Imatinib Mesylate

Do not take it if

Quoted from the official label, section “Contraindications”.

How to take it

These directions are for this exact strength and form. Another one is different.

• Adults with Ph+ CML CP ( 2.2 ): 400 mg/day
• Adults with Ph+ CML AP or BC ( 2.2 ): 600 mg/day
• Pediatrics with Ph+ CML CP ( 2.3 ): 340 mg/m 2 /day
• Adults with Ph+ ALL ( 2.4 ): 600 mg/day
• Pediatrics with Ph+ ALL (2.5): 340 mg/m 2 /day
• Adults with MDS/MPD ( 2.6 ): 400 mg/day
• Adults with ASM ( 2.7 ): 100 mg/day or 400 mg/day
• Adults with HES/CEL ( 2.8 ): 100 mg/day or 400 mg/day
• Adults with DFSP ( 2.9 ): 800 mg/day
• Adults with metastatic and/or unresectable GIST (2.10): 400 mg/day
• Adjuvant treatment of adults with GIST ( 2.11): 400 mg/day
• Patients with mild to moderate hepatic impairment ( 2.12 ): 400 mg/day
• Patients with severe hepatic impairment ( 2.12 ):
• 300 mg/day All doses of imatinib mesylate tablets should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. Imatinib mesylate tablets can be dissolved in water or apple juice for patients having difficulty swallowing. Daily dosing of 800 mg and above should be accomplished using the 400 mg tablet to reduce exposure to iron. 2.1 Drug Administration The prescribed dose should be administered orally, with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice. The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 mL for a 100 mg tablet, and 200 mL for a 400 mg tablet) and stirred with a spoon. The suspension should be administered immediately after complete disintegration of the tablet(s). For daily dosing of 800 mg and above, dosing should be accomplished using the 400 mg tablet to reduce exposure to iron. Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity. 2.2 Adult Patients With Ph+ CML CP, AP, or BC The recommended dose of imatinib mesylate tablets are 400 mg/day for adult patients in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast crisis. In CML, a dose increase from 400 mg to 600 mg in adult patients with chronic phase disease, or from 600 mg to 800 mg (given as 400 mg twice daily) in adult patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances:
• disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6 to 12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response. 2.3 Pediatric Patients With Ph+ CML CP The recommended dose of imatinib mesylate tablets for children with newly diagnosed Ph+ CML is 340 mg/m 2 /day (not to exceed 600 mg). Imatinib mesylate tablets treatment can be given as a once daily dose or the daily dose may be split into two–one portion dosed in the morning and one portion in the evening. There is no experience with imatinib mesylate tablets treatment in
• children under 1 year of age. 2.4 Adult Patients With Ph+ ALL The recommended dose of imatinib mesylate tablets are 600 mg/day for adult patients with relapsed/refractory Ph+ ALL. 2.5 Pediatric Patients With Ph+ ALL The recommended dose of imatinib mesylate tablets to be given in combination with chemotherapy to children with newly diagnosed Ph+ ALL is 340 mg/m 2 /day (not to exceed 600 mg). Imatinib mesylate tablets treatment can be given as a once daily dose. 2.6 Adult Patients With MDS/MPD Determine PDGFRb gene rearrangements status prior to initiating treatment. The recommended dose of imatinib mesylate tablets are 400 mg/day for adult patients with MDS/MPD. 2.7 Adult Patients With ASM Determine D816V c-Kit mutation status prior to initiating treatment. The recommended dose of imatinib mesylate tablets are 400 mg/day for adult patients with ASM without the D816V c-Kit mutation. If c-Kit mutational status is not known or unavailable, treatment with imatinib mesylate tablets 400 mg/day may be considered for patients with ASM not responding satisfactorily to other therapies. For patients with ASM associated with eosinophilia, a clonal hematological disease related to the fusion kinase FIP1L1-PDGFRα, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy. 2.8 Adult Patients With HES/CEL The recommended dose of imatinib mesylate tablets are 400 mg/day for adult patients with HES/CEL. For HES/CEL patients with demonstrated FIP1L1-PDGFRα fusion kinase, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy. 2.9 Adult Patients With DFSP The recommended dose of imatinib mesylate tablets are 800 mg/day for adult patients with DFSP. 2.10 Adult Patients With Metastatic and/or Unresectable GIST The recommended dose of imatinib mesylate tablets is 400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST. A dose increase up to 800 mg daily (given as 400 mg twice daily) may be considered, as clinically indicated, in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions. 2.11 Adult Patients With Adjuvant GIST The recommended dose of imatinib mesylate tablets is 400 mg/day for the adjuvant treatment of adult patients following complete gross resection of GIST. In clinical trials, one year of imatinib mesylate tablets and three years of imatinib mesylate tablets were studied. In the patient population defined in Study 2, three years of imatinib mesylate tablets are recommended [see Clinical Studies (14.8) ] . The optimal treatment duration with imatinib mesylate tablets is not known. 2.12 Dose Modification Guidelines Concomitant Strong CYP3A4 inducers:
• The use of concomitant strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampacin, phenobarbital). If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dosage of imatinib mesylate tablets should be increased by at least 50%, and clinical response should be carefully monitored [see Drug Interactions (7.1) ]. Hepatic Impairment:
• Patients with mild and moderate hepatic impairment do not require a dose adjustment and should be treated per the recommended dose. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment [see Use in Specific Populations (8.6)]. Renal Impairment:
• Patients with moderate renal impairment (creatinine clearance [CrCL] = 20 to 39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL = 40 to 59 mL/min). For patients with moderate renal impairment doses greater than 400 mg are not recommended. Imatinib should be used with caution in patients with severe renal impairment. A dose of 100 mg/day was tolerated in two patients with severe renal impairment [see Warnings and Precautions (5.3) , Use in Specific Populations (8.7) ]. 2.13 Dose Adjustment for Hepatotoxicity and Non-Hematologic Adverse Reactions If elevations in bilirubin greater than 3 times the institutional upper limit of normal (IULN) or in liver transaminases greater than 5 times the IULN occur, imatinib mesylate tablets should be withheld until bilirubin levels have returned to a less than 1.5 times the IULN and transaminase levels to less than 2.5 times the IULN. In
• adults, treatment with imatinib mesylate tablets may then be continued at a reduced daily dose (i.e., 400 mg to 300 mg, 600 mg to 400 mg, or 800 mg to 600 mg). In children, daily doses can be reduced under the same circumstances from 340 mg/m 2 /day to 260 mg/m 2 /day. If a severe non-hematologic adverse reaction develops (such as severe hepatotoxicity or severe fluid retention), imatinib mesylate tablets should be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event. 2.14 Dose Adjustment for Hematologic Adverse Reactions Dose reduction or treatment interruptions for severe neutropenia and thrombocytopenia are recommended as indicated in Table 1. Table 1:
• Dose Adjustments for Neutropenia and Thrombocytopenia ASM associated with eosinophilia (starting dose 100 mg) ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L Stop imatinib mesylate tablets until ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L Resume treatment with imatinib mesylate tablets at previous dose (i.e., dose before severe adverse reaction) HES/CEL with FIP1L1-PDGFRα fusion kinase (starting dose 100 mg) ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L Stop imatinib mesylate tablets until ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L Resume treatment with imatinib mesylate tablets at previous dose (i.e., dose before severe adverse reaction) Chronic Phase CML (starting dose 400 mg) MDS/MPD, ASM and HES/CEL (starting dose 400 mg) GIST (starting dose 400 mg) ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L Stop imatinib mesylate tablets until ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L Resume treatment with imatinib mesylate tablets at the original starting dose of 400 mg If recurrence of ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L, repeat step 1 and resume imatinib mesylate tablets at a reduced dose of 300 mg Ph+ CML:
• Accelerated Phase and Blast Crisis (starting dose 600 mg) Ph+ ALL (starting dose 600 mg) ANC less than 0.5 x 10 9 /L and/or platelets less than 10 x 10 9 /L Check if cytopenia is related to leukemia (marrow aspirate or biopsy) If cytopenia is unrelated to leukemia, reduce dose of imatinib mesylate tablets to 400 mg If cytopenia persists 2 weeks, reduce further to 300 mg If cytopenia persists 4 weeks and is still unrelated to leukemia, stop imatinib mesylate tablets until ANC greater than or equal to 1 x 10 9 /L and platelets greater than or equal to 20 x 10 9 /L and then resume treatment at 300 mg DFSP (starting dose 800 mg) ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L Stop imatinib mesylate tablets until ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L Resume treatment with imatinib mesylate tablets at 600 mg In the event of recurrence of ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L, repeat step 1 and resume imatinib mesylate tablets at reduced dose of 400 mg Pediatric newly diagnosed chronic phase CML (starting dose 340 mg/m 2 ) ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L Stop imatinib mesylate tablets until ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L Resume treatment with imatinib mesylate tablets at previous dose (i.e., dose before severe adverse reaction) In the event of recurrence of ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L, repeat step 1 and resume imatinib mesylate tablets at reduced dose of 260 mg/m 2 Abbreviations:
• ANC, absolute neutrophil count; ASM, aggressive systemic mastocytosis; CEL, chronic eosinophilic leukemia; CML, chronic myeloid leukemia; DFSP, dermatofibrosarcoma protuberans; HES, hypereosinophilic syndrome; MDS/MPD, myelodysplastic/myeloproliferative diseases; PDGFR, platelet-derived growth factor receptor; Ph+ CML, Philadelphia chromosome positive chronic myeloid leukemia; Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia.

Quoted from the official label, section “Dosage & Administration”.

Other warnings

Quoted from the official label, section “Warnings”.

Pregnancy and breastfeeding

Quoted from the official label, section “OTC — Pregnancy or Breast Feeding”.

Other medicines

Quoted from the official label, section “Drug Interactions”.

If you take too much

In an emergency, call your local emergency number or a poison control centre.

Quoted from the official label, section “Overdosage”.

Use in children

• The safety and effectiveness of imatinib mesylate tablets have been demonstrated in pediatric patients with newly diagnosed Ph+ chronic phase CML and Ph+ ALL [see Clinical Studies (14.2, 14.4)] . There are no data in
• children under 1 year of age.

Quoted from the official label, section “Pediatric Use”.

Use in older people

• In the CML clinical studies, approximately 20% of patients were older than 65 years.
• In the study of patients with newly diagnosed CML, 6% of patients were older than 65 years.
• The frequency of edema was higher in patients older than 65 years as compared to younger patients; no other difference in the safety profile was observed [see Warnings and Precautions (5.1) ] .
• The efficacy of imatinib mesylate was similar in older and younger patients.
• In the unresectable or metastatic GIST study, 16% of patients were older than 65 years.
• No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis.
• In the adjuvant GIST study, 221 patients (31%) were older than 65 years.
• No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema.
• The efficacy of imatinib mesylate was similar in patients older than 65 years and younger patients.

Quoted from the official label, section “Geriatric Use”.

Side effects

• The following serious adverse reactions are described elsewhere in the labeling:
• Fluid Retention and Edema [see Warnings and Precautions ( 5.1 )]
• Hematologic Toxicity [see Warnings and Precautions ( 5.2 )]
• Congestive Heart Failure and Left Ventricular Dysfunction [see Warnings and Precautions ( 5.3 )]
• Hepatotoxicity [see Warnings and Precautions ( 5.4 )]
• Hemorrhage [see Warnings and Precautions ( 5.5 )]
• Gastrointestinal Disorders [see Warnings and Precautions ( 5.6 )]
• Hypereosinophilic Cardiac Toxicity [see Warnings and Precautions ( 5.7 )]
• Dermatologic Toxicities [see Warnings and Precautions ( 5.8 )]
• Hypothyroidism [see Warnings and Precautions ( 5.9 )]
• Growth Retardation in Children and Adolescents [see Warnings and Precautions ( 5.11 )]
• Tumor Lysis Syndrome [see Warnings and Precautions ( 5.12 )]
• Impairments Related to Driving and Using Machinery [see Warnings and Precautions ( 5.13 )]
• Renal Toxicity [see Warnings and Precautions ( 5.14 )] The most frequently reported adverse reactions (greater than or equal to 30%) are edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue, and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Chronic Myeloid Leukemia The majority of imatinib mesylate-treated patients experienced adverse reactions at some time. Imatinib mesylate was discontinued due to drug-related adverse reactions in 2.4% of patients receiving imatinib mesylate in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing imatinib mesylate versus IFN+Ara-C, and in 12.5% of patients receiving imatinib mesylate in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing imatinib mesylate and nilotinib. Imatinib mesylate was discontinued due to drug-related adverse reactions in 4% of patients in chronic phase after failure of interferon-alpha therapy, in 4% of patients in accelerated phase and in 5% of patients in blast crisis. The most frequently reported drug-related adverse reactions were edema, nausea and vomiting, muscle cramps, musculoskeletal pain, diarrhea and rash (Table 2 and Table 3 for newly diagnosed CML, Table 4 for other CML patients). Edema was most frequently periorbital or in lower limbs and was managed with diuretics, other supportive measures, or by reducing the dose of imatinib mesylate [see Dosage and Administration (2.13) ] . The frequency of severe superficial edema was 1.5% to 6%. A variety of adverse reactions represent local or general fluid retention, including pleural effusion, ascites, pulmonary edema, and rapid weight gain with or without superficial edema. These reactions appear to be dose related, were more common in the blast crisis and accelerated phase studies (where the dose was 600 mg/day), and are more common in the elderly. These reactions were usually managed by interrupting imatinib mesylate treatment and using diuretics or other appropriate supportive care measures. These reactions may be serious or life threatening. Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the imatinib mesylate-treated patients are shown in Tables 2, 3, and 4. Table 2:
• Adverse Reactions Regardless of Relationship to Study Drug Reported in Newly Diagnosed CML Clinical Trial in the Imatinib Mesylate Versus IFN+Ara-C Study (Greater Than or Equal to 10% of Imatinib Mesylate-Treated Patients) (1) All Grades CTC Grades * 3/4 Preferred term I matinib Mesylate IFN+Ara−C I matinib Mesylate IFN+Ara−C N = 551 (%) N = 533 (%) N = 551 (%) N = 533 (%) Fluid retention 61.7 11.1 2.5 0.9 − Superficial edema 59.9 9.6 1.5 0.4 − Other fluid retention reactions 2 6.9 1.9 1.3 0.6 Nausea 49.5 61.5 1.3 5.1 Muscle cramps 49.2 11.8 2.2 0.2 Musculoskeletal pain 47.0 44.8 5.4 8.6 Diarrhea 45.4 43.3 3.3 3.2 Rash and related terms 40.1 26.1 2.9 2.4 Fatigue 38.8 67.0 1.8 25.1 Headache 37.0 43.3 0.5 3.8 Joint pain 31.4 38.1 2.5 7.7 Abdominal pain 36.5 25.9 4.2 3.9 Nasopharyngitis 30.5 8.8 0 0.4 Hemorrhage 28.9 21.2 1.8 1.7 -GI hemorrhage 1.6 1.1 0.5 0.2 -CNS hemorrhage 0.2 0.4 0 0.4 Myalgia 24.1 38.8 1.5 8.3 Vomiting 22.5 27.8 2.0 3.4 Dyspepsia 18.9 8.3 0 0.8 Cough 20.0 23.1 0.2 0.6 Pharyngolaryngeal pain 18.1 11.4 0.2 0 Upper respiratory tract infection 21.2 8.4 0.2 0.4 Dizziness 19.4 24.4 0.9 3.8 Pyrexia 17.8 42.6 0.9 3.0 Weight increased 15.6 2.6 2.0 0.4 Insomnia 14.7 18.6 0 2.3 Depression 14.9 35.8 0.5 13.1 Influenza 13.8 6.2 0.2 0.2 Bone pain 11.3 15.6 1.6 3.4 Constipation 11.4 14.4 0.7 0.2 Sinusitis 11.4 6.0 0.2 0.2 Abbreviations:
• CML, chronic myeloid leukemia; CNS, central nervous system; CTC, common terminology criteria; GI, gastrointestinal; IFN, Interferon-alpha. *NCI Common Terminology Criteria for Adverse Events, version 3.0. (1) All adverse reactions occurring in greater than or equal to 10% of imatinib mesylate treated patients are listed regardless of suspected relationship to treatment. (2) Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified. Table 3:
• Most Frequently Reported Non-Hematologic Adverse Reactions (regardless of relationship to study drug) in Patients With Newly Diagnosed Ph+ CML-CP in the Imatinib Mesylate Versus Nilotinib Study (Greater Than or Equal to 10% in Imatinib Mesylate 400 mg Once Daily or Nilotinib 300 mg Twice Daily Groups) 60-Month Analysis a Body system and preferred term Patients with newly diagnosed Ph+ CML-CP I matinib Mesylate 400 mg once daily N = 280 Nilotinib 300 mg twice daily N = 279 I matinib Mesylate 400 mg once daily N = 280 Nilotinib 300 mg twice daily N = 279 All Grades (%) CTC Grades b 3/4 (%) Skin and subcutaneous tissue disorders Rash 19 38 2 < 1 Pruritus 7 21 0 < 1 Alopecia 7 13 0 0 Dry skin 6 12 0 0 Gastrointestinal disorders Nausea 41 22 2 2 Constipation 8 20 0 < 1 Diarrhea 46 19 4 1 Vomiting 27 15 < 1 < 1 Abdominal pain 14 18 < 1 1 upper Abdominal pain 12 15 0 2 Dyspepsia 12 10 0 0 Nervous system disorders Headache 23 32 < 1 3 Dizziness 11 12 < 1 < 1 General disorders and administration-site conditions Fatigue 20 23 1 1 Pyrexia 13 14 0 < 1 Asthenia 12 14 0 < 1 Peripheral edema 20 9 0 < 1 Face edema 14 < 1 < 1 0 Musculoskeletal and connective tissue disorders Myalgia 19 19 < 1 < 1 Arthralgia 17 22 < 1 < 1 Muscle spasms 34 12 1 0 Pain in extremity 16 15 < 1 < 1 Back pain 17 19 1 1 Respiratory, thoracic and mediastinal disorders Cough 13 17 0 0 Oropharyngeal pain 6 12 0 0 Dyspnea 6 11 < 1 2 Infections and infestations Nasopharyngitis 21 27 0 0 Upper respiratory tract infection 14 17 0 < 1 Influenza 9 13 0 0 Gastroenteritis 10 7 < 1 0 Eye disorders Eyelid edema 19 1 < 1 0 Periorbital edema 15 < 1 0 0 Psychiatric disorders Insomnia 9 11 0 0 Vascular disorder Hypertension 4 10 < 1 1 Abbreviation:
• Ph+ CML-CP, Philadelphia chromosome positive chronic myeloid leukemia-chronic phase. a Excluding laboratory abnormalities. b NCI Common Terminology Criteria for Adverse Events, version 3.0. Table 4:
• Adverse Reactions Regardless of Relationship to Study Drug Reported in Other CML Clinical Trials (Greater Than or Equal to 10% of All Patients in Any Trial) (1) Myeloid blast Crisis (n = 260) % Accelerated phase (n = 235) % Chronic phase, IFN failure (n = 532) % Preferred term All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Fluid retention 72 11 76 6 69 4 -Superficial edema 66 6 74 3 67 2 -Other fluid retention reactions (2) 22 6 15 4 7 2 Nausea 71 5 73 5 63 3 Muscle cramps 28 1 47 0.4 62 2 Vomiting 54 4 58 3 36 2 Diarrhea 43 4 57 5 48 3 Hemorrhage 53 19 49 11 30 2 -CNS hemorrhage 9 7 3 3 2 1 -GI hemorrhage 8 4 6 5 2 0.4 Musculoskeletal pain 42 9 49 9 38 2 Fatigue 30 4 46 4 48 1 Skin rash 36 5 47 5 47 3 Pyrexia 41 7 41 8 21 2 Arthralgia 25 5 34 6 40 1 Headache 27 5 32 2 36 0.6 Abdominal pain 30 6 33 4 32 1 Weight increased 5 1 17 5 32 7 Cough 14 0.8 27 0.9 20 0 Dyspepsia 12 0 22 0 27 0 Myalgia 9 0 24 2 27 0.2 Nasopharyngitis 10 0 17 0 22 0.2 Asthenia 18 5 21 5 15 0.2 Dyspnea 15 4 21 7 12 0.9 Upper respiratory tract infection 3 0 12 0.4 19 0 Anorexia 14 2 17 2 7 0 Night sweats 13 0.8 17 1 14 0.2 Constipation 16 2 16 0.9 9 0.4 Dizziness 12 0.4 13 0 16 0.2 Pharyngitis 10 0 12 0 15 0 Insomnia 10 0 14 0 14 0.2 Pruritus 8 1 14 0.9 14 0.8 Hypokalemia 13 4 9 2 6 0.8 Pneumonia 13 7 10 7 4 1 Anxiety 8 0.8 12 0 8 0.4 Liver toxicity 10 5 12 6 6 3 Rigors 10 0 12 0.4 10 0 Chest pain 7 2 10 0.4 11 0.8 Influenza 0.8 0.4 6 0 11 0.2 Sinusitis 4 0.4 11 0.4 9 0.4 Abbreviations:
• CML, chronic myeloid leukemia; IFN, Interferon-alpha. (1) All adverse reactions occurring in greater than or equal to 10% of patients are listed regardless of suspected relationship to treatment. (2) Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified. Hematologic and Biochemistry Laboratory Abnormalities Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses greater than or equal to 750 mg (Phase 1 study). The occurrence of cytopenias in CML patients was also dependent on the stage of the disease. In patients with newly diagnosed CML, cytopenias were less frequent than in the other CML patients (see Tables 5, 6, and 7). The frequency of Grade 3 or 4 neutropenia and thrombocytopenia was between 2- and 3-fold higher in blast crisis and accelerated phase compared to chronic phase (see Tables 4 and 5). The median duration of the neutropenic and thrombocytopenic episodes varied from 2 to 3 weeks, and from 2 to 4 weeks, respectively. These reactions can usually be managed with either a reduction of the dose or an interruption of treatment with imatinib mesylate, but may require permanent discontinuation of treatment. Table 5:
• Laboratory Abnormalities in Newly Diagnosed CML Clinical Trial (Imatinib Mesylate Versus IFN+Ara-C) I matinib Mesylate N = 551 % IFN+Ara−C N = 533 % CTC Grades Grade 3 Grade 4 Grade 3 Grade 4 Hematology parameters* - Neutropenia* 13.1 3.6 20.8 4.5 - Thrombocytopenia* 8.5 0.4 15.9 0.6 - Anemia 3.3 1.1 4.1 0.2 Biochemistry parameters - Elevated creatinine 0 0 0.4 0 - Elevated bilirubin 0.9 0.2 0.2 0 - Elevated alkaline phosphatase 0.2 0 0.8 0 - Elevated SGOT (AST)/SGPT (ALT) 4.7 0.5 7.1 0.4 Abbreviations:
• CML, chronic myeloid leukemia; IFN, Interferon-alpha; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT). *p less than 0.001 (difference in Grade 3 plus 4 abnormalities between the two treatment groups). Table 6:
• Percent Incidence of Clinically Relevant Grade 3/4* Laboratory Abnormalities in the Newly Diagnosed CML Clinical Trial (Imatinib Mesylate Versus Nilotinib) I matinib Mesylate 400 mg once daily N = 280 (%) Nilotinib 300 mg twice daily N = 279 (%) Hematologic parameters Thrombocytopenia 9 10 Neutropenia 22 12 Anemia 6 4 Biochemistry parameters Elevated lipase 4 9 Hyperglycemia < 1 7 Hypophosphatemia 10 8 Elevated bilirubin (total) < 1 4 Elevated SGPT (ALT) 3 4 Hyperkalemia 1 2 Hyponatremia < 1 1 Hypokalemia 2 < 1 Elevated SGOT (AST) 1 1 Decreased albumin < 1 0 Hypocalcemia < 1 < 1 Elevated alkaline phosphatase < 1 0 Elevated creatinine < 1 0 Abbreviations:
• CML, chronic myeloid leukemia; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT). *NCI Common Terminology Criteria for Adverse Events, version 3.0. Table 7:
• Laboratory Abnormalities in Other CML Clinical Trials Myeloid blast crisis (n = 260) 600 mg n = 223 400 mg n = 37 % Accelerated phase (n = 235) 600 mg n = 158 400 mg n = 77 % Chronic phase, IFN failure (n = 532) 400 mg % CTC Grades (1) Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 Hematology parameters -Neutropenia 16 48 23 36 27 9 -Thrombocytopenia 30 33 31 13 21 < 1 -Anemia 42 11 34 7 6 1 Biochemistry parameters - Elevated creatinine 1.5 0 1.3 0 0.2 0 - Elevated bilirubin 3.8 0 2.1 0 0.6 0 - Elevated alkaline phosphatase 4.6 0 5.5 0.4 0.2 0 - Elevated SGOT (AST) 1.9 0 3.0 0 2.3 0 - Elevated SGPT (ALT) 2.3 0.4 4.3 0 2.1 0 Abbreviations:
• CML, chronic myeloid leukemia; CTC, common terminology criteria; IFN, Interferon-alpha; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT). (1) CTC Grades:
• neutropenia (Grade 3 greater than or equal to 0.5 to 1.0 x 10 9 /L, Grade 4 less than 0.5 x 10 9 /L), thrombocytopenia (Grade 3 greater than or equal to 10 to 50 x 10 9 /L, Grade 4 less than 10 x 10 9 /L), anemia (hemoglobin greater than or equal to 65 to 80 g/L, Grade 4 less than 65 g/L), elevated creatinine (Grade 3 greater than 3 to 6 x upper limit normal range [ULN], Grade 4 greater than 6 x ULN), elevated bilirubin (Grade 3 greater than 3 to 10 x ULN, Grade 4 greater than 10 x ULN), elevated alkaline phosphatase (Grade 3 greater than 5 to 20 x ULN, Grade 4 greater than 20 x ULN), elevated SGOT or SGPT (Grade 3 greater than 5 to 20 x ULN, Grade 4 greater than 20 x ULN). Hepatotoxicity Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 6 and 7) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1.0% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure. In the Phase 2 GIST trial, Grade 3 or 4 SGPT (ALT) elevations were observed in 6.8% of patients and Grade 3 or 4 SGOT (AST) elevations were observed in 4.8% of patients. Bilirubin elevation was observed in 2.7% of patients. Adverse Reactions in Pediatric Population Single-Agent Therapy The overall safety profile of pediatric patients treated with imatinib mesylate in 93 children studied was similar to that found in studies with adult patients, except that musculoskeletal pain was less frequent (20.5%) and peripheral edema was not reported. Nausea and vomiting were the most commonly reported individual adverse reactions with an incidence similar to that seen in adult patients. Most patients experienced adverse reactions at some time during the study. The incidence of Grade 3/4 events across all types of adverse reactions was 75%; the events with the highest Grade 3/4 incidence in CML pediatric patients were mainly related to myelosuppression. In Combination with Multi-Agent Chemotherapy Pediatric and young adult patients with very high risk ALL, defined as those with an expected 5 year event-free survival (EFS) less than 45%, were enrolled after induction therapy on a multicenter, non-randomized cooperative group pilot protocol. The study population included patients with a median age of 10 years (1 to 21 years), 61% of whom were male, 75% were white, 7% were black, and 6% were Asian/Pacific Islander. Patients with Ph+ ALL (n = 92) were assigned to receive imatinib mesylate and treated in 5 successive cohorts. Imatinib mesylate exposure was systematically increased in successive cohorts by earlier introduction and more prolonged duration. The safety of imatinib mesylate given in combination with intensive chemotherapy was evaluated by comparing the incidence of Grade 3 and 4 adverse events, neutropenia (less than 750/mcL) and thrombocytopenia (less than 75,000/mcL) in the 92 patients with Ph+ ALL compared to 65 patients with Ph- ALL enrolled on the trial who did not receive imatinib mesylate. The safety was also evaluated comparing the incidence of adverse events in cycles of therapy administered with or without imatinib mesylate. The protocol included up to 18 cycles of therapy. Patients were exposed to a cumulative total of 1425 cycles of therapy, 778 with imatinib mesylate, and 647 without imatinib mesylate. The adverse events that were reported with a 5% or greater incidence in patients with Ph+ ALL compared to Ph- ALL or with a 1% or greater incidence in cycles of therapy that included imatinib mesylate are presented in Table 8. Table 8:
• Adverse Reactions Reported More Frequently in Patients Treated With Study Drug (Greater Than 5%) or in Cycles With Study Drug (Greater Than 1%) Adverse event Grade 3 and 4 adverse events Per patient incidence Ph + ALL with imatinib mesylate tablets N = 92 n (%) Per patient incidence Ph - ALL no imatinib mesylate tablets N = 65 n (%) Per patient per cycle incidence with imatinib mesylate tablets* N = 778 n (%) Per patient per cycle incidence no imatinib mesylate tablets** N = 647 n (%) Nausea and/or vomiting 15 (16) 6 (9) 28 (4) 8 (1) Hypokalemia 31 (34) 16 (25) 72 (9) 32 (5) Pneumonitis 7 (8) 1 (1) 7 (1) 1 (< 1) Pleural effusion 6 (7) 0 6 (1) 0 Abdominal pain 8 (9) 2 (3) 9 (1) 3 (< 1) Anorexia 10 (11) 3 (5) 19 (2) 4 (1) Hemorrhage 11 (12) 4 (6) 17 (2) 8 (1) Hypoxia 8 (9) 2 (3) 12 (2) 2 (< 1) Myalgia 5 (5) 0 4 (1) 1 (< 1) Stomatitis 15 (16) 8 (12) 22 (3) 14 (2) Diarrhea 8 (9) 3 (5) 12 (2) 3 (< 1) Rash/Skin disorder 4 (4) 0 5 (1) 0 Infection 49 (53) 32 (49) 131 (17) 92 (14) Hepatic (transaminase and/or bilirubin) 52 (57) 38 (58) 172 (22) 113 (17) Hypotension 10 (11) 5 (8) 16 (2) 6 (1) Myelosuppression Neutropenia (< 750/mcL) 92 (100) 63 (97) 556 (71) 218 (34) Thrombocytopenia (< 75,000/mcL) 90 (92) 63 (97) 431 (55) 329 (51) Abbreviations:
• Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia; Ph-ALL, Philadelphia chromosome negative acute lymphoblastic leukemia. *Defined as the frequency of adverse events (AEs) per patient per treatment cycles that included imatinib mesylate (includes patients with Ph+ ALL that received cycles with imatinib mesylate). **Defined as the frequency of AEs per patient per treatment cycles that did not include imatinib mesylate (includes patients with Ph+ ALL that received cycles without imatinib mesylate as well as all patients with Ph-ALL who did not receive imatinib mesylate in any treatment cycle). Adverse Reactions in Other Subpopulations In older patients (greater than or equal to 65 years old), with the exception of edema, where it was more frequent, there was no evidence of an increase in the incidence or severity of adverse reactions. In women there was an increase in the frequency of neutropenia, as well as Grade 1/2 superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue. No differences were seen that were related to race but the subsets were too small for proper evaluation. Acute Lymphoblastic Leukemia The adverse reactions were similar for Ph+ ALL as for Ph+ CML. The most frequently reported drug-related adverse reactions reported in the Ph+ ALL studies were mild nausea and vomiting, diarrhea, myalgia, muscle cramps, and rash. Superficial edema was a common finding in all studies and were described primarily as periorbital or lower limb edemas. These edemas were reported as Grade 3/4 events in 6.3% of the patients and may be managed with diuretics, other supportive measures, or in some patients by reducing the dose of imatinib mesylate. Myelodysplastic/Myeloproliferative Diseases Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with imatinib mesylate for MDS/MPD in the Phase 2 study, are shown in Table 9. Table 9:
• Adverse Reactions Regardless of Relationship to Study Drug Reported (More Than One Patient) in MPD Patients in the Phase 2 Study (Greater Than or Equal to 10% All Patients) All Grades Preferred term N = 7 n (%) Nausea 4 (57.1) Diarrhea 3 (42.9) Anemia 2 (28.6) Fatigue 2 (28.6) Muscle cramp 3 (42.9) Arthralgia 2 (28.6) Periorbital edema 2 (28.6) Abbreviation:
• MPD, myeloproliferative disease. Aggressive Systemic Mastocytosis All aggressive systemic mastocytosis (ASM) patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were diarrhea, nausea, ascites, muscle cramps, dyspnea, fatigue, peripheral edema, anemia, pruritus, rash, and lower respiratory tract infection. None of the 5 patients in the Phase 2 study with ASM discontinued imatinib mesylate due to drug-related adverse reactions or abnormal laboratory values. Hypereosinophilic Syndrome and Chronic Eosinophilic Leukemia The safety profile in the HES/CEL patient population does not appear to be different from the safety profile of imatinib mesylate observed in other hematologic malignancy populations, such as Ph+ CML. All patients experienced at least one adverse reaction, the most common being GI, cutaneous and musculoskeletal disorders. Hematological abnormalities were also frequent, with instances of CTC Grade 3 leukopenia, neutropenia, lymphopenia, and anemia. Dermatofibrosarcoma Protuberans Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the 12 patients treated with imatinib mesylate for DFSP in the Phase 2 study are shown in Table 10. Table 10:
• Adverse Reactions Regardless of Relationship to Study Drug Reported in DFSP Patients in the Phase 2 Study (Greater Than or Equal to 10% All Patients) All Grades Preferred term N = 12 n (%) Nausea 5 (41.7) Diarrhea 3 (25.0) Vomiting 3 (25.0) Periorbital edema 4 (33.3) Face edema 2 (16.7) Rash 3 (25.0) Fatigue 5 (41.7) Peripheral edema 4 (33.3) Pyrexia 2 (16.7) Eye edema 4 (33.3) Lacrimation increased 3 (25.0) Dyspnea exertional 2 (16.7) Anemia 3 (25.0) Rhinitis 2 (16.7) Anorexia 2 (16.7) Abbreviation:
• DFSP, dermatofibrosarcoma protuberans. Clinically relevant or severe laboratory abnormalities in the 12 patients treated with imatinib mesylate for DFSP in the Phase 2 study are presented in Table 11. Table 11:
• Laboratory Abnormalities Reported in DFSP Patients in the Phase 2 Study N = 12 CTC Grades (1) Grade 3 % Grade 4 % Hematology parameters -Anemia 17 0 -Thrombocytopenia 17 0 -Neutropenia 0 8 Biochemistry parameters -Elevated creatinine 0 8 Abbreviation:
• CTC, common terminology criteria. (1) CTC Grades:
• neutropenia (Grade 3 greater than or equal to 0.5 to 1.0 x 10 9 /L, Grade 4 less than 0.5 x 10 9 /L), thrombocytopenia (Grade 3 greater than or equal to 10 to 50 x 10 9 /L, Grade 4 less than 10 x 10 9 /L), anemia (Grade 3 greater than or equal to 65 to 80 g/L, Grade 4 less than 65 g/L), elevated creatinine (Grade 3 greater than 3 to 6 x upper limit normal range [ULN], Grade 4 greater than 6 x ULN). Gastrointestinal Stromal Tumors Unresectable and/or Malignant Metastatic GIST In the Phase 3 trials, the majority of imatinib mesylate -treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were edema, fatigue, nausea, abdominal pain, diarrhea, rash, vomiting, myalgia, anemia, and anorexia. Drug was discontinued for adverse reactions in a total of 89 patients (5.4%). Superficial edema, most frequently periorbital or lower extremity edema was managed with diuretics, other supportive measures, or by reducing the dose of imatinib mesylate [see Dosage and Administration (2.13) ] . Severe (CTC Grade 3/4) edema was observed in 182 patients (11.1%). Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with imatinib mesylate are shown in Table 12. Overall the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema, which was reported more frequently in the 800 mg group. Table 12:
• Number (%) of Patients With Adverse Reactions Regardless of Relationship to Study Drug Where Frequency is Greater Than or Equal to 10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials Imatinib 400 mg N = 818 Imatinib 800 mg N = 822 Reported or specified term All Grades % Grades 3/4/5 % All Grades % Grades 3/4/5 % Edema 76.7 9.0 86.1 13.1 Fatigue/lethargy, malaise, asthenia 69.3 11.7 74.9 12.2 Nausea 58.1 9.0 64.5 7.8 Abdominal pain/cramping 57.2 13.8 55.2 11.8 Diarrhea 56.2 8.1 58.2 8.6 Rash/desquamation 38.1 7.6 49.8 8.9 Vomiting 37.4 9.2 40.6 7.5 Myalgia 32.2 5.6 30.2 3.8 Anemia 32.0 4.9 34.8 6.4 Anorexia 31.1 6.6 35.8 4.7 Other GI toxicity 25.2 8.1 28.1 6.6 Headache 22.0 5.7 19.7 3.6 Other pain (excluding tumor related pain) 20.4 5.9 20.8 5.0 Other dermatology/skin toxicity 17.6 5.9 20.1 5.7 Leukopenia 17.0 0.7 19.6 1.6 Other constitutional symptoms 16.7 6.4 15.2 4.4 Cough 16.1 4.5 14.5 3.2 Infection (without neutropenia) 15.5 6.6 16.5 5.6 Pruritus 15.4 5.4 18.9 4.3 Other neurological toxicity 15.0 6.4 15.2 4.9 Constipation 14.8 5.1 14.4 4.1 Other renal/genitourinary toxicity 14.2 6.5 13.6 5.2 Arthralgia (joint pain) 13.6 4.8 12.3 3.0 Dyspnea (shortness of breath) 13.6 6.8 14.2 5.6 Fever in absence of neutropenia (ANC < 1.0 x 10 9 /L) 13.2 4.9 12.9 3.4 Sweating 12.7 4.6 8.5 2.8 Other hemorrhage 12.3 6.7 13.3 6.1 Weight gain 12.0 1.0 10.6 0.6 Alopecia 11.9 4.3 14.8 3.2 Dyspepsia/heartburn 11.5 0.6 10.9 0.5 Neutropenia/granulocytopenia 11.5 3.1 16.1 4.1 Rigors/chills 11.0 4.6 10.2 3.0 Dizziness/lightheadedness 11.0 4.8 10.0 2.8 Creatinine increase 10.8 0.4 10.1 0.6 Flatulence 10.0 0.2 10.1 0.1 Stomatitis/pharyngitis (oral/pharyngeal mucositis) 9.2 5.4 10.0 4.3 Lymphopenia 6.0 0.7 10.1 1.9 Abbreviations:
• ANC, absolute neutrophil count; GI, gastrointestinal; GIST, gastrointestinal stromal tumors. Clinically relevant or severe abnormalities of routine hematologic or biochemistry laboratory values were not reported or evaluated in the Phase 3 GIST trials. Severe abnormal laboratory values reported in the Phase 2 GIST trial are presented in Table 13. Table 13:
• Laboratory Abnormalities in the Phase 2 Unresectable and/or Malignant Metastatic GIST Trial 400 mg (n = 73) % 600 mg (n = 74) % CTC Grades 1 Grade 3 Grade 4 Grade 3 Grade 4 Hematology parameters Anemia 3 0 8 1 Thrombocytopenia 0 0 1 0 Neutropenia 7 3 8 3 Biochemistry parameters Elevated creatinine 0 0 3 0 Reduced albumin 3 0 4 0 Elevated bilirubin 1 0 1 3 Elevated alkaline phosphatase 0 0 3 0 Elevated SGOT (AST) 4 0 3 3 Elevated SGPT (ALT) 6 0 7 1 Abbreviations:
• CTC, common terminology criteria; GIST, gastrointestinal stromal tumors; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT). 1 CTC Grades:
• neutropenia (Grade 3 greater than or equal to 0.5–1.0 x 10 9 /L, Grade 4 less than 0.5 x 10 9 /L), thrombocytopenia (Grade 3 greater than or equal to 10–50 x 10 9 /L, Grade 4 less than 10 x 10 9 /L), anemia (Grade 3 greater than or equal to 65–80 g/L, Grade 4 less than 65 g/L), elevated creatinine (Grade 3 greater than 3–6 x upper limit normal range [ULN], Grade 4 greater than 6 x ULN), elevated bilirubin (Grade 3 greater than 3–10 x ULN, Grade 4 greater than 10 x ULN), elevated alkaline phosphatase, SGOT or SGPT (Grade 3 greater than 5–20 x ULN, Grade 4 greater than 20 x ULN), albumin (Grade 3 less than 20 g/L). Adjuvant Treatment of GIST In Study 1, the majority of both imatinib mesylate and placebo treated patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain. No new adverse reactions were reported in the adjuvant GIST treatment setting that had not been previously reported in other patient populations, including patients with unresectable and/or malignant metastatic GIST. Drug was discontinued for adverse reactions in 57 patients (17%) and 11 patients (3%) of the imatinib mesylate and placebo-treated patients, respectively. Edema, GI disturbances (nausea, vomiting, abdominal distention, and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation. In Study 2, discontinuation of therapy due to adverse reactions occurred in 15 patients (8%) and 27 patients (14%) of the imatinib mesylate 12-month, and 36-month treatment arms, respectively. As in previous trials the most common adverse reactions were diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain. Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with imatinib mesylate are shown in Table 14 (Study 1) and Table 15 (Study 2). There were no deaths attributable to imatinib mesylate treatment in either trial. Table 14:
• Adverse Reactions Regardless of Relationship to Study Drug Reported in Study 1 (Greater Than or Equal to 5% of Imatinib Mesylate-Treated Patients) (1) All CTC Grades CTC Grade 3* and Above Preferred term I matinib Mesylate (n = 337) % Placebo (n = 345) % I matinib Mesylate (n = 337) % Placebo (n = 345) % Diarrhea 59.3 29.3 3.0 1.4 Fatigue 57.0 40.9 2.1 1.2 Nausea 53.1 27.8 2.4 1.2 Periorbital edema 47.2 14.5 1.2 0 Hemoglobin decreased 46.9 27.0 0.6 0 Peripheral edema 26.7 14.8 0.3 0 Rash (Exfoliative) 26.1 12.8 2.7 0 Vomiting 25.5 13.9 2.4 0.6 Abdominal pain 21.1 22.3 3.0 1.4 Headache 19.3 20.3 0.6 0 Dyspepsia 17.2 13.0 0.9 0 Anorexia 16.9 8.7 0.3 0 Weight increased 16.9 11.6 0.3 0 Liver enzymes (ALT) increased 16.6 13.0 2.7 0 Muscle spasms 16.3 3.3 0 0 Neutrophil count decreased 16.0 6.1 3.3 0.9 Arthralgia 15.1 14.5 0 0.3 White blood cell count decreased 14.5 4.3 0.6 0.3 Constipation 12.8 17.7 0 0.3 Dizziness 12.5 10.7 0 0.3 Liver enzymes (AST) increased 12.2 7.5 2.1 0 Myalgia 12.2 11.6 0 0.3 Blood creatinine increased 11.6 5.8 0 0.3 Cough 11.0 11.3 0 0 Pruritus 11.0 7.8 0.9 0 Weight decreased 10.1 5.2 0 0 Hyperglycemia 9.8 11.3 0.6 1.7 Insomnia 9.8 7.2 0.9 0 Lacrimation increased 9.8 3.8 0 0 Alopecia 9.5 6.7 0 0 Flatulence 8.9 9.6 0 0 Rash 8.9 5.2 0.9 0 Abdominal distension 7.4 6.4 0.3 0.3 Back pain 7.4 8.1 0.6 0 Pain in extremity 7.4 7.2 0.3 0 Hypokalemia 7.1 2.0 0.9 0.6 Depression 6.8 6.4 0.9 0.6 Facial edema 6.8 1.2 0.3 0 Blood alkaline phosphatase increased 6.5 7.5 0 0 Dry skin 6.5 5.2 0 0 Dysgeusia 6.5 2.9 0 0 Abdominal pain upper 6.2 6.4 0.3 0 Neuropathy peripheral 5.9 6.4 0 0 Hypocalcemia 5.6 1.7 0.3 0 Leukopenia 5.0 2.6 0.3 0 Platelet count decreased 5.0 3.5 0 0 Stomatitis 5.0 1.7 0.6 0 Upper respiratory tract infection 5.0 3.5 0 0 Vision blurred 5.0 2.3 0 0 Abbreviations:
• CTC, common terminology criteria; GIST, gastrointestinal stromal tumors; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT). *NCI Common Terminology Criteria for Adverse Events, version 3.0. (1) All adverse reactions occurring in greater than or equal to 5% of patients are listed regardless of suspected relationship to treatment. A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category. Table 15:
• Adverse Reactions Regardless of Relationship to Study Drug by Preferred Term All Grades and 3/4 Grades (Greater Than or Equal to 5% of Imatinib Mesylate-Treated Patients) Study 2 (1) Preferred term All CTC Grades CTC Grades 3 and above I matinib Mesylate 12 Months (N = 194) % I matinib Mesylate 36 Months (N = 198) % I matinib Mesylate 12 Months (N = 194) % I matinib Mesylate 36 Months (N = 198) % Patients with at least one AE 99.0 100.0 20.1 32.8 Hemoglobin decreased 72.2 80.3 0.5 0.5 Periorbital edema 59.3 74.2 0.5 1.0 Blood lactate dehydrogenase increased 43.3 60.1 0 0 Diarrhea 43.8 54.0 0.5 2.0 Nausea 44.8 51.0 1.5 0.5 Muscle spasms 30.9 49.0 0.5 1.0 Fatigue 48.5 48.5 1.0 0.5 White blood cell count decreased 34.5 47.0 2.1 3.0 Pain 25.8 45.5 1.0 3.0 Blood creatinine increased 30.4 44.4 0 0 Peripheral edema 33.0 40.9 0.5 1.0 Dermatitis 29.4 38.9 2.1 1.5 Aspartate aminotransferase increased 30.9 37.9 1.5 3.0 Alanine aminotransferase increased 28.9 34.3 2.1 3.0 Neutrophil count decreased 24.2 33.3 4.6 5.1 Hypoproteinemia 23.7 31.8 0 0 Infection 13.9 27.8 1.5 2.5 Weight increased 13.4 26.8 0 0.5 Pruritus 12.9 25.8 0 0 Flatulence 19.1 24.7 1.0 0.5 Vomiting 10.8 22.2 0.5 1.0 Dyspepsia 17.5 21.7 0.5 1.0 Hypoalbuminemia 11.9 21.2 0 0 Edema 10.8 19.7 0 0.5 Abdominal distension 11.9 19.2 0.5 0 Headache 8.2 18.2 0 0 Lacrimation increased 18.0 17.7 0 0 Arthralgia 8.8 17.2 0 1.0 Blood alkaline phosphatase increased 10.8 16.7 0 0.5 Dyspnea 6.2 16.2 0.5 1.5 Myalgia 9.3 15.2 0 1.0 Platelet count decreased 11.3 14.1 0 0 Blood bilirubin increased 11.3 13.1 0 0 Dysgeusia 9.3 12.6 0 0 Paresthesia 5.2 12.1 0 0.5 Vision blurred 10.8 11.1 1.0 0.5 Alopecia 11.3 10.6 0 0 Decreased appetite 9.8 10.1 0 0 Constipation 8.8 9.6 0 0 Pyrexia 6.2 9.6 0 0 Depression 3.1 8.1 0 0 Abdominal pain 2.6 7.6 0 0 Conjunctivitis 5.2 7.6 0 0 Photosensitivity reaction 3.6 7.1 0 0 Dizziness 4.6 6.6 0.5 0 Hemorrhage 3.1 6.6 0 0 Dry skin 6.7 6.1 0.5 0 Nasopharyngitis 1.0 6.1 0 0.5 Palpitations 5.2 5.1 0 0 Abbreviations:
• AE, adverse event; CTC, common terminology criteria. (1) All adverse reactions occurring in greater than or equal to 5% of patients are listed regardless of suspected relationship to treatment. A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category. Adverse Reactions from Multiple Clinical Trials Cardiac Disorders:
• Estimated 1% to 10%:
• palpitations, pericardial effusion Estimated 0.1% to 1%:
• congestive cardiac failure, tachycardia, pulmonary edema Estimated 0.01% to 0.1%:
• arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris Vascular Disorders:
• Estimated 1% to 10%:
• flushing, hemorrhage Estimated 0.1% to 1%:
• hypertension, hypotension, peripheral coldness, Raynaud’s phenomenon, hematoma, subdural hematoma Investigations:
• Estimated 1% to 10%:
• blood creatine phosphokinase (CPK) increased, blood amylase increased Estimated 0.1% to 1%:
• blood lactate dehydrogenase (LDH) increased Skin and Subcutaneous Tissue Disorders:
• Estimated 1% to 10%:
• dry skin, alopecia, face edema, erythema, photosensitivity reaction, nail disorder, purpura Estimated 0.1% to 1%:
• exfoliative dermatitis, bullous eruption, psoriasis, rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, skin hyperpigmentation, onychoclasis, folliculitis, petechiae, erythema multiforme, panniculitis (including erythema nodosum) Estimated 0.01% to 0.1%:
• vesicular rash, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discoloration, angioneurotic edema, leucocytoclastic vasculitis Gastrointestinal Disorders:
• Estimated 1% to 10%:
• abdominal distention, gastroesophageal reflux, dry mouth, gastritis Estimated 0.1% to 1%:
• gastric ulcer, stomatitis, mouth ulceration, eructation, melena, esophagitis, ascites, hematemesis, chelitis, dysphagia, pancreatitis Estimated 0.01% to 0.1%:
• colitis, ileus, inflammatory bowel disease General Disorders and Administration-Site Conditions:
• Estimated 1% to 10%:
• weakness, anasarca, chills Estimated 0.1% to 1%:
• malaise Blood and Lymphatic System Disorders:
• Estimated 1% to 10%:
• pancytopenia, febrile neutropenia, lymphopenia, eosinophilia Estimated 0.1% to 1%:
• thrombocythemia, bone marrow depression, lymphadenopathy Estimated 0.01% to 0.1%:
• hemolytic anemia, aplastic anemia Hepatobiliary Disorders:
• Estimated 0.1% to 1%:
• hepatitis, jaundice Estimated 0.01% to 0.1%:
• hepatic failure and hepatic necrosis 1 Immune System Disorders:
• Estimated 0.01% to 0.1%:
• angioedema Infections and Infestations:
• Estimated 0.1% to 1%:
• sepsis, herpes simplex, herpes zoster, cellulitis, urinary tract infection, gastroenteritis Estimated 0.01% to 0.1%:
• fungal infection Metabolism and Nutrition Disorders:
• Estimated 1% to 10%:
• weight decreased, decreased appetite Estimated 0.1% to 1%:
• dehydration, gout, increased appetite, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia, hyperkalemia, hypomagnesemia Musculoskeletal and Connective Tissue Disorders:
• Estimated 1% to 10%:
• joint swelling Estimated 0.1% to 1%:
• joint and muscle stiffness, muscular weakness, arthritis Nervous System/Psychiatric Disorders:
• Estimated 1% to 10%:
• paresthesia, hypesthesia Estimated 0.1% to 1%:
• syncope, peripheral neuropathy, somnolence, migraine, memory impairment, libido decreased, sciatica, restless leg syndrome, tremor Estimated 0.01% to 0.1%:
• increased intracranial pressure 1 , confusional state, convulsions, optic neuritis Renal and Urinary Disorders:
• Estimated 0.1% to 1%:
• renal failure acute, urinary frequency increased, hematuria, renal pain Reproductive System and Breast Disorders:
• Estimated 0.1% to 1%:
• breast enlargement, menorrhagia, sexual dysfunction, gynecomastia, erectile dysfunction, menstruation irregular, nipple pain, scrotal edema Respiratory, Thoracic and Mediastinal Disorders:
• Estimated 1% to 10%:
• epistaxis Estimated 0.1% to 1%:
• pleural effusion Estimated 0.01% to 0.1%:
• interstitial pneumonitis, pulmonary fibrosis, pleuritic pain, pulmonary hypertension, pulmonary hemorrhage Endocrine Disorders:
• Estimated 0.1% to 1%:
• hypothyroidism, hyperthyroidism Eye, Ear, and Labyrinth Disorders:
• Estimated 1% to 10%:
• conjunctivitis, vision blurred, orbital edema, conjunctival hemorrhage, dry eye Estimated 0.1% to 1%:
• vertigo, tinnitus, eye irritation, eye pain, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema, hearing loss, cataract Estimated 0.01% to 0.1%:
• papilledema 1 , glaucoma 1 Including some fatalities. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of imatinib mesylate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders:
• thrombotic microangiopathy Cardiac Disorders:
• pericarditis, cardiac tamponade 1 Eye Disorders:
• vitreous hemorrhage Gastrointestinal Disorders:
• ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, GI perforation 1 [see Warnings and Precautions (5.6) ], diverticulitis, gastric antral vascular ectasia Infections:
• hepatitis B virus reactivation 1 Musculoskeletal and Connective Tissue Disorders:
• osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children, musculoskeletal pain upon treatment discontinuation (including myalgia, pain in extremity, arthalgia, bone pain) Nervous System Disorders:
• cerebral edema 1 Reproduction Disorders:
• hemorrhagic corpus luteum/hemorrhagic ovarian cyst Respiratory, Thoracic and Mediastinal Disorders:
• acute respiratory failure 1 , interstitial lung disease Skin and Subcutaneous Tissue Disorders:
• lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), pseudoporphyria, pemphigus Vascular Disorders:
• thrombosis/embolism, anaphylactic shock 1 Including some fatalities.

Quoted from the official label, section “Adverse Reactions”.

What to discuss with your doctor

• Dosing and Administration Advise patients to take imatinib mesylate tablets exactly as prescribed, not to change their dose or to stop taking imatinib mesylate tablets unless they are told to do so by their doctor.
• If the patient missed a dose of imatinib mesylate tablets, the patient should take the next scheduled dose at its regular time.
• The patient should not take two doses at the same time.
• Advise patients to take imatinib mesylate tablets with a meal and a large glass of water [see Dosage and Administration (2.1) ].
• Fluid Retention and Edema Inform patients of the possibility of developing edema and fluid retention.
• Advise patients to contact their health care provider if unexpected rapid weight gain occurs [see Warnings and Precautions (5.1) ].
• Hepatotoxicity Inform patients of the possibility of developing liver function abnormalities and serious hepatic toxicity.
• Advise patients to immediately contact their health care provider if signs of liver failure occur, including jaundice, anorexia, bleeding, or bruising [see Warnings and Precautions (5.4) ].
• Pregnancy and Breastfeeding Advise patients to inform their doctor if they are or think they may be pregnant.
• Advise women of reproductive potential to
• avoid becoming pregnant while taking imatinib mesylate tablets.
• Female patients of reproductive potential taking imatinib mesylate tablets should use highly effective contraception during treatment and for fourteen days after stopping treatment with imatinib mesylate tablets [see Use in Specific Populations (8.3) ] .
• Avoid breastfeeding during treatment and for 1 month after the last dose [see Use in Specific Populations (8.2)] .
• Drug Interactions Imatinib mesylate tablets and certain other medicines, such as warfarin, erythromycin, and phenytoin, including over-the-counter medications, such as herbal products, can interact with each other.
• Advise patients to tell their doctor if they are taking or plan to take iron supplements.
• Avoid grapefruit juice and other foods known to inhibit CYP3A4 while taking imatinib mesylate tablets [see Drug Interactions (7)] .
• Pediatric Advise patients that growth retardation has been reported in children and pre-adolescents receiving imatinib mesylate tablets.
• The long term effects of prolonged treatment with imatinib mesylate tablets on growth in children are unknown.
• Therefore, closely monitor growth in
• children under imatinib mesylate tablets treatment [see Warnings and Precautions (5.11)] .
• Driving and Using Machines Advise patients that they may experience side effects, such as dizziness, blurred vision, or somnolence during treatment with imatinib mesylate tablets.
• Therefore, caution patients about driving a car or operating machinery [see Warnings and Precautions (5.13) ].
• Manufactured for:
• Camber Pharmaceuticals, Inc., Piscataway, NJ 08854 Manufactured by:
• HETERO TM Hetero Labs Limited Jeedimetla, Hyderabad - 500 055, India.
• (or) Manufactured by:
• HETERO TM Hetero Labs Limited, Unit V, Polepally, Jadcherla, Mahabubnagar - 509 301, India.
• Revised: 07/2025 imatinibcamberlogo

Quoted from the official label, section “Patient Counseling Information”.

Strengths and forms

• FORMS AND STRENGTHS Imatinib mesylate tablets, 100 mg are white to off white colored, round, biconvex scored, bevel edged, film coated tablets, debossed with 'H' on one side and '7' on the other side with score line.
• Imatinib mesylate tablets, 400 mg are white to off white colored, oval, biconvex scored, bevel edged, film coated tablets, debossed with 'H' on one side and '4' on the other side with score line.
• Tablets (scored): 100 mg and 400 mg (3)

Quoted from the official label, section “Dosage Forms & Strengths”.

What it looks like and how it is packed

• Imatinib mesylate tablets are supplied as 100 mg and 400 mg tablets for oral administration.
• Each 100 mg tablet contains 119.50 mg of imatinib mesylate equivalent to 100 mg of imatinib free base.
• Each 400 mg tablet contains 478 mg of imatinib mesylate equivalent to 400 mg of imatinib free base.
• Imatinib mesylate tablets, 100 mg are white to off white colored, round, biconvex scored, bevel edged, film coated tablets, debossed with 'H' on one side and '7' on the other side with score line.
• Bottle of 90 tablets NDC 31722-296-90 Imatinib mesylate tablets, 400 mg are white to off white colored, oval, biconvex scored, bevel edged, film coated tablets, debossed with 'H' on one side and '4' on the other side with score line.
• Bottle of 30 tablets NDC 31722-297-30 Storage and Handling
• Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
• Protect from moisture.
• Dispense in a tight container, USP.
• Do not crush imatinib mesylate tablets.
• Avoid direct contact of crushed tablets with the skin or mucous membranes.
• If such contact occurs, wash thoroughly as outlined in the references.
• Avoid exposure to crushed tablets.

Quoted from the official label, section “How Supplied”.

What is in it

• Imatinib is a small molecule kinase inhibitor. Imatinib mesylate film-coated tablets are supplied as 100 mg and 400 mg tablets for oral administration. Each 100 mg tablet contains 119.50 mg of imatinib mesylate equivalent to 100 mg of imatinib free base. Each 400 mg tablet contains 478 mg of imatinib mesylate equivalent to 400 mg of imatinib free base. Imatinib mesylate is designated chemically as 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino]-phenyl] benzamide methanesulfonate and its structural formula is:
• Imatinib mesylate is a white to off-white colored powder. Its molecular formula is C 29 H 31 N 7 O
• CH 3 SO 3 H and its molecular weight is 589.7 g/mol. Imatinib mesylate is freely soluble in water. Inactive Ingredients:
• colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate and microcrystalline cellulose. Tablet coating:
• hypromellose, polyethylene glycol, talc and titanium dioxide. imatinibstructure

Quoted from the official label, section “Description”.

Ingredients people check for

Lactose, gluten, dyes, sugars and other ingredients that matter with an allergy, intolerance or diet — as this product’s FDA label lists them.

Same active substance, strength and form in other countries

Matched on active substance, strength and kind of form only. This is not a statement that the products are equivalent or interchangeable: other ingredients, release and approved uses can differ — ask a pharmacist before swapping.

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Details

Source: NDC Directory · 2026-09-13 · not reviewed by a clinician

Source: US Food and Drug Administration, NDC Directory. Reuse terms: US government work (FDA).

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Other strengths and forms

38 products are sold under this name. Grouped by form; a number on a strength means several companies make it.

Same active substance

These contain the same substance. That does not mean one can replace another — ask a pharmacist.

See every product with Imatinib Mesylate