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adverse reactions
6 ADVERSE REACTIONS The most serious adverse reactions from the use of Letrozole Tablets are: Bone effects [s e e W arnings and Pr ec autions ( 5.1 ) ] Increases in cholesterol [s e e W arnings and Pr ec a utions ( 5.2 ) ] Because clinical trials are conducted under widely varying conditions, adverse reactions 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. The most common adverse reactions (>20%) were hot flashes, arthralgia ( 6.1 ); flushing, asthenia, edema, arthralgia, headache, dizziness, hypercholesterolemia, sweating increased, bone pain ( 6.2 , 6.3 ); and musculoskeletal ( 6.4 ). To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-877-233-2001 or the FDA at 1-800-FDA-1088, or www.fda.gov/medwatch 6.1 Adjuvant Treatment of Early Breast Cancer The median treatment duration of adjuvant treatment was 60 months and the median duration of follow-up for safety was 73 months for patients receiving Letrozole Tablets and tamoxifen. Certain adverse reactions were prospectively specified for analysis, based on the known pharmacologic properties and side effect profiles of the two drugs. Adverse reactions were analyzed irrespective of whether a symptom was present or absent at baseline. Most adverse reactions reported (approximately 75% of patients reporting 1 or more AE) were Grade 1 or Grade 2 applying the Common Toxicity Criteria Version 2.0/ Common Terminology Criteria for Adverse Events, version 3.0. Table 1 describes adverse reactions (Grades 1-4) irrespective of relationship to study treatment in the adjuvant trial for the monotherapy arms analysis (safety population). Table 1: Patients with Adverse Reactions (CTC Grades 1-4, Irrespective of Relationship to Study Drug) in the Adjuvant Study – Monotherapy Arms Analysis (Median Follow-up 73 Months; Median Treatment 60 Months) Grades 1-4 Grades 3-4 Adverse Reaction Letrozole Tablets USP N=2448 n (%) tamoxifen N=2447 n (%) Letrozole Tablets USP N=2448 n (%) tamoxifen N=2447 n (%) Pts with any adverse event 2310 (94.4) 2214 (90.5) 635 (25.9) 604 (24.7) Hypercholesterolemia 1280 (52.3) 700 (28.6) 11 ( 0.4) 6 ( 0.2) Hot Flashes/Flushes 821 (33.5) 929 (38.0) 0 - 0 - Arthralgia/Arthritis 618 (25.2) 501 (20.4) 85 ( 3.5) 50 ( 2.0) Night Sweats 357 (14.6) 426 (17.4) 0 - 0 - Bone Fractures 2 338 (13.8) 257 (10.5) - - - - Weight Increase 317 (12.9) 378 (15.4) 27 ( 1.1) 39 ( 1.6) Nausea 283 (11.6) 277 (11.3) 6 ( 0.2) 9 ( 0.4) Bone Fractures 1 247 (10.1) 174 ( 7.1) - - - - Fatigue (Lethargy, Malaise, Asthenia) 235 ( 9.6) 250 (10.2) 6 ( 0.2) 7 ( 0.3) Myalgia 217 ( 8.9) 212 ( 8.7) 18 ( 0.7) 14 ( 0.6) Edema 164 ( 6.7) 160 ( 6.5) 3 ( 0.1) 1 (<0.1) Weight Decrease 140 ( 5.7) 129 ( 5.3) 8 ( 0.3) 5 ( 0.2) Vaginal Bleeding 128 ( 5.2) 320 (13.1) 1 (<0.1) 8 ( 0.3) Back Pain 125 ( 5.1) 136 ( 5.6) 7 ( 0.3) 11 ( 0.4) Osteoporosis NOS 124 ( 5.1) 66 ( 2.7) 10 ( 0.4) 5 ( 0.2) Bone pain 123 ( 5.0) 109 ( 4.5) 6 ( 0.2) 4 ( 0.2) Depression 119 ( 4.9) 114 ( 4.7) 16 ( 0.7) 14 ( 0.6) Vaginal Irritation 111 ( 4.5) 77 ( 3.1) 2 (<0.1) 2 (<0.1) Headache 105 ( 4.3) 94 ( 3.8) 9 ( 0.4) 5 ( 0.2) Pain in extremity 103 ( 4.2) 79 ( 3.2) 6 ( 0.2) 4 ( 0.2) Osteopenia 87 ( 3.6) 74 ( 3.0) 0 - 2 (<0.1) Dizziness/Light-Headedness 84 ( 3.4) 84 ( 3.4) 1 (<0.1) 6 (0.2) Alopecia 83 ( 3.4) 84 ( 3.4) 0 - 0 - Vomiting 80 ( 3.3) 80 ( 3.3) 3 ( 0.1) 5 (0.2) Cataract 49 ( 2.0) 54 ( 2.2) 16 ( 0.7) 17 ( 0.7) Constipation 49 ( 2.0) 71 ( 2.9) 3 ( 0.1) 1 (<0.1) Breast pain 37 ( 1.5) 43 ( 1.8) 1 (<0.1) 0 - Anorexia 20 ( 0.8) 20 ( 0.8) 1 (<0.1) 1 (<0.1) Endometrial Hyperplasia/ Cancer 2, 3 11/1909 ( 0.6) 70/1943 ( 3.6) - - - - Endometrial Proliferation 10 (0.3) 71 (1.8) 0 - 14 (0.6) Disorders Endometrial Hyperplasia/ 6/1909 ( 0.3) 57/1943 (2.9) - - - - Cancer 1, 3 Other Endometrial Disorders 2 (<0.1) 3 ( 0.1) 0 - 0 - Myocardial Infarction 1 24 ( 1.0) 12 ( 0.5) - - - - Endometrial Proliferation 10 (0.3) 71 (1.8) 0 - 14 (0.6) Disorders Myocardial Infarction 2 37 ( 1.5) 25 (1.0) - - - - Myocardial Ischemia 6 ( 0.2) 9 ( 0.4) - - - - Cerebrovascular Accident 1 52 ( 2.1) 46 ( 1.9) - - - - Cerebrovascular Accident 2 70 ( 2.9) 63 ( 2.6) - - - - Angina 1 26 ( 1.1) 24 ( 1.0) - - - - Angina 2 32 ( 1.3) 31 ( 1.3) - - - - Thromboembolic Event 1 51 ( 2.1) 89 ( 3.6) - - - - Thromboembolic Event 2 71 ( 2.9) 111 ( 4.5) - - - - Other Cardiovascular 1 260 (10.6) 256 (10.5) - - - - Other Cardiovascular 2 312 (12.7) 337 (13.8) - - - - Second Malignancies 1 53 ( 2.2) 78 ( 3.2) - - - - Second Malignancies 2 102 ( 4.2) 119 ( 4.9) - - - - 1 During study treatment, based on Safety Monotherapy population 2 Any time after randomization, including post treatment follow-up 3 Excluding women who had undergone hysterectomy before study entry Note: Cardiovascular (including cerebrovascular and thromboembolic), skeletal and urogenital/endometrial events and second malignancies were collected life-long. All of these events were assumed to be of CTC grade 3-5 and were not individually graded When considering all grades during study treatment, a higher incidence of events was seen for Letrozole Tablets regarding fractures (10.1% vs 7.1%), myocardial infarctions (1.0% vs 0.5%), and arthralgia (25.2% vs 20.4%) (Letrozole Tablets vs tamoxifen respectively). A higher incidence was seen for tamoxifen regarding thromboembolic events (2.1% vs 3.6%), endometrial hyperplasia/cancer (0.3% vs 2.9%), and endometrial proliferation disorders (0.3% vs 1.8%) (Letrozole Tablets vs tamoxifen respectively). At a median follow up of 73 months, a higher incidence of events was seen for Letrozole Tablets (13.8%) than for tamoxifen (10.5%) regarding fractures. A higher incidence was seen for tamoxifen compared to Letrozole Tablets regarding thromboembolic events (4.5% vs 2.9%), and endometrial hyperplasia or cancer (2.9% vs 0.4%) (tamoxifen vs Letrozole Tablets respectively). Bone Study: Results of a phase 3 safety trial in 262 postmenopausal women with resected receptor positive early breast cancer in the adjuvant setting comparing the effect on lumbar spine (L2-L4) bone mineral density (BMD) of adjuvant treatment with letrozole to that with tamoxifen showed at 24 months a median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 4.4%) ( P <0.0001). No patients with a normal BMD at baseline became osteoporotic over the 2 years and only 1 patient with osteopenia at baseline (T score of -1.9) develop osteoporosis during the treatment period (assessment by central review). The results for total hip BMD were similar, although the differences between the two treatments were less pronounced. During the 2 year period, fractures were reported by 4 of 103 patients (4%) in the letrozole arm, and 6 of 97 patients (6%) in the tamoxifen arm. Lipid Study: In a phase 3 safety trial in 262 postmenopausal women with resected receptor positive early breast cancer at 24 months comparing the effects on lipid profiles of adjuvant letrozole to tamoxifen, 12% of patients on letrozole had at least one total cholesterol value of a higher CTCAE grade than at baseline compared with 4% of patients on tamoxifen. 6.2 Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months The median duration of extended adjuvant treatment was 24 months and the median duration of follow-up for safety was 28 months for patients receiving Letrozole Tablets and placebo. Table 2 describes the adverse reactions occurring at a frequency of at least 5% in any treatment group during treatment. Most adverse reactions reported were Grade 1 and Grade 2 based on the Common Toxicity Criteria Version 2.0. In the extended adjuvant setting, the reported drug-related adverse reactions that were significantly different from placebo were hot flashes, arthralgia/arthritis, and myalgia. Table 2: Percentage of Patients with Adverse Reactions Number (%) of Patients with Grade 1-4 Adverse Reaction Nu mber (%) of Patients with Grade 3-4 Adverse Reaction Letrozole Tablets USP N=2563 Placebo N=2573 Letrozole Tablets USP N=2563 Placebo N=2573 Any Adverse Reaction 2232 (87.1) 2174 (84.5) 419 (16.3) 389 (15.1) Vascular Disorders 1375 (53.6) 1230 (47.8) 59 (2.3) 74 (2.9) Flushing 1273 (49.7) 1114 (43.3) 3 (0.1) 0 General Disorders 1154 (45) 1090 (42.4) 30 (1.2) 28 (1.1) Asthenia 862 (33.6) 826 (32.1) 16 (0.6) 7 (0.3) Edema NOS 471 (18.4) 416 (16.2) 4 (0.2) 3 (0.1) Musculoskeletal Disorders 978 (38.2) 836 (32.5) 71 (2.8) 50 (1.9) Arthralgia 565 (22) 465 (18.1) 25 (1) 20 (0.8) Arthritis NOS 173 (6.7) 124 (4.8) 10 (0.4) 5 (0.2) Myalgia 171 (6.7) 122 (4.7) 8 (0.3) 6 (0.2) Back Pain 129 (5) 112 (4.4) 8 (0.3) 7 (0.3) Nervous System Disorders 863 (33.7) 819 (31.8) 65 (2.5) 58 (2.3) Headache 516 (20.1) 508 (19.7) 18 (0.7) 17 (0.7) Dizziness 363 (14.2) 342 (13.3) 9 (0.4) 6 (0.2) Skin Disorders 830 (32.4) 787 (30.6) 17 (0.7) 16 (0.6) Sweating Increased 619 (24.2) 577 (22.4) 1 (<0.1) 0 Gastrointestinal Disorders 725 (28.3) 731 (28.4) 43 (1.7) 42 (1.6) Constipation 290 (11.3) 304 (11.8) 6 (0.2) 2 (<0.1) Nausea 221 (8.6) 212 (8.2) 3 (0.1) 10 (0.4) Diarrhea NOS 128 (5) 143 (5.6) 12 (0.5) 8 (0.3) Metabolic Disorders 551 (21.5) 537 (20.9) 24 (0.9) 32 (1.2) Hypercholesterolemia 401 (15.6) 398 (15.5) 2 (<0.1) 5 (0.2) Reproductive Disorders 303 (11.8) 357 (13.9) 9 (0.4) 8 (0.3) Vaginal Hemorrhage 123 (4.8) 171 (6.6) 2 (<0.1) 5 (0.2) Vulvovaginal Dryness 137 (5.3) 127 (4.9) 0 0 Psychiatric Disorders 320 (12.5) 276 (10.7) 21 (0.8) 16 (0.6) Insomnia 149 (5.8) 120 (4.7) 2 (<0.1) 2 (<0.1) Respiratory Disorders 279 (10.9) 260 (10.1) 30 (1.2) 28 (1.1) Dyspnea 140 (5.5) 137 (5.3) 21 (0.8) 18 (0.7) Investigations 184 (7.2) 147 (5.7) 13 (0.5) 13 (0.5) Infections and Infestations 166 (6.5) 163 (6.3) 40 (1.6) 33 (1.3) Renal Disorders 130 (5.1) 100 (3.9) 12 (0.5) 6 (0.2) Based on a median follow-up of patients for 28 months, the incidence of clinical fractures from the core randomized study in patients who received Letrozole Tablets was 5.9% (152) and placebo was 5.5% (142). The incidence of self-reported osteoporosis was higher in patients who received Letrozole Tablets 6.9% (176) than in patients who received placebo 5.5% (141). Bisphosphonates were administered to 21.1% of the patients who received Letrozole Tablets and 18.7% of the patients who received placebo. The incidence of cardiovascular ischemic events from the core randomized study was comparable between patients who received Letrozole Tablets 6.8% (175) and placebo 6.5% (167). A patient-reported measure that captures treatment impact on important symptoms associated with estrogen deficiency demonstrated a difference in favor of placebo for vasomotor and sexual symptom domains. B o n e Su b - st u d y : [s e e W arnings and Pr ec autions ( 5.1 ) ] . Lipid Su b - st u d y : In the extended adjuvant setting, based on a median duration of follow-up of 62 months, there was no significant difference between Letrozole Tablets and placebo in total cholesterol or in any lipid fraction at any time over 5 years. Use of lipid lowering drugs or dietary management of elevated lipids was allowed. [s e e W arnings and Pr e c autions ( 5.2 ) ] . 6.3 Updated Analysis, Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment D u r a t ion of 60 M o n t h s The extended adjuvant treatment trial was unblinded early [ s e e A d ve rse R e a c tions ( 6.2 )]. At the updated (final analysis), overall the side effects seen were consistent to those seen at a median treatment duration of 24 months. During treatment or within 30 days of stopping treatment (median duration of treatment 60 months) a higher rate of fractures was observed for Letrozole Tablets (10.4%) compared to placebo (5.8%), as also a higher rate of osteoporosis (Letrozole Tablets 0.2% vs placebo 6.4%). Based on 62 months median duration of follow-up in the randomized letrozole arm in the Safety population the incidence of new fractures at any time after randomization was 13.3% for letrozole and 7.8% for placebo. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo. During treatment or within 30 days of stopping treatment (median duration of treatment 60 months) the incidence of cardiovascular events was 9.8% for Letrozole Tablets and 7.0% for placebo. Based on 62 months median duration of follow-up in the randomized letrozole arm in the Safety population the incidence of cardiovascular disease at any time after randomization was 14.4% for letrozole and 9.8% for placebo. Lipid sub-study: In the extended adjuvant setting, based on a median duration of follow-up of 62 months, there was no significant difference between Letrozole Tablets and placebo in total cholesterol or in any lipid fraction over 5 years. Use of lipid lowering drugs or dietary management of elevated lipids was allowed. [s e e W arnings and Pr ec aution s ( 5.2 ) ] 6.4 First-Line Treatment of Advanced Breast Cancer A total of 455 patients were treated for a median time of exposure of 11 months. The incidence of adverse reactions was similar for Letrozole Tablets and tamoxifen. The most frequently reported adverse reactions were bone pain, hot flushes, back pain, nausea, arthralgia and dyspnea. Discontinuations for adverse reactions other than progression of tumor occurred in 10/455 (2%) of patients on Letrozole Tablets and in 15/455 (3%) of patients on tamoxifen. Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with Letrozole Tablets 2.5 mg or tamoxifen 20 mg in the first-line treatment study are shown in Table 3 Table 3: Percentage (%) of Patients with Adverse Reactions Adverse Reaction Letrozole Tablets 2.5 mg (N=455) % T amoxifen 20 mg (N=455) % General Disorders Fatigue 13 13 Chest Pain 8 9 Edema 5 6 Peripheral Pain 5 7 NOS Weakness 6 4 Investigations Weight Decreased 7 5 Vascular Disorders Hot Flushes 19 16 Hypertension 8 4 Gastrointestinal Disorders Nausea 17 17 Constipation 10 11 Diarrhea 8 4 Vomiting 7 8 Infections/Infestations Influenza 6 4 Urinary Tract Infection NOS 6 3 Injury, Poisoning and Procedural Complications Post-Mastectomy Lymphedema 7 7 Metabolism and Nutrition Disorders Anorexia 4 6 Musculoskeletal and Connective Tissue Disorders Bone Pain 22 21 Back Pain 18 19 Arthralgia 16 15 Pain in Limb 10 8 Nervous System Disorders Headache NOS 8 7 Psychiatric Disorders Insomnia 7 4 Reproductive System and Breast Disorders Breast Pain 7 7 Respiratory, Thoracic and Mediastinal Disorders Dyspnea 18 17 Cough 13 13 Chest Wall Pain 6 6 Other less frequent (≤2%) adverse reactions considered consequential for both treatment groups, included peripheral thromboembolic events, cardiovascular events, and cerebrovascular events. Peripheral thromboembolic events included venous thrombosis, thrombophlebitis, portal vein thrombosis and pulmonary embolism. Cardiovascular events included angina, myocardial infarction, myocardial ischemia, and coronary heart disease. Cerebrovascular events included transient ischemic attacks, thrombotic or hemorrhagic strokes and development of hemiparesis. 6.5 Second- Line Treatment of Advanced Breast Cancer Study discontinuations in the megestrol acetate comparison study for adverse reactions other than progression of tumor were 5/188 (2.7%) on Letrozole Tablets 0.5 mg, in 4/174 (2.3%) on Letrozole Tablets 2.5 mg, and in 15/190 (7.9%) on megestrol acetate. There were fewer thromboembolic events at both Letrozole Tablets doses than on the megestrol acetate arm (0.6% vs 4.7%). There was also less vaginal bleeding (0.3% vs 3.2%) on Letrozole Tablets than on megestrol acetate. In the aminoglutethimide comparison study, discontinuations for reasons other than progression occurred in 6/193 (3.1%) on 0.5 mg Letrozole Tablets 7/185 (3.8%) on 2.5 mg Letrozole Tablets and 7/178 (3.9%) of patients on aminoglutethimide. Comparisons of the incidence of adverse reactions revealed no significant differences between the high and low dose Letrozole Tablets groups in either study. Most of the adverse reactions observed in all treatment groups were mild to moderate in severity and it was generally not possible to distinguish adverse reactions due to treatment from the consequences of the patient’s metastatic breast cancer, the effects of estrogen deprivation, or intercurrent illness. Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with Femara 0.5 mg, Femara 2.5 mg, megestrol acetate, or aminoglutethimide in the two controlled trials are shown in Table 4. Table 4: Percentage (%) of Patients with Adverse Reactions Adverse Reaction Pooled Letrozole tablets USP 2.5 mg (N=359) % Pooled Letrozole tablets 0.5 mg (N=380) % megestrol acetate 160 mg (N=189) % aminoglutethimide 500 mg (N=178) % Body as a Whole Fatigue 8 6 11 3 Chest Pain 6 3 7 3 Peripheral Edema 1 5 5 8 3 Asthenia 4 5 4 5 Weight Increase Cardiovascular 2 2 9 3 Hypertension Digestive System 5 7 5 6 Nausea 13 15 9 14 Vomiting 7 7 5 9 Constipation 6 7 9 7 Diarrhea 6 5 3 4 Pain-Abdominal 6 5 9 8 Anorexia 5 3 5 5 Dyspepsia Infections/Infestations 3 4 6 5 Viral Infection Lab Abnormality 6 5 6 3 Hypercholesterolemia Musculoskeletal System 3 3 0 6 Musculoskeletal 2 21 22 30 14 Arthralgia Nervous System 8 8 8 3 Headache 9 12 9 7 Somnolence 3 2 2 9 Dizziness Respiratory System 3 5 7 3 Dyspnea 7 9 16 5 Coughing Skin and Appendages Hot Flushes Rash 3 Prurities 6 6 5 1 5 5 4 2 7 4 3 5 5 3 12 3 1 Includes peripheral edema, leg edema, dependent edema, edema 2 Includes musculoskeletal pain, skeletal pain, back pain, arm pain, leg pain 3 Includes rash, erythematous rash, maculopapular rash, psoriasiform rash,vesicular rash Other less frequent (<5%) adverse reactions considered consequential and reported in at least 3 patients treated with Letrozole Tablets USP, included hypercalcemia, fracture, depression, anxiety, pleural effusion, alopecia, increased sweating and vertigo. 6.6 First and Second-Line Treatment of Advanced Breast Cancer In the combined analysis of the first- and second-line metastatic trials and post-marketing experiences other adverse reactions that were reported were cataract, eye irritation, palpitations, cardiac failure, tachycardia, dysesthesia (including hypesthesia/paresthesia), arterial thrombosis, memory impairment, irritability, nervousness, urticaria, increased urinary frequency, leukopenia, stomatitis cancer pain, pyrexia, vaginal discharge, appetite increase, dryness of skin and mucosa (including dry mouth), and disturbances of taste and thirst. 6.7 Postmarketing Experience Cases of blurred vision, increased hepatic enzymes, angioedema, anaphylactic reactions, toxic epidermal necrolysis, erythema multiforme, and hepatitis have been reported. Cases of carpal tunnel syndrome and trigger .nger have been identied during post approval use of Letrozole tablets.