microl or a platelet count of <20,000/microl. Twenty-seven of the 28 patients continued treatment for a median of 34 weeks. Eleven patients developed thrombocytopenia following an average of 8.4 +/- 1.4 weeks of therapy. The onset of thrombocytopenia was associated with disease progression in one patient and a decline in bone marrow megakaryocytes in the other 10. Nine patients recovered to a platelet count of >20,000/microl after an average of 19.7 +/- 1.8 weeks. Patients who developed thrombocytopenia had a longer duration of disease (9.39 vs. 4.35 years; P < 0.01) and were more likely to be diagnosed with accelerated phase CML by hematologic criteria. Hematologic responses in patients with and without thrombocytopenia were comparable; however, 31.3% of patients without thrombocytopenia had a complete cytogenetic response compared to none of those with thrombocytopenia. Grade III-IV thrombocytopenia is common in accelerated phase CML and may be a marker for the inability to achieve cytogenetic response using single agent imatinib mesylate.|Imatinib is indicated for the treatment of gastrointestinal stromal tumors (GISTs). /NOT included in US product labeling/|Imatinib is indicated for the treatment of patients with chronic myeloid leukemia (MCL) in blast crisis; accelerated phase, or in chronic phase after failure of interferon-alpha therapy. (NOTE: Effectiveness is based on overall hematologic and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.) /Included in US product labeling/|Imatinib mesylate (STI571, Gleevec, Glivec, a selective inhibitor of the BCR-ABL tyrosine kinase causative of chronic myeloid leukemia (CML), represents the paradigm of how a better understanding of the pathogenetic mechanisms of a neoplastic disease can lead to the development of a targeted molecular therapy. Phase II clinical trials have shown marked therapeutic activity of imatinib in all evolutive phases of CML, but notably in the chronic phase, where it induces complete hematological responses in almost 100% of patients resistant or intolerant to interferon, with a major cytogenetic response rate of 60%, including 41% complete cytogenetic responses. The preliminary results of an ongoing phase III multicenter randomized study comparing imatinib with interferon plus cytarabine as first-line treatment for CML favor imatinib in terms of efficacy and safety. If confirmed with longer follow-up,these results would establish imatinib as the choice therapy for the majority of CML patients, with allogeneic transplantation being restricted as initial therapy only to younger patients with a family donor.

Imatinib mesylate blocks bcr/abl kinase activity effectively, and thus is a promising drug in Philadelphia chromosome positive leukemias. While under imatinib treatment high hematological and cytogenetic response rates could be observed, usually only mild non-hematological side-effects like skin rash, edema, and muscular cramps occur. ... Two severe cases of acute generalized exanthematous pustulosis due to imatinib /are reported/. In both patients the generalized pustular eruptions could be observed 12 wk after initiation of imatinib treatment. Numerous microbiological investigations excluded an infectious etiology, and histopathology of cutaneous lesions was consistent with acute generalized exanthematous pustulosis. ... Withdrawal of imatinib led to a restitution at integrum of the integument. ...|A tyrosine kinase inhibitor (STI571, Gleevec) has recently been applied in the treatment of chronic myeloid leukemia. /A/ ... case of pityriasis rosea occurring as a reaction to Gleevec in a woman with blast crisis of this disorder /is detailed/.|Imatinib or STI 571 is ... a member of a new class of drugs known as signal transduction inhibitors. These compounds specifically inhibit the proliferation of v-abl- and bcr-abl-expressing cells and have recently been approved as treatment for chronic myeloid leukaemia (CML). ... An erosive oral lichenoid eruption confined to the buccal mucosa and dorsum of the tongue which appeared 12 weeks after commencement of imatinib in a 72-year-old woman with CML /is presented/. The histology was consistent with a lichenoid drug eruption. The lesions resolved upon withdrawal of the drug.|Adverse effects occurring in 10% or more of patients include nausea, vomiting, edema, muscle cramps, diarrhea, GI or CNS hemorrhage, musculoskeletal pain, rash, headache, fatigue, arthralgia, dyspepsia, myalgia, weight increase, pyrexia, abdominal pain, cough, dyspnea, anorexia, constipation, nasopharyngitis, night sweats, pruritus, epistaxis, hypokalemia, petechiae, pneumonia, and weakness.|For more Drug Warnings (Complete) data for IMATINIB MESYLATE (11 total), please visit the HSDB record page.

Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)|Agents that inhibit PROTEIN KINASES. (See all compounds classified as Protein Kinase Inhibitors.)

Imatinib is well absorbed after oral administration with Cmax achieved within 2-4 hours post-dose. Mean absolute bioavailability for the capsule formulation is 98%. Following oral administration in healthy volunteers, the elimination half-lives of imitanib and its major active metabolite, the N-desmethyl derivative, were approximately 18 and 40 hours, respectively. Mean imatinib AUC increased proportionally with increasing dose in the range 25 mg-1000 mg. There was no signficant change in the pharmacokinetics of imatinib on repeated dosing, and accumulation is 1.5-2.5 fold at steady state when Gleevec 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 (alpha)1-acid glycoprotein.|Fecal /elimination/ - 68% within 7 days (20% of dose unchanged); Renal /elimination/ - 13% within 7 days (5% of dose unchanged).|Typically, clearance of imitanib in a 50-year-old patient weighing 50 kg is expected to be 8 L/hr, while for a 50-year-old patient weighing 100 kg the clearance will increase to 14 L/hr. However, the inter-patient variability of 40% in clearance does not warrant initial dose adjustment based on body weight and/or age but indicates the need for close monitoring for treatment related toxicity.|In lactating female rats administered 100 mg/kg ... imatinib and/or its metabolites were extensively excreted in milk. It is estimated that approximately 1.% of a maternal dose is excreted into milk, which is equivalent to a dose to the infant of 30% the maternal dose per unit body weight.

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 imatinib. The plasma AUC for this metabolite is about 15% of the AUC for imatinib.

Elimination - Approximately 18 and 40 hours, for imatinib and its primary metabolite, respectively.

Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the Bcr-Abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in chronic myeloid leukemia (CML). It inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines as as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. In colony formation assays using ex vivo peripheral blood and bone marrow samples, imatinib shows inhibition of Bcr-Abl positive colonies from CML patients.In vivo, it inhibits tumor growth of Bcr-Abl transfected murine myeloid cells as well as Bcr-Abl positive leukemia lines derived from CML patients in blast crisis.|Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF=and SCF-mediated cellular events, In vitro, imatinib inhibits proliferation and induces apoptosis in gastrointestinal stromal tumor (GIST) cells, which express an activating c-kit mutation.

alpha-(4-methyl-1-piperazinyl)-3'-((4-(3-pyridyl)-2-pyrimidinyl)amino)-p-tolu-p-toluidide

... distributed by Novartis Pharmaceuticals Corp., East Hanover, NJ 07936

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