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adverse reactions
6 ADVERSE REACTIONS In the adjuvant treatment of early breast cancer, the most common adverse reactions occurring in ≥ 10% of patients in any treatment group (exemestane tablets vs. tamoxifen) were mild to moderate hot flushes (21.2% vs. 19.9%), fatigue (16.1% vs. 14.7%), arthralgia (14.6% vs. 8.6%), headache (13.1% vs. 10.8%), insomnia (12.4% vs. 8.9%), and increased sweating (11.8% vs. 10.4%). Discontinuation rates due to AEs were similar between exemestane tablets and tamoxifen (6.3% vs. 5.1%). Incidences of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) were exemestane tablets 1.6%, tamoxifen 0.6%. Incidence of cardiac failure: exemestane tablets 0.4%, tamoxifen 0.3%. In the treatment of advanced breast cancer, the most common adverse reactions were mild to moderate and included hot flushes (13% vs. 5%), nausea (9% vs. 5%), fatigue (8% vs. 10%), increased sweating (4% vs. 8%), and increased appetite (3% vs. 6%) for exemestane tablets and megestrol acetate, respectively. • Early breast cancer: Adverse reactions occurring in ≥ 10% of patients in any treatment group (exemestane tablets vs. tamoxifen) were hot flushes (21.2% vs. 19.9%), fatigue (16.1% vs. 14.7%), arthralgia (14.6% vs. 8.6%), headache (13.1% vs. 10.8%), insomnia (12.4% vs. 8.9%), and increased sweating (11.8% vs. 10.4%). Discontinuation rates due to AEs were similar between exemestane tablets and tamoxifen (6.3% vs. 5.1%). Incidences of cardiac ischemic events (myocardial infarction, angina, and myocardial ischemia) were exemestane tablets 1.6%, tamoxifen 0.6%. Incidence of cardiac failure: exemestane tablets 0.4%, tamoxifen 0.3% ( 6 , 6.1 ). • Advanced breast cancer: Most common adverse reactions were mild to moderate and included hot flushes (13% vs. 5%), nausea (9% vs. 5%), fatigue (8% vs. 10%), increased sweating (4% vs. 8%), and increased appetite (3% vs. 6%) for exemestane tablets and megestrol acetate, respectively ( 6 , 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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 clinical practice. Adjuvant Therapy The data described below reflect exposure to exemestane tablets in 2325 postmenopausal women with early breast cancer. Exemestane tablets tolerability in postmenopausal women with early breast cancer was evaluated in two well-controlled trials: the IES study [See Clinical Studies (14.1) ] 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). The median duration of adjuvant treatment was 27.4 months and 27.3 months for patients receiving exemestane tablets or tamoxifen, respectively, within the IES study and 23.9 months for patients receiving exemestane tablets or placebo within the 027 study. Median duration of observation after randomization for exemestane tablets 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. Certain adverse reactions, which were 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. Within the IES study, discontinuations due to adverse reactions occurred in 6.3% and 5.1% of patients receiving exemestane tablets and tamoxifen, respectively, and in 12.3% and 4.1% of patients receiving exemestane or placebo respectively 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 reactions 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 2. Table 2. Incidence (%) of Adverse Reactions of all Grades Graded according to Common Toxicity Criteria; 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 Reaction by MedDRA dictionary Exemestane Tablets 25 mg daily (N = 2252) Tamoxifen 20 mg daily 75 patients received tamoxifen 30 mg daily; (N = 2280) Eye Visual disturbances Event actively sought. 5.0 3.8 Gastrointestinal Nausea 8.5 8.7 General Disorders Fatigue 16.1 14.7 Musculoskeletal Arthralgia 14.6 8.6 Pain in limb 9.0 6.4 Back pain 8.6 7.2 Osteoarthritis 5.9 4.5 Nervous System Headache 13.1 10.8 Dizziness 9.7 8.4 Psychiatric Insomnia 12.4 8.9 Depression 6.2 5.6 Skin & Subcutaneous Tissue Increased sweating 11.8 10.4 Vascular Hot flushes 21.2 19.9 Hypertension 9.8 8.4 In the IES study, as compared to tamoxifen, exemestane tablets were associated with a higher incidence of events in musculoskeletal disorders and in 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 exemestane tablets group compared to tamoxifen (0.7% vs. < 0.1%). The majority of patients on exemestane tablets 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 reactions occurring in study 027 are described in Table 3. Table 3. Incidence of Selected Treatment-Emergent Adverse Reactions of all CTC Grades Most events were CTC grade 1-2 Occurring in ≥ 5% of Patients in Either Arm in Study 027 Adverse Reaction 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 Treatment of Advanced Breast Cancer A total of 1058 patients were treated with exemestane 25 mg once daily in the clinical trials program. 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 reactions, mainly within the first 10 weeks of treatment; late discontinuations because of adverse reactions were uncommon (0.3%). In the comparative study, adverse reactions were assessed for 358 patients treated with exemestane tablets and 400 patients treated with megestrol acetate. Fewer patients receiving exemestane tablets discontinued treatment because of adverse reactions than those treated with megestrol acetate (2% vs. 5%). Adverse reactions 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%) for exemestane tablets and megestrol acetate, respectively. The proportion of patients experiencing an excessive weight gain (> 10% of their baseline weight) was significantly higher with megestrol acetate than with exemestane tablets (17% vs. 8%). Table 4 shows the adverse reactions of all CTC grades, regardless of causality, reported in 5% or greater of patients in the study treated either with exemestane tablets or megestrol acetate. Table 4. Incidence (%) of Adverse Reactions of all Grades Graded according to Common Toxicity Criteria and Causes Occurring in ≥ 5% of Advanced Breast Cancer Patients In Each Treatment Arm in the Comparative Study Body system and Adverse Reaction by WHO ART dictionary Exemestane Tablets 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 appetite 18 7 6 6 5 4 3 12 4 11 5 8 5 6 Respiratory Dyspnea Coughing 10 6 15 7 Less frequent adverse reactions of any cause (from 2% to 5%) reported in the comparative study for patients receiving exemestane tablets 25 mg once daily were fever, generalized weakness, paresthesia, pathological fracture, bronchitis, sinusitis, rash, itching, urinary tract infection, and lymphedema. Additional adverse reactions 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 reactions 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. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post approval use of exemestane tablets. 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. Immune System Disorders: hypersensitivity Hepatobiliary Disorders: hepatitis including cholestatic hepatitis Nervous System Disorders: paresthesia Skin and Subcutaneous Tissue Disorders: acute generalized exanthematous pustulosis, urticaria, pruritus