Imatinib

493.6

493.60

1308068-626-2

BKJ8M8G5HI

759854|743414

DTXSID3037125

C62035

L01XE01|L - Antineoplastic and immunomodulating agents

29339900

86.3

3

Solid

1'+-.0.06 g/cm3(Predicted)

208-209 °C @ Solvent: Dichloromethane, Hexane

754.9ºC at 760 mmHg

410.3ºC

Very soluble in water at pH < 5.5 (mesylate salt)

Refrigerator

6.03E-24mmHg at 25°C

214.6 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

II

6.1

UN 1662 6.1/PG 2

3

R23/24/25; R40; R48/23/24; R51/53

24/25

CV5585673

T; N

P201, P202, P260, P263, P264, P270, P273, P280, P281, P301+P312, P302+P352, P305+P351+P338, P308+P313, P314, P321, P330, P332+P313, P337+P313, P362, P391, P405, P501

H302

|Danger|H302 (22.22%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P263, P264, P270, P273, P280, P281, P301+P312, P302+P352, P305+P351+P338, P308+P313, P314, P321, P330, P332+P313, P337+P313, P362, P391, P405, and P501|Aggregated GHS information provided by 9 companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The most frequently reported adverse reactions (>30%) were edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue and abdominal pain.

Imatinib therapy is associated with three forms of acute liver injury: transient and usually asymptomatic elevations in serum enzymes during treatment, clinically apparent acute hepatitis, and reactivation of an underlying chronic hepatitis B.

95% protein bound, mostly to albumin and alpha-1-acid glycoprotein.

For the treatment of Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML), Ph+ acute lymphoblastic leukaemia, myelodysplastic/myeloproliferative diseases, aggressive systemic mastocytosis, hypereosinophilic syndrome and/or chronic eosinophilic leukemia (CEL), dermatofibrosarcoma protuberans, and malignant gastrointestinal stromal tumors (GIST).|FDA Label|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 medac 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;adult and paediatric 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;adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with recurrent and/or metastatic DFSP who are not eligible for surgery.The effect of imatinib on the outcome of bone marrow transplantation has not been determined.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 DFSP.The experience with imatinib in patients with MDS/MPD associated with PDGFR gene re-arrangements is very limited. Except in newly diagnosed chronic phase CML, there are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.|Imatinib Accord 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 patients with newly diagnosed Ph+ acute lymphoblastic leukaemia (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-arrangementsadult patients with advanced hypereosinophilic syndrome (HES) and / or chronic eosinophilic leukaemia (CEL) with FIP1L1-PDGFRα rearrangement;adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with recurrent and / or metastatic DFSP who are not eligible for surgery.|Imatinib Actavis 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 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-PDGFR rearrangement;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.The effect of imatinib on the outcome of bone marrow transplantation has not been determined.Imatinib Actavis is indicated for: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 DFSP. 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.|Imatinib Teva 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 Teva is indicated forThe treatment of adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with recurrent and/or metastatic DFSP who are not eligible for surgery.|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.,|Treatment of acute lymphoblastic leukaemia, Treatment of chronic myeloid leukaemia|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.

Imatinib is specific tyrosine kinase receptor inhibitor that is used in the therapy of Philadelphia chromosome-positive chronic myelogenous leukemia and gastrointestinal stromal tumors, both of which are marked by an abnormal, constitutively expressed tyrosine kinase that causes unregulated cell growth. Imatinib therapy is associated with transient elevations in serum aminotransferase levels and rare instances of clinically apparent acute liver injury which can be severe and sometimes fatal.

Antineoplastic Agents

Imatinib is an antineoplastic agent and a 2-phenylaminopyrimidine derivative that is used to treat chronic myelogenous leukemia. It works as a specific inhibitor of a number of tyrosine kinase enzymes. Chronic myelogenous leukemia is associated with the Philadelphia chromosome promoting the generation of BCR-ABL mutation, which results from the combination of two genes, known as BCR and ABL. BCR-ABL generates a fusion protein that acts as a constitutively active tyrosine kinase and imatinib works to inhibit this constitutive enzymatic activity.

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.)

The pharmacokinetics in CML and GIST patients are similar. Imatinib is well absorbed with mean absolute bioavailability is 98% and maximum plasma levels achieved within 2-4 hours of dosing|Imatinib elimination is predominately in the feces, mostly as metabolites. 81% of the dose is eliminated within 7 days, in feces (68% of the dose) and urine (13% of the dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% faces), the remainder being metabolites.|8 L/h [50-year-old CML and GIST patient weighing 50 kg]

Primarily hepatic via CYP3A4. 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. This metabolite is similar in potency to the parent compound.|Imatinib has known human metabolites that include N-desmethylimatinib.

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.

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 well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. Imatinib also inhibits the receptor tyrosine kinases for platelet derived growth factor (PDGF) and stem cell factor (SCF) - called c-kit. Imatinib was identified in the late 1990s by Dr Brian J. Druker. Its development is an excellent example of rational drug design. Soon after identification of the bcr-abl target, the search for an inhibitor began. Chemists used a high-throughput screen of chemical libraries to identify the molecule 2-phenylaminopyrimidine. This lead compound was then tested and modified by the introduction of methyl and benzamide groups to give it enhanced binding properties, resulting in imatinib.

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

Human drugs -> Glivec -> EMA Drug Category|Antineoplastic agents -> Human pharmacotherapeutic group|Human drugs -> Imatinib medac -> EMA Drug Category|Protein kinase inhibitors -> Human pharmacotherapeutic group|Human drugs -> Imatinib Accord -> EMA Drug Category|Human drugs -> Imatinib Actavis -> EMA Drug Category|Protein kinase inhibitors, Antineoplastic agents -> Human pharmacotherapeutic group|Human drugs -> Imatinib Teva -> EMA Drug Category|Antineoplastic agents, Protein kinase inhibitors -> Human pharmacotherapeutic group|Human drugs -> Imatinib Teva B.V. -> EMA Drug Category|Human drugs -> Rare disease (orphan)|Human Drugs -> EU pediatric investigation plans|Human drugs -> Imatinib Koanaa -> EMA Drug Category