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Imatinib Mesylate

PubChem CID
123596
Structure
Imatinib Mesylate_small.png
Imatinib Mesylate_3D_Structure.png
Molecular Formula
Synonyms
  • Imatinib mesylate
  • 220127-57-1
  • Gleevec
  • Glivec
  • Imatinib mesilate
Molecular Weight
589.7 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Parent Compound
Dates
  • Create:
    2005-03-26
  • Modify:
    2025-01-18
Description
Imatinib methanesulfonate is a methanesulfonate (mesylate) salt that is the monomesylate salt of imatinib. Used for treatment of chronic myelogenous leukemia and gastrointestinal stromal tumours. It has a role as an antineoplastic agent, an apoptosis inducer, a tyrosine kinase inhibitor and an anticoronaviral agent. It contains an imatinib.
Imatinib Mesylate is the mesylate salt of imatinib, a tyrosine kinase inhibitor with antineoplastic activity. Imatinib binds to an intracellular pocket located within tyrosine kinases (TK), thereby inhibiting ATP binding and preventing phosphorylation and the subsequent activation of growth receptors and their downstream signal transduction pathways. This agent inhibits TK encoded by the bcr-abl oncogene as well as receptor TKs encoded by the c-kit and platelet-derived growth factor receptor (PDGFR) oncogenes. Inhibition of the bcr-abl TK results in decreased proliferation and enhanced apoptosis in malignant cells of Philadelphia-positive (Ph+) hematological malignancies such as CML and ALL; effects on c-kit TK activity inhibit mast-cell and cellular proliferation in those diseases overexpressing c-kit, such as mastocytosis and gastrointestinal stromal tumor (GIST).
IMATINIB MESYLATE is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 2001 and is indicated for chronic myelogenous leukemia and has 77 investigational indications.
See also: Imatinib (has active moiety).

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Imatinib Mesylate.png

1.2 3D Conformer

3D Conformer of Parent

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

methanesulfonic acid;4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]benzamide
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C29H31N7O.CH4O3S/c1-21-5-10-25(18-27(21)34-29-31-13-11-26(33-29)24-4-3-12-30-19-24)32-28(37)23-8-6-22(7-9-23)20-36-16-14-35(2)15-17-36;1-5(2,3)4/h3-13,18-19H,14-17,20H2,1-2H3,(H,32,37)(H,31,33,34);1H3,(H,2,3,4)
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

YLMAHDNUQAMNNX-UHFFFAOYSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

CC1=C(C=C(C=C1)NC(=O)C2=CC=C(C=C2)CN3CCN(CC3)C)NC4=NC=CC(=N4)C5=CN=CC=C5.CS(=O)(=O)O
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C30H35N7O4S
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

2.3.2 European Community (EC) Number

2.3.3 UNII

2.3.4 ChEBI ID

2.3.5 ChEMBL ID

2.3.6 DSSTox Substance ID

2.3.7 KEGG ID

2.3.8 NCI Thesaurus Code

2.3.9 NSC Number

2.3.10 RXCUI

2.3.11 Wikidata

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • alpha-(4-methyl-1-piperazinyl)-3'-((4-(3-pyridyl)-2-pyrimidinyl)amino)-p-tolu-p-toluidide
  • CGP 57148
  • CGP-57148
  • CGP57148
  • CGP57148B
  • Gleevec
  • Glivec
  • imatinib
  • imatinib mesylate
  • imatinib methanesulfonate
  • Mesylate, Imatinib
  • Methanesulfonate, Imatinib
  • ST 1571
  • ST1571
  • STI 571
  • STI-571
  • STI571

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
589.7 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
3
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
10
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
7
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
589.24712380 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
589.24712380 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
149 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
42
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
799
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
2
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Color / Form

White to off white to brownish or yellowish tinged crystalline powder
Physicians' Desk Reference. 57th ed. Montvale, NJ: Medical Economics Co., Inc., p. 2278 (2002)

3.2.2 Melting Point

MP: 226 °C (alpha form); 217 °C (beta form)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 880

3.2.3 Solubility

Soluble in aqueous buffers =<pH 5.5, but very slightly soluble in neutral to alkaline aqueous buffers; freely soluble to very soluble in dimethyl sulfoxide, methanol, and ethanol; insoluble in n-octanol, acetone, and acetonitrile.
Physicians' Desk Reference. 57th ed. Montvale, NJ: Medical Economics Co., Inc., p. 2278 (2002)
In water, >100 g/l @ pH 4.2; 49 mg/l @ pH 7.4
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 880

3.2.4 Other Experimental Properties

Lipophilic at pH 7.4
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 880
Molecular weight: 493.60; melting point: 211-213 °C; pKa1: 8.07; pKa2: 3.73; pKa3: 2.56; pKa 4: 1.52 /Imatinib/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 880

3.3 Chemical Classes

3.3.1 Drugs

3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Antineoplastic Agents; Enzyme Inhibitors; Protein Kinase Inhibitors; Signal Transduction Inhibitors; Tyrosine Kinase Inhibitors
Human drug -> Prescription; Discontinued
Human drug -> Prescription; Discontinued; Active ingredient (IMATINIB MESYLATE)
Human drugs -> Antineoplastic agents -> Human pharmacotherapeutic group -> EMA Drug Category
Human drugs -> imatinib -> Human pharmacotherapeutic group -> EMA Drug Category
Human drugs -> Protein kinase inhibitors -> Human pharmacotherapeutic group -> EMA Drug Category
Paediatric drug

4 Spectral Information

4.1 Mass Spectrometry

4.1.1 LC-MS

1 of 2
MS Category
Experimental
MS Type
LC-MS
MS Level
MS2
Precursor Type
[M+2H]+
Precursor m/z
247.637
Instrument
qTof
Ionization Mode
positive
Top 5 Peaks

247.638199 100

250.118195 68.82

248.139557 58.56

250.619278 17.39

262.108978 14.59

Thumbnail
Thumbnail
2 of 2
MS Category
Experimental
MS Type
LC-MS
MS Level
MS2
Precursor Type
[M+H]+
Precursor m/z
494.266
Instrument
qTof
Ionization Mode
positive
Top 5 Peaks

494.265717 100

394.165192 53.49

495.267822 46

395.169586 20.75

222.091766 9.26

Thumbnail
Thumbnail

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

Glivec is indicated for the treatment of, , , adult 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 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 Accord is indicated for the treatment of- adult 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. - adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with recurrent and/or metastatic DFSP who are not eligible for surgery. - 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 treatmentThe 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 (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.   

7.2 Drug Classes

Breast Feeding; Lactation; Milk, Human; Antineoplastic Agents; Enzyme Inhibitors; Protein Kinase Inhibitors; Signal Transduction Inhibitors; Tyrosine Kinase Inhibitors

7.3 FDA Approved Drugs

7.4 FDA Orange Book

7.5 FDA National Drug Code Directory

7.6 Drug Labels

Drug and label
Active ingredient and drug

7.7 Cancer Drugs

Drug Name
Gleevec (Imatinib Mesylate)
Brand Name(s)

Gleevec

Imkeldi

FDA Approved
Yes
Drug Use

Imatinib mesylate is approved to treat:

• Acute lymphoblastic leukemia in adults and children that is Philadelphia chromosomepositive. In adults, it is used for cancer that has come back or does not respond to treatment. In children, it is used with chemotherapy as the first treatment after the cancer is diagnosed.

• Chronic eosinophilic leukemia or hypereosinophilic syndrome in adults.

• Chronic myelogenous leukemia that is Philadelphia chromosome positive. It is used in adults and children with:

• Newly-diagnosed chronic phase cancer.

• Chronic phase, accelerated phase, or blastic phase cancer that got worse after interferon-alpha therapy.

• Dermatofibrosarcoma protuberans in adults whose cancer has come back, has spread to other parts of the body, and/or cannot be removed by surgery.

• Gastrointestinal stromal tumor (GIST) that is KIT positive and cannot be removed by surgery and/or has spread to other parts of the body. It is also used after surgery to completely remove the tumor in adults with KIT-positive cancer.

• Myelodysplastic/myeloproliferative neoplasms in adults.

• Systemic mastocytosis that is aggressive and has a certain mutation in the c-KIT gene.

Imatinib mesylate is also being studied in the treatment of other conditions and types of cancer.

7.8 Clinical Trials

7.8.1 ClinicalTrials.gov

7.8.2 EU Clinical Trials Register

7.9 EMA Drug Information

1 of 7
View All
Medicine
Category
Human drugs
Therapeutic area
Precursor Cell Lymphoblastic Leukemia-Lymphoma; Gastrointestinal Stromal Tumors; Dermatofibrosarcoma; Myelodysplastic-Myeloproliferative Diseases; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Hypereosinophilic Syndrome
Active Substance
imatinib
INN/Common name
imatinib
Pharmacotherapeutic Classes
Antineoplastic agents
Status
This medicine is authorized for use in the European Union
Company
Novartis Europharm Limited
Market Date
2001-11-07
2 of 7
View All
Category
Human drugs
Therapeutic area
Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myelodysplastic-Myeloproliferative Diseases; Hypereosinophilic Syndrome; Dermatofibrosarcoma; Gastrointestinal Stromal Tumors
Active Substance
imatinib mesilate
INN/Common name
imatinib
Pharmacotherapeutic Classes
Antineoplastic agents
Status
Withdrawn
Company
Koanaa Healthcare GmbH
Market Date
2021-09-22

7.10 Therapeutic Uses

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.
Pardanani AD et al; Blood 101 (9): 3391-7 (2003)
/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.
van Deventer HW et al; Am J Hematol 71 (3): 184-90 (2002)
Imatinib is indicated for the treatment of gastrointestinal stromal tumors (GISTs). /NOT included in US product labeling/
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1520
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/
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1520
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.
Hernandez-Boluda JC, Cervantes F; Drugs Today 38 (9): 601-13 (2002)

7.11 Drug Warnings

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. ...
Schwarz M et al; Eur J Hematol 69 (4): 254-6 (2002)
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/.
Konstantopoulos K et al; Dermatology 205 (2): 172-3 (2002)
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.
Lim DS, Muir J; Dermatology 205 (2): 169-71 (2002)
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.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1027
For more Drug Warnings (Complete) data for IMATINIB MESYLATE (11 total), please visit the HSDB record page.

8 Pharmacology and Biochemistry

8.1 MeSH Pharmacological Classification

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

8.2 FDA Pharmacological Classification

Non-Proprietary Name
IMATINIB MESYLATE
Pharmacological Classes
Protein Kinase Inhibitors [MoA]; Kinase Inhibitor [EPC]; Cytochrome P450 3A4 Inhibitors [MoA]; Kinase Inhibitor [EPC]; Cytochrome P450 2D6 Inhibitors [MoA]; Bcr-Abl Tyrosine Kinase Inhibitors [MoA]

8.3 ATC Code

L01EA01
L01XE01

8.4 Absorption, Distribution and Excretion

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.
Medical Economics Co; Physicians Desk Reference on line version as of July 24, 2003
Fecal /elimination/ - 68% within 7 days (20% of dose unchanged); Renal /elimination/ - 13% within 7 days (5% of dose unchanged).
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1520
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.
Medical Economics Co; Physicians Desk Reference on line version as of July 24, 2003
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.
Medical Economics Co; Physicians Desk Reference on line version as of July 24, 2003

8.5 Metabolism / Metabolites

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.
Medical Economics Co; Physicians Desk Reference on line version as of July 24, 2003

8.6 Biological Half-Life

Elimination - Approximately 18 and 40 hours, for imatinib and its primary metabolite, respectively.
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1520

8.7 Mechanism of Action

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.
Medical Economics Co; Physicians Desk Reference on line version as of July 24, 2003
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.
Medical Economics Co; Physicians Desk Reference on line version as of July 24, 2003

8.8 Transformations

9 Use and Manufacturing

9.1 Uses

MEDICATION

9.1.1 Use Classification

Human drugs -> Antineoplastic agents -> Human pharmacotherapeutic group -> EMA Drug Category
Human drugs -> imatinib -> Human pharmacotherapeutic group -> EMA Drug Category
Human drugs -> Protein kinase inhibitors -> Human pharmacotherapeutic group -> EMA Drug Category
Human Drugs -> EU pediatric investigation plans
Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

9.2 General Manufacturing Information

... distributed by Novartis Pharmaceuticals Corp., East Hanover, NJ 07936
Physicians' Desk Reference. 57th ed. Montvale, NJ: Thompson PDR p. 2278 (2003)

10 Safety and Hazards

10.1 Hazards Identification

10.1.1 GHS Classification

Note
Pictograms displayed are for 99.1% (115 of 116) of reports that indicate hazard statements. This chemical does not meet GHS hazard criteria for 0.9% (1 of 116) of reports.
Pictogram(s)
Irritant
Health Hazard
Signal
Danger
GHS Hazard Statements

H302 (82.8%): Harmful if swallowed [Warning Acute toxicity, oral]

H351 (17.2%): Suspected of causing cancer [Warning Carcinogenicity]

H360 (13.8%): May damage fertility or the unborn child [Danger Reproductive toxicity]

Precautionary Statement Codes

P203, P264, P270, P280, P301+P317, P318, P330, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 116 reports by companies from 18 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Reported as not meeting GHS hazard criteria per 1 of 116 reports by companies. For more detailed information, please visit ECHA C&L website.

There are 17 notifications provided by 115 of 116 reports by companies with hazard statement code(s).

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

10.1.2 Hazard Classes and Categories

Acute Tox. 4 (82.8%)

Carc. 2 (17.2%)

Repr. 1B (13.8%)

10.2 Accidental Release Measures

10.2.1 Disposal Methods

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.

10.3 Regulatory Information

10.3.1 FDA Requirements

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.
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of July 1, 2003: https://www.fda.gov/cder/ob/
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).
21 CFR 200-299, 300-499, 820, and 860; U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of July 1, 2003: https://www.ecfr.gov

10.4 Other Safety Information

10.4.1 Special Reports

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).]

11 Toxicity

11.1 Toxicological Information

11.1.1 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Limited information indicates that maternal doses of imatinib up to 400 mg daily produce low levels of the drug and its active metabolite in milk. Although a few breastfed infants apparently experienced no adverse effects during maternal use of imatinib, no long-term data are available. Until more data are available, imatinib should be used only with careful monitoring during breastfeeding. National Comprehensive Cancer Network guidelines, the manufacturer and some authors recommend that breastfeeding be discontinued during imatinib therapy and for 1 month after therapy.

◉ Effects in Breastfed Infants

A woman receiving oral imatinib 400 mg daily for chronic myeloid leukemia breastfed her infant. No adverse effects were noted in the infant during the first 2 months of nursing.

One woman with chronic myelogenous leukemia received imatinib 400 mg daily throughout pregnancy and during breastfeeding (extent not stated) for nearly 6 months postpartum. Her infant reportedly grew and developed normally.

A woman with chronic myeloid leukemia received imatinib 400 mg daily starting at week 8 of pregnancy and continuing throughout 8 months of breastfeeding (extent not stated). The infant was healthy, but an atrial septal defect was repaired at 30 months of age. It was thought to be unrelated to imatinib therapy.

A pregnant woman with Philadelphia chromosome-positive chronic myelogenous leukemia was started on imatinib 400 mg daily during pregnancy. After delivery, her preterm infant was fed colostrum until the middle of the fifth day postpartum when exclusive formula feeding was instituted. The infant was treated for apnea of prematurity and discharged on day 25 of life. No adverse effects on growth or development were noted during the first year of life.

◉ Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

11.1.2 Interactions

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.
Ruchatz H et al; Leukemia 17 (2): 298-304 (2003)
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.
Medical Economics Co; Physicians Desk Reference on line version as of July 24, 2003
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.
Medical Economics Co; Physicians Desk Reference on line version as of July 24, 2003
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.).
Medical Economics Co; Physicians Desk Reference on line version as of July 24, 2003
For more Interactions (Complete) data for IMATINIB MESYLATE (6 total), please visit the HSDB record page.

11.1.3 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ An oral dose of 1200 mg/sq m/day .... was not lethal to rats following 14 days of administration. A dose of 3600 mg/sq m/day ... was lethal to rats after 7-10 administrations, due to general deterioration of the animals with secondary degenerative histological changes in many tissues.
Medical Economics Co; Physicians Desk Reference on line version as of July 24, 2003
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased BUN and creatinine were observed in several of these animals. An increased rate of opportunistic infections was observed with chronic imatinib treatment. In a 39-week monkey study, treatment with imatinib resulted in worsening of normally suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in humans).
Medical Economics Co; Physicians Desk Reference on line version as of July 24, 2003
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In a study of fertility, in male rats dosed for 70 days prior to mating, testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg ...This was not seen at doses </=20 mg/kg ... When female rats were dosed 14 days prior to mating and through to gestational day 6, there was no effect on mating or on number of pregnant females. At a dose of 60 mg/kg ..., female rats had significant post-implantation fetal loss and a reduced number of live fetuses. This was not seen at doses </=20 mg/kg ...
Medical Economics Co; Physicians Desk Reference on line version as of July 24, 2003
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses >/=100 mg/kg ... Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones. Female rats administered this dose also experienced significant post-implantation loss in the form of early fetal resorption. At doses higher than 100 mg/kg, total fetal loss was noted in all animals. These effects were not seen at doses
Medical Economics Co; Physicians Desk Reference on line version as of July 24, 2003
/GENOTOXICITY/ Positive genotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberrations) in the presence of metabolic activation. Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay. one of these intermediates was also positive in the mouse lymphoma assay. Imatinib was not genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in vitro mammalian cell assay (mouse lymphoma) and in vivo rat micronucleus assay.
Medical Economics Co; Physicians Desk Reference on line version as of July 24, 2003

11.2 Ecological Information

11.2.1 Milk Concentrations

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.
Medical Economics Co; Physicians Desk Reference on line version as of July 24, 2003

12 Associated Disorders and Diseases

13 Literature

13.1 Consolidated References

13.2 NLM Curated PubMed Citations

13.3 Springer Nature References

13.4 Wiley References

13.5 Chemical Co-Occurrences in Literature

13.6 Chemical-Gene Co-Occurrences in Literature

13.7 Chemical-Disease Co-Occurrences in Literature

14 Patents

14.1 Depositor-Supplied Patent Identifiers

14.2 WIPO PATENTSCOPE

14.3 FDA Orange Book Patents

14.4 Chemical Co-Occurrences in Patents

14.5 Chemical-Disease Co-Occurrences in Patents

14.6 Chemical-Gene Co-Occurrences in Patents

15 Interactions and Pathways

15.1 Chemical-Target Interactions

16 Biological Test Results

16.1 BioAssay Results

17 Classification

17.1 MeSH Tree

17.2 NCI Thesaurus Tree

17.3 ChEBI Ontology

17.4 KEGG: Drug

17.5 KEGG: USP

17.6 KEGG: ATC

17.7 KEGG: Target-based Classification of Drugs

17.8 KEGG: Drug Groups

17.9 KEGG: Drug Classes

17.10 ChemIDplus

17.11 ChEMBL Target Tree

17.12 UN GHS Classification

17.13 NORMAN Suspect List Exchange Classification

17.14 EPA DSSTox Classification

17.15 FDA Drug Type and Pharmacologic Classification

17.16 EPA Substance Registry Services Tree

17.17 MolGenie Organic Chemistry Ontology

18 Information Sources

  1. CAS Common Chemistry
    LICENSE
    The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc/4.0/
  2. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  3. DTP/NCI
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  4. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  5. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
    4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide methanesulfonate
    https://echa.europa.eu/substance-information/-/substanceinfo/100.111.437
    4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide methanesulfonate (EC: 606-892-3)
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/25407
    4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide methanesulfonate
    https://echa.europa.eu/substance-information/-/substanceinfo/100.207.296
  6. FDA Global Substance Registration System (GSRS)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  7. Hazardous Substances Data Bank (HSDB)
  8. ChEBI
  9. NCI Thesaurus (NCIt)
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  10. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  11. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  12. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  13. DailyMed
  14. Drugs and Lactation Database (LactMed)
  15. Drugs@FDA
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  16. European Medicines Agency (EMA)
    LICENSE
    Information on the European Medicines Agency's (EMA) website is subject to a disclaimer and copyright and limited reproduction notices.
    https://www.ema.europa.eu/en/about-us/legal-notice
  17. EU Clinical Trials Register
  18. FDA Orange Book
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  19. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Therapeutic category of drugs in Japan
    http://www.genome.jp/kegg-bin/get_htext?br08301.keg
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  20. MassBank of North America (MoNA)
    LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
    https://mona.fiehnlab.ucdavis.edu/documentation/license
  21. National Drug Code (NDC) Directory
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  22. NCI Cancer Drugs
  23. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  24. Springer Nature
  25. Wikidata
  26. Wiley
  27. Medical Subject Headings (MeSH)
    LICENSE
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    https://www.nlm.nih.gov/copyright.html
  28. PubChem
  29. GHS Classification (UNECE)
  30. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  31. EPA Substance Registry Services
  32. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  33. PATENTSCOPE (WIPO)
CONTENTS