Imatinib
Generic: IMATINIB
Basic Information
Manufacturer
Dr.Reddy's Laboratories Inc
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
559dd8e5-11f9-70cd-3fb0-9f9eb8484a37
Indications & Usage
1 INDICATIONS AND USAGE Imatinib mesylate 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) 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) Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) (1.3) Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy (1.4) Adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements (1.5) Adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown (1.6) 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) Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP) (1.8) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST) ( 1.9 ) Adjuvant treatment of adult patients following resection of Kit (CD117) positive GIST ( 1.10 ) 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.
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.
1.3 Adult Patients With Ph+ Acute Lymphoblastic Leukemia (ALL) Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL).
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.
1.5 Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) Adult patients with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.
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.
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.
1.8 Dermatofibrosarcoma Protuberans (DFSP) Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.
1.9 Kit+ Gastrointestinal Stromal Tumors (GIST) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.
1.10 Adjuvant Treatment of GIST Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.
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.
1.3 Adult Patients With Ph+ Acute Lymphoblastic Leukemia (ALL) Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL).
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.
1.5 Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) Adult patients with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.
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.
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.
1.8 Dermatofibrosarcoma Protuberans (DFSP) Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.
1.9 Kit+ Gastrointestinal Stromal Tumors (GIST) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.
1.10 Adjuvant Treatment of GIST Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.
Adverse Reactions
6 ADVERSE REACTIONS 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 Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 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 Imatinib Mesylate IFN+Ara - C Imatinib Mesylate IFN+Ara - C Preferred term 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 Patients with newly Diagnosed Ph+ CML-CP Imatinib Mesylate 400 mg once daily Nilotinib 300 mg twice daily Imatinib Mesylate 400 mg once daily Nilotinib 300 mg twice daily N=280 N=279 N=280 N=279 Body system and preferred term 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 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.
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 Accelerated phase Chronic phase, IFN Failure (n=260) (n=235) (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 (I matinib Mesylate Versus IFN+Ara-C) Imatinib 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 (I matinibMesylate 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% 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 Per patient incidence Ph+ALL with i matinib mesylate N=92 Per patient incidence Ph-ALL no i matinib mesylate N=65 Per patient per cycle incidence with imatinib mesylate* N=778 Per patient per cycle incidence no imatinib mesylate* * N=647 Grade 3 and 4 adverse events n (%) n (%) n (%) 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 Reported or specified term Imatinib 400 mg N=818 Imatinib 800 mg N=822 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 to 1.0 x 10 9 /L, Grade 4 less than 0.5 x 10 9 /L), thrombocytopenia (Grade 3greater 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), elevated bilirubin (Grade 3 greater than 3 to 10 x ULN, Grade 4 greater than 10 x ULN), elevated alkaline phosphatase, SGOT or SGPT (Grade 3 greater than 5 to 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) Preferred term All CTC Grades CTC Grade 3* and Above Imatinib Mesylate (n=337) Placebo (n=345) Imatinib 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 Abbreviations: CTC, common terminology criteria; GIST, gastrointestinal stromal tumors; SGOT, serum glutamicoxaloacetic 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 Imatinib Mesylate 12 Months (N=194) % Imatinib Mesylate 36 Months (N=198) % Imatinib Mesylate 12 Months (N=194) % Imatinib 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% to1%: 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: l ichenoid 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
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 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 Imatinib Mesylate IFN+Ara - C Imatinib Mesylate IFN+Ara - C Preferred term 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 Patients with newly Diagnosed Ph+ CML-CP Imatinib Mesylate 400 mg once daily Nilotinib 300 mg twice daily Imatinib Mesylate 400 mg once daily Nilotinib 300 mg twice daily N=280 N=279 N=280 N=279 Body system and preferred term 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 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.
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 Accelerated phase Chronic phase, IFN Failure (n=260) (n=235) (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 (I matinib Mesylate Versus IFN+Ara-C) Imatinib 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 (I matinibMesylate 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% 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 Per patient incidence Ph+ALL with i matinib mesylate N=92 Per patient incidence Ph-ALL no i matinib mesylate N=65 Per patient per cycle incidence with imatinib mesylate* N=778 Per patient per cycle incidence no imatinib mesylate* * N=647 Grade 3 and 4 adverse events n (%) n (%) n (%) 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 Reported or specified term Imatinib 400 mg N=818 Imatinib 800 mg N=822 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 to 1.0 x 10 9 /L, Grade 4 less than 0.5 x 10 9 /L), thrombocytopenia (Grade 3greater 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), elevated bilirubin (Grade 3 greater than 3 to 10 x ULN, Grade 4 greater than 10 x ULN), elevated alkaline phosphatase, SGOT or SGPT (Grade 3 greater than 5 to 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) Preferred term All CTC Grades CTC Grade 3* and Above Imatinib Mesylate (n=337) Placebo (n=345) Imatinib 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 Abbreviations: CTC, common terminology criteria; GIST, gastrointestinal stromal tumors; SGOT, serum glutamicoxaloacetic 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 Imatinib Mesylate 12 Months (N=194) % Imatinib Mesylate 36 Months (N=198) % Imatinib Mesylate 12 Months (N=194) % Imatinib 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% to1%: 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: l ichenoid 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