Letrozoleside effects

The following adverse reactions are discussed in greater detail in other sections of the labeling. Bone effects Increases in cholesterol Fatigue and Dizziness The most common adverse reactions (greater than 20%) were hot flashes, arthralgia; flushing, asthenia, edema, arthralgia, headache, dizziness, hypercholesterolemia, sweating increased, bone pain; and musculoskeletal. To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 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 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. Adjuvant Treatment of Early Breast Cancer In study, BIG 1-98, the median treatment duration of adjuvant treatment was 60 months and the median duration of follow-up for safety was 96 months for patients receiving Femara and tamoxifen. Certain adverse reactions were prospectively specified for analysis (see Table 1), 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 who reported AEs) were Grade 1 or Grade 2 applying the Common Toxicity Criteria (CTC) Version 2.0/Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0. Table 1 describes adverse reactions (Grades 1-4 and Grades 3-4) 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) in the Adjuvant Study – Monotherapy Arms Analysis (Median Follow-up 96 Months; Median Treatment 60 Months) Grades 1-4 Grades 3-4 Femara Tamoxifen Femara Tamoxifen Adverse R eaction s N = 2448 N = 2447 N = 2448 N = 2447 n (%) n (%) n (%) n (%) Patients with any adverse reaction 2309 2212 636 606 Hypercholesterolemia* 1280 700 11 6 Hot flashes* 819 929 - - - - Arthralgia/arthritis* 621 504 84 50 Bone fractures 1 361 280 - - - - Night sweats* 356 426 - - - - Weight increase* 317 378 27 39 Nausea* 284 277 6 9 Bone fractures** 2 249 175 - - - - Fatigue (lethargy, malaise, asthenia)* 235 250 6 7 Myalgia* 221 212 18 14 Vaginal bleeding* 129 320 1 (< 0.1) 8 Edema* 164 160 3 1 (< 0.1) Weight decrease 140 129 8 5 Osteoporosis** 126 67 10 5 Back pain 125 136 7 11 Bone pain 123 109 6 4 Depression 119 114 16 14 Vaginal irritation* 112 77 2 (< 0.1) 2 (< 0.1) Headache* 105 94 8 4 Pain in extremity 103 79 6 4 Osteopenia* 87 76 0 - 3 Dizziness/light-headedness* 84 80 1 (< 0.1) 6 Alopecia 83 84 - - - - Vomiting* 80 80 3 5 Cataract* 49 54 16 17 Constipation* 49 71 3 1 (< 0.1) Myocardial infarction 1 42 28 - - - - Breast pain* 37 43 1 (< 0.1) - - Anorexia* 20 20 1 (< 0.1) 1 (< 0.1) Endometrial proliferation disorders* 14 86 0 - 14 Ovarian cyst* 11 18 4 4 Endometrial hyperplasia/cancer** 1 11 72 - - - - Endometrial hyperplasia/cancer**, 3 6/1909 57/1943 - - - - Other endometrial disorders* 2 (< 0.1) 3 0 - 0 - Myocardial infarction** 2 24 12 - - - - Myocardial ischemia 6 9 - - - - Cerebrovascular accident/TIA** 1 74 68 - - - - Cerebrovascular accident/TIA** 2 51 47 - - - - Angina requiring surgery** 1 35 33 - - - - Angina requiring surgery** 2 25 25 - - - - Thromboembolic event** 1 79 113 - - - - Thromboembolic event** 2 51 89 - - - - Cardiac failure 1 39 34 - - - - Cardiac failure 2 27 15 - - - - Hypertension 1 160 175 - - - - Hypertension 2 138 139 - - - - Other cardiovascular** 1 172 174 - - - - Other cardiovascular** 2 120 119 - - - - Second primary malignancy 1 129 150 - - - - Second primary malignancy 2 54 79 - - - - *Target events pre-specified for analysis **Events pre-printed on CRF 1 At median follow-up of 96 months (i.e., any time after randomization) for Femara (range up to 144 months) and 95 months for tamoxifen (range up to 143 months). 2 At median treatment duration of 60 months (i.e. during treatment + 30 days after discontinuation of treatment) for Femara and tamoxifen (range up to 68 months). 3 Excluding women who had undergone hysterectomy before study entry. TIA = Transient ischemic attack.

Note: Cardiovascular events (including cerebrovascular and thromboembolic events), skeletal and urogenital/endometrial events and second primary malignancies were collected life -long. All of these events were assumed to be of CTC Grade 3 to 5 and were not individually graded. When considering all grades during study treatment, a higher incidence of events was seen for Femara regarding fractures (10.1% vs 7.1%), myocardial infarctions (1.0% vs 0.5%), and arthralgia (25.2% vs 20.4%) (Femara 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%) (Femara vs tamoxifen respectively). At a median follow-up of 96 months, a higher incidence of events was seen for Femara (14.7%) than for tamoxifen (11.4%) regarding fractures. A higher incidence was seen for tamoxifen compared to Femara regarding thromboembolic events (4.6% vs 3.2%), and endometrial hyperplasia or cancer (2.9% vs 0.4%) (tamoxifen vs Femara, respectively).

Bone Study: Results of a safety trial in 263 postmenopausal women with resected receptor positive early breast cancer in the adjuvant setting comparing the effect on lumbar spine (L2-L4) 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) developed 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 safety trial in 263 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. In another postapproval randomized, multicenter, open label, study of letrozole vs anastrozole in the adjuvant treatment of postmenopausal women with hormone receptor and node positive breast cancer (FACE, NCT00248170), the median duration of treatment was 60 months for both treatment arms. Table 2 describes adverse reactions (Grades 1-4 and Grades 3-4) irrespective of relationship to study treatment in the adjuvant study (safety population).

Table 2: Adverse Reactions (CTC Grades 1-4), Occurring in at Least 5% of Patients in Either Treatment Arm, by Preferred Term (Safety set) Adverse Reactions Letrozole N = 2049 n (%) Anastrozole N = 2062 n (%) Grade 3/4 n (%) All Grades n (%) Grade 3/4 n (%) All Grades n (%) Patients with at least one AR 628 2049 591 2062 Arthralgia 80 987 69 987 Hot flush 17 666 9 666 Fatigue 8 345 10 343 Osteoporosis 5 223 11 225 Myalgia 16 233 15 212 Back pain 11 212 17 193 Osteopenia 4 203 1 173 Pain in extremity 9 168 3 174 Lymphoedema 5 159 2 179 Insomnia 7 160 3 149 Hypercholesterolaemia 2 155 1 151 Hypertension 25 156 20 149 Depression 16 147 13 137 Bone pain 10 138 9 122 Nausea 6 137 5 152 Headache 3 130 5 168 Alopecia 2 127 0 134 Musculoskeletal pain 6 123 9 147 Radiation skin injury 11 120 6 88 Dyspnea 16 118 10 96 Cough 1 106 1 120 Musculoskeletal stiffness 2 102 2 84 Dizziness 2 94 7 109 The following adverse reactions were also identified in less than 5% of the 2049 patients treated with letrozole and not included in the table: fall, vertigo, hyperbilirubinemia, jaundice, and chest pain. Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 M onths In study MA-17, 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 Femara and placebo. Table 3 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 CTC 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 3: Adverse Reactions Occurring in at Least 5% of Patients in Either Treatment Arm Number (%) of Patients with Grade 1-4 Adverse Reaction s Number (%) of Patients with Grade 3-4 Adverse Reaction s Femara Placebo Femara Placebo N = 2563 N = 2573 N = 2563 N = 2573 Any Adverse Reaction s 2232 2174 419 389 Vascular Disorders 1375 1230 59 74 Flushing 1273 1114 3 0 General Disorders 1154 1090 30 28 Asthenia 862 826 16 7 Edema NOS 471 416 4 3 Musculoskeletal Disorders 978 836 71 50 Arthralgia 565 465 25 20 Arthritis NOS 173 124 10 5 Myalgia 171 122 8 6 Back Pain 129 112 8 7 Nervous System Disorders 863 819 65 58 Headache 516 508 18 17 Dizziness 363 342 9 6 Skin Disorders 830 787 17 16 Sweating Increased 619 577 1 (< 0.1) 0 Gastrointestinal Disorders 725 731 43 42 Constipation 290 304 6 2 (< 0.1) Nausea 221 212 3 10 Diarrhea NOS 128 143 12 8 Metabolic Disorders 551 537 24 32 Hypercholesterolemia 401 398 2 (< 0.1) 5 Reproductive Disorders 303 357 9 8 Vaginal Hemorrhage 123 171 2 (< 0.1) 5 Vulvovaginal Dryness 137 127 0 0 Psychiatric Disorders 320 276 21 16 Insomnia 149 120 2 (< 0.1) 2 (< 0.1) Respiratory Disorders 279 260 30 28 Dyspnea 140 137 21 18 Investigations 184 147 13 13 Infections and Infestations 166 163 40 33 Renal Disorders 130 100 12 6 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 Femara was 5.9% and placebo was 5.5%. The incidence of self-reported osteoporosis was higher in patients who received Femara 6.9% than in patients who received placebo 5.5%. Bisphosphonates were administered to 21.1% of the patients who received Femara 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 Femara 6.8% and placebo 6.5%. 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.

Bone Substudy: [ s ee Warnings and Preca u tions (5. 1 ) ] Lipid Substudy: In the extended adjuvant setting, based on a median duration of follow-up of 62 months, there was no significant difference between Femara 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. Updated Analy s is, Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months The extended adjuvant treatment trial (MA-17) was unblinded early. 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 Femara (10.4%) compared to placebo (5.8%), as also a higher rate of osteoporosis (Femara 12.2% 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 Femara 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 Substudy: In the extended adjuvant setting (MA-17), based on a median duration of follow-up of 62 months, there was no significant difference between Femara 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. First-Line Treatment of Advanced Breast Cancer In study P025 a total of 455 patients were treated for a median time of exposure of 11 months in the Femara arm (median 6 months in the tamoxifen arm). The incidence of adverse reactions was similar for Femara 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 Femara and in 15/455 (3%) of patients on tamoxifen. Adverse reactions that were reported in at least 5% of the patients treated with Femara 2.5 mg or tamoxifen 20 mg in the first-line treatment study are shown in Table 4.

Table 4: Adverse Reactions Occurring in at Least 5% of Patients in Either Treatment Arm Adverse Reactions Femara Tamoxifen 2.5 mg 20 mg (N = 455) (N = 455) % % General Disorders Fatigue 13 13 Chest Pain 8 9 Edema Peripheral 5 6 Pain NOS 5 7 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 (less than or equal to 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. Second-Line Treatment of Advanced Breast Cancer Study discontinuations in the megestrol acetate comparison study (AR/BC2) for adverse reactions other than progression of tumor were 5/188 (2.7%) on Femara 0.5 mg, in 4/174 (2.3%) on Femara 2.5 mg, and in 15/190 (7.9%) on megestrol acetate. There were fewer thromboembolic events at both Femara doses than on the megestrol acetate arm (0.6% vs 4.7%). There was also less vaginal bleeding (0.3% vs 3.2%) on Femara than on megestrol acetate. In the aminoglutethimide comparison study (AR/BC3), discontinuations for reasons other than progression occurred in 6/193 (3.1%) on 0.5 mg Femara, 7/185 (3.8%) on 2.5 mg Femara, 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 Femara 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 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 AR/BC2 and AR/BC3 are shown in Table 5.

Table 5: Adverse Reactions Occurring at a Frequency of at Least 5% of Patients in Either Treatment Arm 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. Adverse Reactions Pooled Pooled Megestrol Femara Femara Acetate Aminoglutethimide 2.5 mg 0.5 mg 160 mg 500 mg (N = 359) (N = 380) (N = 189) (N = 178) % % % % Body as a Whole Chest Pain 6 3 7 3 Peripheral Edema 1 5 5 8 3 Asthenia 4 5 4 5 Weight Increase 2 2 9 3 Cardiovascular Hypertension 5 7 5 6 Digestive System 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 3 4 6 5 Infections/Infestations Viral Infection 6 5 6 3 Lab Abnormality Hypercholesterolemia 3 3 0 6 Musculoskeletal System Musculoskeletal 2 21 22 30 14 Arthralgia 8 8 8 3 Nervous System Headache 9 12 9 7 Somnolence 3 2 2 9 Dizziness 3 5 7 3 Respiratory System Dyspnea 7 9 16 5 Coughing 6 5 7 5 Skin and Appendages Hot Flushes 6 5 4 3 Rash 3 5 4 3 12 Pruritus 1 2 5 3 Other less frequent (less than 5%) adverse reactions considered consequential and reported in at least 3 patients treated with Femara, included hypercalcemia, fracture, depression, anxiety, pleural effusion, alopecia, increased sweating, and vertigo. First and Second-Line Treatment of Advanced Breast Cancer In the combined analysis of the first- and second-line metastatic trials and postmarketing 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.

6.2 Postmarketing

Experience The following adverse reactions have been identified during postapproval use of Femara. 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.

Eye Disorders: blurred vision Hepatobiliary Disorders: increased hepatic enzymes, hepatitis Immune System Disorders: anaphylactic reactions, hypersensitivity reactions Nervous System Disorders: carpal tunnel syndrome Pregnancy: spontaneous abortions, congenital birth defects Skin and subcutaneous disorders: angioedema, toxic epidermal necrolysis, erythema multiforme Musculoskeletal and connective tissue disorders: tendon disorders including tendon rupture, tendonitis, tenosynovitis, and tenosynovitis stenosans (trigger finger)