Imatinib Mesylate (Page 4 of 11)

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) *
*
All adverse reactions occurring in greater than or equal to 10% of imatinib mesylate treated patients are listed regardless of suspected relationship to treatment.
NCI common Terminology Criteria for Adverse Events, version 3.0.
Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified.

All Grades

CTC Grades 3/4

Preferred Term

Imatinib Mesylate N=551 (%)

IFN+Ara−C N=533 (%)

Imatinib Mesylate N=551 (%)

IFN+Ara−C 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
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
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
1.8
25.1
Headache
37
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
3.4
Dyspepsia
18.9
8.3
0
0.8
Cough
20
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
Weight increased
15.6
2.6
2
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
0.2
0.2

Abbreviations: CML, chronic myeloid leukemia; CNS, central nervous system; CTC, common terminology criteria; GI, gastrointestinal; IFN, Interferon-alpha.

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 *
*
Excluding laboratory abnormalities
NCI Common Terminology Criteria for Adverse Events, Version 3.0

Patients With Newly Diagnosed Ph+ CML-CP

imatinib mesylate 400 mg once daily N=280

nilotinib 300 mg twice daily N=279

imatinib mesylate 400 mg once daily N=280

nilotinib 300 mg twice daily N=279

Body System and Preferred Term

All Grades (%)

CTC Grades 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 upper
14
18
<1
1
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.

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)*

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**
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

*All adverse reactions occurring in greater than or equal to 10% of patients are listed regardless of suspected relationship to treatment.

**Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified.


Abbreviations: CML, chronic myeloid leukemia; IFN, Interferon-alpha.
Hematologic and Biochemistry Laboratory Abnormalitie
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)
*
p less than 0.001 (difference in Grade 3 plus 4 abnormalities between the two treatment groups)

CTC Grades

Imatinib Mesylate N=551 %

IFN+Ara−C N=533 %

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).

Table 6: Percent Incidence of Clinically Relevant Grade 3/4 * Laboratory Abnormalities in the Newly Diagnosed CML Clinical Trial (imatinib mesylate versus nilotinib)
*
NCI Common Terminology Criteria for Adverse Events, version 3.0

imatinib 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).

Table 7: Laboratory Abnormalities in Other CML Clinical Trials
*
CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5 to 1 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 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)

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 *

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
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).

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% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure.

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%)

*
Defined as the frequency of 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 Event Grade 3 and 4 Adverse Events

Per Patient Incidence Ph+ ALL With Imatinib Mesylate N=92 n (%)

Per Patient Incidence Ph- ALL With Imatinib Mesylate N=65 n (%)

Per Patient Per Cycle Incidence With Imatinib Mesylate * N=778 n (%)

Per Patient Per Cycle Incidence No Imatinib Mesylate 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.
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)
Vomiting
3 (25)
Periorbital edema
4 (33.3)
Face Edema
2 (16.7)
Rash
3 (25)
Fatigue
5 (41.7)
Peripheral edema
4 (33.3)
Pyrexia
2 (16.7)
Eye edema
4 (33.3)
Lacrimation increased
3 (25)
Dyspnea exertional
2 (16.7)
Anemia
3 (25)
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
*
CTC Grades: neutropenia (Grade 3 greater than or equal to 0.5 to 1 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)

N=12

CTC Grades *

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.

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
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%–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

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