LETROZOLE

Letrozole tablets for oral administration contain 2.5 mg of letrozole, a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis). It is chemically described as 4,4'-(1H-1,2,4-Triazol-1-ylmethylene)dibenzonitrile, and its structural formula is Letrozole is a white to yellowish crystalline powder, practically odorless, freely soluble in dichloromethane, slightly soluble in ethanol, and practically insoluble in water. It has a molecular weight of 285.31, empirical formula C 17 H 11 N 5 , and a melting range of 184°C to 185°C. Letrozole tablets are available as 2.5 mg tablets for oral administration. Inactive Ingredients: Colloidal silicon dioxide, ferric oxide (yellow), hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, polyethylene glycol, sodium starch glycolate, talc and titanium dioxide. Chemical Structure

Letrozole tablets are an aromatase inhibitor indicated for: Adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer ( 1.1 ) Extended adjuvant treatment of postmenopausal women with early breast cancer who have received prior standard adjuvant tamoxifen therapy ( 1.2 ) First and second-line treatment of postmenopausal women with hormone receptor positive or unknown advanced breast cancer ( 1.3 ) 1.1 Adjuvant Treatment of Early Breast Cancer Letrozole tablets are indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. 1.2 Extended Adjuvant Treatment of Early Breast Cancer Letrozole tablets are indicated for the extended adjuvant treatment of early breast cancer in postmenopausal women, who have received 5 years of adjuvant tamoxifen therapy. The effectiveness of letrozole tablets in extended adjuvant treatment of early breast cancer is based on an analysis of disease-free survival in patients treated with letrozole tablets for a median of 60 months [see Clinical Studies (14.2 , 14.3) ] . 1.3 First and Second-Line Treatment of Advanced Breast Cancer Letrozole tablets are indicated for first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer. Letrozole tablets are also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy [see Clinical Studies (14.4 , 14.5) ].

Letrozole tablets are taken orally without regard to meals ( 2 ): Recommended dose: 2.5 mg once daily ( 2.1 ) Patients with cirrhosis or severe hepatic impairment: 2.5 mg every other day ( 2.5 , 5.3 ) 2.1 Recommended Dose The recommended dose of letrozole tablets is one 2.5 mg tablet administered once a day, without regard to meals. 2.2 Use in Adjuvant Treatment of Early Breast Cancer In the adjuvant setting, the optimal duration of treatment with letrozole is unknown. In both the adjuvant study and the postapproval adjuvant study, median treatment duration was 5 years. Treatment should be discontinued at relapse [see Clinical Studies (14.1) ]. 2.3 Use in Extended Adjuvant Treatment of Early Breast Cancer In the extended adjuvant setting, the optimal treatment duration with letrozole tablets is not known. The planned duration of treatment in the study was 5 years. In the final updated analysis, conducted at a median follow-up of 62 months, the median treatment duration for letrozole tablets was 60 months. Seventy-one (71%) percent of patients were treated for at least 3 years and 58% of patients completed at least 4.5 years of extended adjuvant treatment. The treatment should be discontinued at tumor relapse [see Clinical Studies (14.2) ]. 2.4 Use in First and Second-Line Treatment of Advanced Breast Cancer In patients with advanced disease, treatment with letrozole tablets should continue until tumor progression is evident. [see Clinical Studies (14.4 , 14.5) ] 2.5 Use in Hepatic Impairment No dosage adjustment is recommended for patients with mild to moderate hepatic impairment, although letrozole tablets blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis. The dose of letrozole tablets in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% [see Warnings and Precautions (5.3) ]. The recommended dose of letrozole tablets for such patients is 2.5 mg administered every other day. The effect of hepatic impairment on letrozole tablets exposure in noncirrhotic cancer patients with elevated bilirubin levels has not been determined. 2.6 Use in Renal Impairment No dosage adjustment is required for patients with renal impairment if creatinine clearance is greater than or equal to 10 mL/min. [see Clinical Pharmacology (12.3) ] .

Pregnancy: Letrozole can cause fetal harm [see Use in Specific Populations (8.1) ] . Pregnancy: Letrozole can cause fetal harm [see Use in Specific Populations (8.1) ] . Known hypersensitivity to the active substance, or to any of the excipients [see Adverse Reactions (6) ] . Known hypersensitivity to the active substance, or to any of the excipients [see Adverse Reactions (6) ] . Pregnancy ( 4 ) Known hypersensitivity to the active substance, or to any of the excipients ( 4 )

The following adverse reactions are discussed in greater detail in other sections of the labeling. Bone effects [see Warnings and Precautions (5.1) ] Increases in cholesterol [see Warnings and Precautions (5.2) ] Fatigue and Dizziness [see Warnings and Precautions (5.4) ] 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 ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact AvKARE, Inc. at 1-855-361-3993 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 letrozole tablets 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) Adverse Reactions Grades 1-4 Grades 3-4 Letrozole tablets N=2448 n (%) Tamoxifen N=2447 n (%) Letrozole tablets N=2448 n (%) Tamoxifen N=2447 n (%) 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 Patients with any adverse reaction 2309 (94.3) 2212 (90.4) 636 (26.0) 606 (24.8) Hypercholesterolemia Target events pre-specified for analysis 1280 (52.3) 700 (28.6) 11 (0.4) 6 (0.2) Hot flashes 819 (33.5) 929 (38.0) - - - - Arthralgia/arthritis 621 (25.4) 504 (20.6) 84 (3.4) 50 (2.0) Bone fractures At median follow-up of 96 months (i.e. any time after randomization) for letrozole tablets (range up to 144 months) and 95 months for tamoxifen (range up to 143 months ) 361 (14.7) 280 (11.4) - - - - Night sweats 356 (14.5) 426 (17.4) - - - - Weight increase 317 (12.9) 378 (15.4) 27 (1.1) 39 (1.6) Nausea 284 (11.6) 277 (11.3) 6 (0.2) 9 (0.4) Bone fractures Events pre-printed on CRF At median treatment duration of 60 months (i.e. during treatment + 30 days after discontinuation of treatment) for letrozole tablets and tamoxifen (range up to 68 months) 249 (10.2) 175 (7.2) - - - - Fatigue (lethargy, malaise, asthenia) 235 (9.6) 250 (10.2) 6 (0.2) 7 (0.3) Myalgia 221 (9.0) 212 (8.7) 18 (0.7) 14 (0.6) Vaginal bleeding 129 (5.3) 320 (13.1) 1 (<0.1) 8 (0.3) 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) Osteoporosis 126 (5.1) 67 (2.7) 10 (0.4) 5 (0.2) Back pain 125 (5.1) 136 (5.6) 7 (0.3) 11 (0.4) 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 112 (4.6) 77 (3.1) 2 (<0.1) 2 (<0.1) Headache 105 (4.3) 94 (3.8) 8 (0.3) 4 (0.2) Pain in extremity 103 (4.2) 79 (3.2) 6 (0.2) 4 (0.2) Osteopenia 87 (3.6) 76 (3.1) 0 - 3 (0.1) Dizziness/light-headedness 84 (3.4) 80 (3.3) 1 (<0.1) 6 (0.2) Alopecia 83 (3.4) 84 (3.4) - - - - 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) Myocardial infarction 42 (1.7) 28 (1.1) - - - - Breast pain 37 (1.5) 43 (1.8) 1 (<0.1) - - Anorexia 20 (0.8) 20 (0.8) 1 (<0.1) 1 (<0.1) Endometrial proliferation disorders 14 (0.6) 86 (3.5) 0 - 14 (0.6) Ovarian cyst 11 (0.4) 18 (0.7) 4 (0.2) 4 (0.2) Endometrial hyperplasia/cancer 11 (0.4) 72 (2.9) - - - - Endometrial hyperplasia/cancer , Excluding women who had undergone hysterectomy before study entry 6/1909 (0.3) 57/1943 (2.9) - - - - Other endometrial disorders 2 (<0.1) 3 (0.1) 0 - 0 - Myocardial infarction 24 (1.0) 12 (0.5) - - - - Myocardial ischemia 6 (0.2) 9 (0.4) - - - - Cerebrovascular accident/TIA 74 (3.0) 68 (2.8) - - - - Cerebrovascular accident/TIA 51 (2.1) 47 (1.9) - - - - Angina requiring surgery 35 (1.4) 33 (1.3) - - - - Angina requiring surgery 25 (1.0) 25 (1.0) - - - - Thromboembolic event 79 (3.2) 113 (4.6) - - - - Thromboembolic event 51 (2.1) 89 (3.6) - - - - Cardiac failure 39 (1.6) 34 (1.4) - - - - Cardiac failure 27 (1.1) 15 (0.6) - - - - Hypertension 160 (6.5) 175 (7.2) - - - - Hypertension 138 (5.6) 139 (5.7) - - - - Other cardiovascular 172 (7.0) 174 (7.1) - - - - Other cardiovascular 120 (4.9) 119 (4.9) - - - - Second primary malignancy 129 (5.3) 150 (6.1) - - - - Second primary malignancy 54 (2.2) 79 (3.2) - - - - 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 96 months, a higher incidence of events was seen for letrozole tablets (14.7%) than for tamoxifen (11.4%) regarding fractures. A higher incidence was seen for tamoxifen compared to letrozole tablets regarding thromboembolic events (4.6% vs 3.2%), and endometrial hyperplasia or cancer (2.9% vs 0.4%) (tamoxifen vs letrozole tablets, 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 (30.6) 2049 (100.0) 591 (28.7) 2062 (100.0) Arthralgia 80 (3.9) 987 (48.2) 69 (3.3) 987 (47.9) Hot flush 17 (0.8) 666 (32.5) 9 (0.4) 666 (32.3) Fatigue 8 (0.4) 345 (16.8) 10 (0.5) 343 (16.6) Osteoporosis 5 (0.2) 223 (10.9) 11 (0.5) 225 (10.9) Myalgia 16 (0.8) 233 (11.4) 15 (0.7) 212 (10.3) Back pain 11 (0.5) 212 (10.3) 17 (0.8) 193 (9.4) Osteopenia 4 (0.2) 203 (9.9) 1 (0.0) 173 (8.4) Pain in extremity 9 (0.4) 168 (8.2) 3 (0.1) 174 (8.4) Lymphoedema 5 (0.2) 159 (7.8) 2 (0.1) 179 (8.7) Insomnia 7 (0.3) 160 (7.8) 3 (0.1) 149 (7.2) Hypercholesterolaemia 2 (0.1) 155 (7.6) 1 (0.0) 151 (7.3) Hypertension 25 (1.2) 156 (7.6) 20 (1.0) 149 (7.2) Depression 16 (0.8) 147 (7.2) 13 (0.6) 137 (6.6) Bone pain 10 (0.5) 138 (6.7) 9 (0.4) 122 (5.9) Nausea 6 (0.3) 137 (6.7) 5 (0.2) 152 (7.4) Headache 3 (0.1) 130 (6.3) 5 (0.2) 168 (8.1) Alopecia 2 (0.1) 127 (6.2) 0 (0.0) 134 (6.5) Musculoskeletal pain 6 (0.3) 123 (6.0) 9 (0.4) 147 (7.1) Radiation skin injury 11 (0.5) 120 (5.9) 6 (0.3) 88 (4.3) Dyspnoea 16 (0.8) 118 (5.8) 10 (0.5) 96 (4.7) Cough 1 (0.0) 106 (5.2) 1 (0.0) 120 (5.8) Musculoskeletal stiffness 2 (0.1) 102 (5.0) 2 (0.1) 84 (4.1) Dizziness 2 (0.2) 94 (4.6) 7 (0.3) 109 (5.3) 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 Months 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 letrozole tablets 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 Reactions Number (%) of Patients with Grade 3-4 Adverse Reactions Letrozole tablets N=2563 Placebo N=2573 Letrozole tablets 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. Bone Substudy: [see Warnings and Precautions (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 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. [see Warnings and Precautions (5.2) ]. Updated Analysis, Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months The extended adjuvant treatment trial (MA-17) was unblinded early [see Adverse Reactions (6) ] . 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 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 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 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 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. [see Warnings and Precautions (5.2) ] . 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 letrozole tablets arm (median 6 months in the tamoxifen arm). 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 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 4. Table 4: Adverse Reactions Occurring in at least 5% of Patients in either Treatment Arm Adverse Reaction Letrozole tablets 2.5 mg (N=455) % Tamoxifen 20 mg (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 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 (AR/BC3), 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 tablet 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 letrozole tablets 0.5 mg, letrozole tablets 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 Adverse Reaction Pooled Letrozole tablets 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 Chest Pain 6 3 7 3 Peripheral Edema Includes peripheral edema, leg edema, dependent edema, edema 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 Includes musculoskeletal pain, skeletal pain, back pain, arm pain, leg pain 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 Includes rash, erythematous rash, maculopapular rash, psoriasiform rash, vesicular rash 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 letrozole tablets, 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 letrozole 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. Eye Disorders: blurred vision Hepatobiliary Disorders: increased hepatic enzymes, hepatitis Immune System Disorders: anaphylactic reactions, hypersensitivity reactions Nervous System Disorders: carpal tunnel syndrome, trigger finger Pregnancy: spontaneous abortions, congenital birth defects Skin and subcutaneous disorders: angioedema, toxic epidermal necrolysis, erythema multiforme To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email [email protected]; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Tamoxifen Coadministration of letrozole tablets and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels of 38% on average (study P015). Clinical experience in the second-line breast cancer trials (AR/BC2 and AR/BC3) indicates that the therapeutic effect of letrozole tablets therapy is not impaired if letrozole tablets are administered immediately after tamoxifen. Cimetidine A pharmacokinetic interaction study with cimetidine (study P004) showed no clinically significant effect on letrozole pharmacokinetics. Warfarin An interaction study (P017) with warfarin showed no clinically significant effect of letrozole on warfarin pharmacokinetics. Other anticancer agents There is no clinical experience to date on the use of letrozole tablets in combination with other anticancer agents.

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].