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adverse reactions
ADVERSE REACTIONS Adjuvant Treatment of Early Breast Cancer AROMASIN tolerability in postmenopausal women with early breast cancer was evaluated in two well-controlled trials: the IES study (see CLINICAL STUDIES ) and the 027 study (a randomized, placebo-controlled, double-blind, parallel group study specifically designed to assess the effects of exemestane on bone metabolism, hormones, lipids and coagulation factors over 2 years of treatment). Certain adverse events, expected based on the known pharmacological properties and side effect profiles of test drugs, were actively sought through a positive checklist. Signs and symptoms were graded for severity using CTC in both studies. Within the IES study, the presence of some illnesses/conditions was monitored through a positive checklist without assessment of severity. These included myocardial infarction, other cardiovascular disorders, gynecological disorders, osteoporosis, osteoporotic fractures, other primary cancer, and hospitalizations. The median duration of adjuvant treatment was 27.4 months and 27.3 months for patients receiving AROMASIN or tamoxifen, respectively, within the IES study and 23.9 months for patients receiving AROMASIN or placebo within the 027 study. Median duration of observation after randomization for AROMASIN was 34.5 months and for tamoxifen was 34.6 months. Median duration of observation was 30 months for both groups in the 027 study. AROMASIN was generally well tolerated and adverse events were usually mild to moderate. Within the IES study discontinuations due to adverse events occurred in 6.3% and 5.1% of patients receiving AROMASIN and tamoxifen, respectively, and in 12.3% and 4.1% of patients receiving exemestane or placebo within study 027. Deaths due to any cause were reported for 1.3% of the exemestane-treated patients and 1.4% of the tamoxifen-treated patients within the IES study. There were 6 deaths due to stroke on the exemestane arm compared to 2 on tamoxifen. There were 5 deaths due to cardiac failure on the exemestane arm compared to 2 on tamoxifen. The incidence of cardiac ischemic events (myocardial infarction, angina and myocardial ischemia) was 1.6% in exemestane treated patients and 0.6% in tamoxifen treated patients in the IES study. Cardiac failure was observed in 0.4% of exemestane treated patients and 0.3% of tamoxifen treated patients. Treatment-emergent adverse events and illnesses including all causalities and occurring with an incidence of ≥5% in either treatment group of the IES study during or within one month of the end of treatment are shown in Table 8. Table 8. Incidence (%) of Adverse Events of all Grades* and Illnesses Occurring in ( ≥5%) of Patients in Any Treatment Group in Study IES in Postmenopausal Women with Early Breast Cancer % of patients Body system and Adverse Event by MedDRA dictionary AROMASIN 25 mg daily (N=2252) Tamoxifen 20 mg daily† (N=2280) Eye Visual disturbances‡ 5.0 3.8 Gastrointestinal Nausea‡ 8.5 8.7 General Disorders Fatigue‡ 16.1 14.7 Musculoskeletal Arthralgia Pain in limb Back pain Osteoarthritis 14.6 9.0 8.6 5.9 8.6 6.4 7.2 4.5 Nervous System Headache‡ Dizziness‡ 13.1 9.7 10.8 8.4 Psychiatric Insomnia‡ Depression 12.4 6.2 8.9 5.6 Skin & Subcutaneous Tissue Increased sweating‡ 11.8 10.4 Vascular Hot flushes‡ Hypertension 21.2 9.8 19.9 8.4 * Graded according to Common Toxicity Creiteria; † 75 patients received tamoxifen 30 mg daily; ‡ Event actively sought. In the IES study, as compared to tamoxifen, AROMASIN was associated with a higher incidence of events in the musculoskeletal disorders and in the nervous system disorders, including the following events occurring with frequency lower than 5% (osteoporosis [4.6% vs. 2.8%], osteochondrosis and trigger finger [0.3% vs 0 for both events], paresthesia [2.6% vs. 0.9%], carpal tunnel syndrome [2.4% vs. 0.2%], and neuropathy [0.6% vs. 0.1%]. Diarrhea was also more frequent in the exemestane group (4.2% vs. 2.2%). Clinical fractures were reported in 94 patients receiving exemestane (4.2%) and 71 patients receiving tamoxifen (3.1%). After a median duration of therapy of about 30 months and a median follow-up of about 52 months, gastric ulcer was observed at a slightly higher frequency in the AROMASIN group compared to tamoxifen (0.7% versus less than 0.1%). The majority of patients on AROMASIN with gastric ulcer received concomitant treatment with non-steroidal anti-inflammatory agents and/or had a prior history. Tamoxifen was associated with a higher incidence of muscle cramps [3.1% vs. 1.5%], thromboembolism [2.0% vs. 0.9%], endometrial hyperplasia [1.7% vs. 0.6%], and uterine polyps [2.4% vs. 0.4%]. Common adverse events occurring on study 027 are described in Table 9. Table 9: Incidence of Selected Treatment-Emergent Adverse Events of all CTC Grades* Occurring in ≥ 5% of Patients in Either Arm on Study 027 Adverse Event Exemestane N=73 (% incidence) Placebo N=73 (% incidence) Hot flushes 32.9 24.7 Arthralgia 28.8 28.8 Increased Sweating 17.8 20.6 Alopecia 15.1 4.1 Hypertension 15.1 6.9 Insomnia 13.7 15.1 nausea 12.3 16.4 Fatigue 11.0 19.2 Abdominal pain 11.0 13.7 Depression 9.6 6.9 Diarrhea 9.6 1.4 Dizziness 9.6 9.6 Dermatitis 8.2 1.4 Headache 6.9 4.1 Myalgia 5.5 4.1 Edema 5.5 6.9 Anxiety 4.1 5.5 * Most events were CTC grade 1-2 Treatment of Advanced Breast Cancer A total of 1058 patients were treated with exemestane 25 mg once daily in the clinical trials program. Exemestane was generally well tolerated, and adverse events were usually mild to moderate. Only one death was considered possibly related to treatment with exemestane; an 80-year-old woman with known coronary artery disease had a myocardial infarction with multiple organ failure after 9 weeks on study treatment. In the clinical trials program, only 3% of the patients discontinued treatment with exemestane because of adverse events, mainly within the first 10 weeks of treatment; late discontinuations because of adverse events were uncommon (0.3%). In the comparative study, adverse reactions were assessed for 358 patients treated with AROMASIN and 400 patients treated with megestrol acetate. Fewer patients receiving AROMASIN discontinued treatment because of adverse events than those treated with megestrol acetate (2% vs. 5%). Adverse events that were considered drug related or of indeterminate cause included hot flashes (13% vs. 5%), nausea (9% vs. 5%), fatigue (8% vs. 10%), increased sweating (4% vs. 8%), and increased appetite (3% vs. 6%). The proportion of patients experiencing an excessive weight gain (greater than 10% of their baseline weight) was significantly higher with megestrol acetate than with AROMASIN (17% vs. 8%). Table 10 shows the adverse events of all CTC grades, regardless of causality, reported in 5% or greater of patients in the study treated either with AROMASIN or megestrol acetate. Table 10. Incidence (%) of Adverse Events of all Grades* and Causes Occurring in ≥5% of Advanced Breast Cancer Patients In Each Treatment Arm in the Comparative Study Body system and Adverse Event by WHO ART dictionary AROMASIN 25 mg once daily (N=358) Megestrol Acetate 40 mg QID (N=400) Autonomic Nervous Increased sweating 6 9 Body as a Whole Fatigue Hot flashes Pain Influenza-like symptoms Edema (includes edema, peripheral edema, leg edema) 22 13 13 6 7 29 6 13 5 6 Cardiovascular Hypertension 5 6 Nervous Depression Insomnia Anxiety Dizziness Headache 13 11 10 8 8 9 9 11 6 7 Gastrointestinal Nausea Vomiting Abdominal pain Anorexia Constipation Diarrhea Increased appetit 18 7 6 6 5 4 3 12 4 11 5 8 5 6 Respiratory Dyspnea Coughing 10 6 15 7 * Graded according to Common Toxicity Criteria Less frequent adverse events of any cause (from 2% to 5%) reported in the comparative study for patients receiving AROMASIN 25 mg once daily were fever, generalized weakness, paresthesia, pathological fracture, bronchitis, sinusitis, rash, itching, urinary tract infection, and lymphedema. Additional adverse events of any cause observed in the overall clinical trials program (N = 1058) in 5% or greater of patients treated with exemestane 25 mg once daily but not in the comparative study included pain at tumor sites (8%), asthenia (6%) and fever (5%). Adverse events of any cause reported in 2% to 5% of all patients treated with exemestane 25 mg in the overall clinical trials program but not in the comparative study included chest pain, hypoesthesia, confusion, dyspepsia, arthralgia, back pain, skeletal pain, infection, upper respiratory tract infection, pharyngitis, rhinitis, and alopecia. Post-marketing Experience The following adverse reactions have been identified during post approval use of Aromasin. Because 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. Cases of hepatitis including cholestatic hepatitis have been observed in clinical trials and reported through post-marketing surveillance.