Imatinib Mesylate

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Imatinib Mesylate Prescribing Information

Imatinib mesylate tablet is a kinase inhibitor indicated for the treatment of:

• Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

1.1 Newly Diagnosed Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML)

Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

• Patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in blast crisis (BC), accelerated phase (AP), or in chronic phase (CP) after failure of interferon-alpha therapy.

1.2 Ph+ CML in Blast Crisis (BC), Accelerated Phase (AP) or Chronic Phase (CP) After Interferon-alpha (IFN) Therapy

Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.

• Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

1.3 Adult Patients With Ph+ Acute Lymphoblastic Leukemia (ALL)

Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

• Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy.

1.4 Pediatric Patients With Ph+ Acute Lymphoblastic Leukemia (ALL)

Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy.

• Adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.

1.5 Myelodysplastic/Myeloproliferative Diseases (MDS/MPD)

Adult patients with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.

• Adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown.

1.6 Aggressive Systemic Mastocytosis (ASM)

Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown.

• Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or fluorescence in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown.

1.7 Hypereosinophilic Syndrome (HES) and/or Chronic Eosinophilic Leukemia (CEL)

Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or fluorescence in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown.

• Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP).

1.8 Dermatofibrosarcoma Protuberans (DFSP)

Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

• Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST).

1.9 Kit+ Gastrointestinal Stromal Tumors (GIST)

Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

• Adjuvant treatment of adult patients following resection of Kit (CD117) positive GIST.

1.10 Adjuvant Treatment of GIST

Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.

• Adults with Ph+ CML CP (

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.

): 400 mg/day

• Adults with Ph+ CML AP or BC (

2.2 Adult Patients With Ph+ CML CP, AP, or BC

): 600 mg/day

• Pediatrics with Ph+ CML CP (

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/m²/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.

): 340 mg/m
²/day

• Adults with Ph+ ALL (

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.

): 600 mg/day

• Pediatrics with 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/m²/day (not to exceed 600 mg). Imatinib mesylate tablets treatment can be given as a once daily dose.

340 mg/m
²/day

• Adults with MDS/MPD (

2.5 Pediatric Patients With Ph+ ALL

): 400 mg/day

• Adults with ASM (

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.

): 100 mg/day or 400 mg/day

• Adults with HES/CEL (

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.

): 100 mg/day or 400 mg/day

• Adults with DFSP (

2.9 Adult Patients With DFSP

The recommended dose of imatinib mesylate tablets are 800 mg/day for adult patients with DFSP.

): 800 mg/day

• Adults with metastatic and/or unresectable GIST

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.

400 mg/day

• Adjuvant treatment of adults with GIST (

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.

400 mg/day

• Patients with mild to moderate hepatic impairment (

2.10 Adult Patients With Metastatic and/or Unresectable GIST

): 400 mg/day

• Patients with severe hepatic impairment (

2.10 Adult Patients With Metastatic and/or Unresectable GIST

): 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.

Risk Summary

Imatinib mesylate can cause fetal harm when administered to a pregnant woman based on human and animal data. There are no clinical studies regarding use of imatinib mesylate in pregnant women. There have been postmarket reports of spontaneous abortions and congenital anomalies from women who have been exposed to imatinib mesylate during pregnancy. Reproductive studies in rats have demonstrated that imatinib mesylate induced teratogenicity and increased incidence of congenital abnormalities following prenatal exposure to imatinib mesylate at doses equal to the highest recommended human dose of 800 mg/day based on BSA. Advise women to avoid pregnancy when taking imatinib mesylate. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is not known; however, in the U.S. general population, the estimated background risk of major birth defects of clinically recognized pregnancies is 2% to 4% and of miscarriage is 15% to 20%.

Data

Animal Data

In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of imatinib mesylate up to 100 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis.

In rats, imatinib mesylate was teratogenic at 100 mg/kg/day (approximately equal to the maximum human dose of 800 mg/day based on BSA), the number of fetuses with encephalocoele and exencephaly was higher than historical control values and these findings were associated with missing or underdeveloped cranial bones. Lower mean fetal body weights were associated with retarded skeletal ossifications.

In rabbits, at doses 1.5 times higher than the maximum human dose of 800 mg/day based on BSA, no effects on the reproductive parameters with respect to implantation sites, number of live fetuses, sex ratio or fetal weight were observed. The examinations of the fetuses did not reveal any drug related morphological changes.

In a pre- and postnatal development study in rats, pregnant rats received oral doses of imatinib mesylate during gestation (organogenesis) and lactation up to 45 mg/kg/day. Five animals developed a red vaginal discharge in the 45 mg/kg/day group on Days 14 or 15 of gestation, the significance of which is unknown since all females produced viable litters and none had increased post-implantation loss. Other maternal effects noted only at the dose of 45 mg/kg/day (approximately one-half the maximum human dose of 800 mg/day based on BSA) included an increased number of stillborn pups and pups dying between postpartum Days 0 and 4. In the F1 offspring at this same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased. There were no other significant effects in developmental parameters or behavioral testing. F1 fertility was not affected but reproductive effects were noted at 45 mg/kg/day, including an increased number of resorptions and a decreased number of viable fetuses. The no-observed-effect level (NOEL) for both maternal animals and the F1 generation was 15 mg/kg/day.

• Edema and severe fluid retention have occurred. Weigh patients regularly and manage unexpected rapid weight gain by drug interruption and diuretics.

5.1 Fluid Retention and Edema

Imatinib mesylate is often associated with edema and occasionally serious fluid retention

[see Adverse Reactions (6.1)]

. Weigh and monitor patients regularly for signs and symptoms of fluid retention. Investigate unexpected rapid weight gain carefully and provide appropriate treatment. The probability of edema was increased with higher imatinib mesylate dose and age greater than 65 years in the CML studies. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking imatinib mesylate, and in 2% to 6% of other adult CML patients taking imatinib mesylate. In addition, other severe fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) reactions were reported in 1.3% of newly diagnosed CML patients taking imatinib mesylate, and in 2% to 6% of other adult CML patients taking imatinib mesylate. Severe fluid retention was reported in 9% to 13.1% of patients taking imatinib mesylate for GIST

[see Adverse Reactions (6.1)]

. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing imatinib mesylate and nilotinib, severe (Grade 3 or 4) fluid retention occurred in 2.5% of patients receiving imatinib mesylate and in 3.9% of patients receiving nilotinib 300 mg twice daily. Effusions (including pleural effusion, pericardial effusion, ascites) or pulmonary edema were observed in 2.1% (none were Grade 3 or 4) of patients in the imatinib mesylate arm and 2.2% (0.7% Grade 3 or 4) of patients in the nilotinib 300 mg twice daily arm.

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 reactions²	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^b3/4 (%)
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
	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. ^aExcluding laboratory abnormalities. ^bNCI 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 10⁹/L, Grade 4 less than 0.5 x 10⁹/L), thrombocytopenia (Grade 3 greater than or equal to 10 to 50 x 10⁹/L, Grade 4 less than 10 x 10⁹/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 10⁹/L, Grade 4 less than 0.5 x 10⁹/L), thrombocytopenia (Grade 3 greater than or equal to 10 to 50 x 10⁹/L, Grade 4 less than 10 x 10⁹/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 10⁹/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 Grades¹	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). ¹CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5–1.0 x 10⁹/L, Grade 4 less than 0.5 x 10⁹/L), thrombocytopenia (Grade 3 greater than or equal to 10–50 x 10⁹/L, Grade 4 less than 10 x 10⁹/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 necrosis¹

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 pressure¹, 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%: papilledema¹, glaucoma

¹Including some fatalities.

• Cytopenias, particularly anemia, neutropenia, and thrombocytopenia, have occurred. Manage with dose reduction, dose interruption, or discontinuation of treatment. Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter.

5.2 Hematologic Toxicity

Treatment with imatinib mesylate is associated with anemia, neutropenia, and thrombocytopenia. Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2 to 3 months). In CML, the occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML. In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias, including neutropenia, thrombocytopenia, and anemia. These generally occur within the first several months of therapy

[see Dosage and Administration (2.14)].

• Severe congestive heart failure and left ventricular dysfunction have been reported, particularly in patients with comorbidities and risk factors. Monitor and treat patients with cardiac disease or risk factors for cardiac failure.

5.3 Congestive Heart Failure and Left Ventricular Dysfunction

Congestive heart failure and left ventricular dysfunction have been reported in patients taking imatinib mesylate. Cardiac adverse reactions were more frequent in patients with advanced age or co-morbidities, including previous medical history of cardiac disease. In an international randomized Phase 3 study in 1106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking imatinib mesylate compared to 0.9% of patients taking IFN + Ara-C. In another randomized trial with newly diagnosed Ph+ CML patients in chronic phase that compared imatinib mesylate and nilotinib, cardiac failure was observed in 1.1% of patients in the imatinib mesylate arm and 2.2% of patients in the nilotinib 300 mg twice daily arm and severe (Grade 3 or 4) cardiac failure occurred in 0.7% of patients in each group. Carefully monitor patients with cardiac disease or risk factors for cardiac or history of renal failure. Evaluate and treat any patient with signs or symptoms consistent with cardiac or renal failure.

• Severe hepatotoxicity, including fatalities may occur. Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction.

5.4 Hepatotoxicity

Hepatotoxicity, occasionally severe, may occur with imatinib mesylate

[see Adverse Reactions (6.1)]

. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of imatinib mesylate. Monitor liver function (transaminases, bilirubin, and alkaline phosphatase) before initiation of treatment and monthly, or as clinically indicated. Manage laboratory abnormalities with imatinib mesylate interruption and/or dose reduction

[see Dosage and Administration (2.13)]

. When imatinib mesylate is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended.

• Grade 3/4 hemorrhage has been reported in clinical studies in patients with newly diagnosed CML and with GIST. GI tumor sites may be the source of GI bleeds in GIST.

5.5 Hemorrhage

In a trial of imatinib mesylate versus IFN+Ara-C in patients with the newly diagnosed CML, 1.8% of patients had Grade 3/4 hemorrhage. In the Phase 3 unresectable or metastatic GIST studies, 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study, 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI hemorrhages. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing imatinib mesylate and nilotinib, GI hemorrhage occurred in 1.4% of patients in the imatinib mesylate arm, and in 2.9% of patients in the nilotinib 300 mg twice daily arm. None of these events were Grade 3 or 4 in the imatinib mesylate arm; 0.7% were Grade 3 or 4 in the nilotinib 300 mg twice daily arm. In addition, gastric antral vascular ectasia has been reported in postmarketing experience.

• Gastrointestinal (GI) perforations, some fatal, have been reported.

5.6 Gastrointestinal Disorders

Imatinib mesylate is sometimes associated with GI irritation. Imatinib mesylate should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of GI perforation.

• Cardiogenic shock/left ventricular dysfunction has been associated with the initiation of imatinib mesylate in patients with conditions associated with high eosinophil levels (e.g., HES, MDS/MPD, and ASM).

5.7 Hypereosinophilic Cardiac Toxicity

In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of imatinib mesylate therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding imatinib mesylate.

Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels. Consider performing an echocardiogram and determining serum troponin in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, consider prophylactic use of systemic steroids (1 to 2 mg/kg) for one to two weeks concomitantly with imatinib mesylate at the initiation of therapy.

• Bullous dermatologic reactions (e.g., erythema multiforme and Stevens-Johnson syndrome) have been reported with the use of imatinib mesylate.

5.8 Dermatologic Toxicities

Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of imatinib mesylate. In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon rechallenge. Several foreign postmarketing reports have described cases in which patients tolerated the reintroduction of imatinib mesylate therapy after resolution or improvement of the bullous reaction. In these instances, imatinib mesylate was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines.

• Hypothyroidism has been reported in thyroidectomy patients undergoing levothyroxine replacement. Closely monitor TSH levels in such patients.

5.9 Hypothyroidism

Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with imatinib mesylate. Monitor TSH levels in such patients.

• Fetal harm can occur when administered to a pregnant woman. Apprise women of the potential harm to the fetus, and to use effective contraception.

5.10 Embryo-Fetal Toxicity

Imatinib mesylate can cause fetal harm when administered to a pregnant woman. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on body surface area (BSA). Significant post-implantation loss was seen in female rats administered imatinib mesylate at doses approximately one-half the maximum human dose of 800 mg/day based on BSA. Advise sexually active female patients of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) when using imatinib mesylate and for 14 days after stopping imatinib mesylate. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus

[see Use in Specific Populations (8.1)].

8.1 Pregnancy

Risk Summary

Data

Animal Data

• Growth retardation occurring in children and pre-adolescents receiving imatinib mesylate has been reported. Close monitoring of growth in children under imatinib mesylate treatment is recommended.

5.11 Growth Retardation in Children and Adolescents

Growth retardation has been reported in children and pre-adolescents receiving imatinib mesylate. The long-term effects of prolonged treatment with imatinib mesylate on growth in children are unknown. Therefore, monitor growth in children under imatinib mesylate treatment

[see Adverse Reactions (6.1)].

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 tamponade¹

Eye Disorders:

vitreous hemorrhage

Gastrointestinal Disorders:

ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, GI perforation¹

[see Warnings and Precautions (5.6)],

diverticulitis, gastric antral vascular ectasia

Infections:

hepatitis B virus reactivation¹

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 edema¹

Reproduction Disorders:

hemorrhagic corpus luteum/hemorrhagic ovarian cyst

Respiratory, Thoracic and Mediastinal Disorders:

acute respiratory failure¹, 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

¹Including some fatalities.

• Tumor Lysis Syndrome. Close monitoring is recommended.

5.12 Tumor Lysis Syndrome

Cases of Tumor Lysis Syndrome (TLS), including fatal cases, have been reported in patients with CML, GIST, ALL, and eosinophilic leukemia receiving imatinib mesylate. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. Monitor these patients closely and take appropriate precautions. Due to possible occurrence of TLS, correct clinically significant dehydration and treat high uric acid levels prior to initiation of imatinib mesylate.

• Reports of motor vehicle accidents have been received in patients receiving imatinib mesylate. Caution patients about driving a car or operating machinery.

5.13 Impairments Related to Driving and Using Machinery

Motor vehicle accidents have been reported in patients receiving imatinib mesylate. Advise patients that they may experience side effects, such as dizziness, blurred vision, or somnolence during treatment with imatinib mesylate. Recommend caution when driving a car or operating machinery.

• Renal Toxicity. A decline in renal function may occur in patients receiving imatinib mesylate. Evaluate renal function at baseline and during therapy, with attention to risk factors for renal dysfunction.

5.14 Renal Toxicity

A decline in renal function may occur in patients receiving imatinib mesylate. Median estimated glomerular filtration rate (eGFR) values in patients on imatinib mesylate 400 mg daily for newly-diagnosed CML (four randomized trials) and malignant GIST (one single-arm trial) declined from a baseline value of 85 mL/min/1.73 m²(N = 1190) to 75 mL/min/1.73 m²at 12 months (N = 1082) and 69 mL/min/1.73 m²at 60 months (N = 549). Evaluate renal function prior to initiating imatinib mesylate and monitor during therapy, with attention to risk factors for renal dysfunction, such as preexisting renal impairment, diabetes mellitus, hypertension, and congestive heart failure.

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