1 4 ) ] The most frequently reported adverse reactions (greater than or equal to 30%) were edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue and abdominal pain. 1 ) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp.
gov/medwatch. 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. 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).
13 ) ]. 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.
2 Abbreviations: CML, chronic myeloid leukemia; CNS, central nervous system; CTC, common terminology criteria; GI, gastrointestinal; IFN, Interferon-alpha. 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 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 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. 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.
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).
001 (difference in Grade 3 plus 4 abnormalities between the two treatment groups).
Table 6:
Percent Incidence of Clinically Relevant Grade 3/4* Laboratory Abnormalities in the Newly Diagnosed CML Clinical Trial (Imatinib Mesylate Versus Nilotinib). 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).
0. 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).
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).
0% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure. 8% of patients. 7% of patients. 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 tablets and treated in 5 successive cohorts.
Imatinib mesylate tablets exposure was systematically increased in successive cohorts by earlier introduction and more prolonged duration. The safety of imatinib mesylate tablets 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 tablets.
The safety was also evaluated comparing the incidence of adverse events in cycles of therapy administered with or without imatinib mesylate tablets. The protocol included up to 18 cycles of therapy. Patients were exposed to a cumulative total of 1,425 cycles of therapy, 778 with imatinib mesylate tablets, and 647 without imatinib mesylate tablets.
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 tablets are presented in Table 8.
Table 8:
Adverse Reactions Reported More Frequently in Patients Treated With Study Drug (Greater Than 5%) or in Cycles With Study Drug (Greater Than 1%) Adverse event Grade 3 and 4 adverse events Per patient incidence Ph+ ALL with Imatinib Mesylate Tablets N = 92 n (%) Per patient incidence Ph- ALL no Imatinib Mesylate Tablets N = 65 n (%) Per patient per cycle incidence with Imatinib Mesylate Tablets* N = 778 n (%) Per patient per cycle incidence no Imatinib Mesylate Tablets** N = 647 n (%) Nausea and/or vomiting 15 (16) 6 (9) 28 (4) 8 (1) Hypokalemia 31 (34) 16 (25) 72 (9) 32 (5) Pneumonitis 7 (8) 1 (1) 7 (1) 1 (< 1) Pleural effusion 6 (7) 0 6 (1) 0 Abdominal pain 8 (9) 2 (3) 9 (1) 3 (< 1) Anorexia 10 (11) 3 (5) 19 (2) 4 (1) Hemorrhage 11 (12) 4 (6) 17 (2) 8 (1) Hypoxia 8 (9) 2 (3) 12 (2) 2 (< 1) Myalgia 5 (5) 0 4 (1) 1 (< 1) Stomatitis 15 (16) 8 (12) 22 (3) 14 (2) Diarrhea 8 (9) 3 (5) 12 (2) 3 (< 1) Rash/Skin disorder 4 (4) 0 5 (1) 0 Infection 49 (53) 32 (49) 131 (17) 92 (14) Hepatic (transaminase and/or bilirubin) 52 (57) 38 (58) 172 (22) 113 (17) Hypotension 10 (11) 5 (8) 16 (2) 6 (1) Myelosuppression Neutropenia (< 750/mcL) 92 (100) 63 (97) 556 (71) 218 (34) Thrombocytopenia (< 75,000/mcL) 90 (92) 63 (97) 431 (55) 329 (51) Abbreviations: Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia; Ph- ALL, Philadelphia chromosome negative acute lymphoblastic leukemia.
*Defined as the frequency of adverse events (AEs) per patient per treatment cycles that included imatinib mesylate tablets (includes patients with Ph+ ALL that received cycles with imatinib mesylate tablets). **Defined as the frequency of AEs per patient per treatment cycles that did not include imatinib mesylate tablets (includes patients with Ph+ ALL that received cycles without imatinib mesylate tablets as well as all patients with Ph- ALL who did not receive imatinib mesylate tablets 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. 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 .
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. 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 1 N = 12 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.
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.
4%). 13 )]. 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.
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).
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), 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. 3 0 0 Abbreviations: CTC, common terminology criteria; GIST, gastrointestinal stromal tumors; SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); SGPT, serum glutamic-pyruvic transaminase is now referred to as alanine aminotransferase (ALT).
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.
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.
1%: papilledema 1 , glaucoma 1 Including some fatalities. 2 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of imatinib mesylate tablets. 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.
6 ) ], diverticulitis, gastric antral vascular ectasia Infections: hepatitis B virus reactivation 1 Musculoskeletal and Connective Tissue Disorders: osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children, musculoskeletal pain upon treatment discontinuation (including myalgia, pain in extremity, arthalgia, bone pain) Nervous System Disorders: cerebral edema 1 Reproduction Disorders: hemorrhagic corpus luteum/hemorrhagic ovarian cyst Respiratory, Thoracic and Mediastinal Disorders: acute respiratory failure 1 , interstitial lung disease Skin and Subcutaneous Tissue Disorders: lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), pseudoporphyria, pemphigus Vascular Disorders: thrombosis/embolism, anaphylactic shock 1 Including some fatalities.