ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. 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)] 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 Accord Healthcare Inc. at 1-866-941-7875 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 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 CancerIn 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 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 symptom was present or absent at baseline. Most adverse reactions reported (approximately 75% of patients who reported AEs) were Grade or Grade applying the Common Toxicity Criteria (CTC) Version 2.0/ Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0. Table 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 1-4Grades 3-4Adverse ReactionsLetrozole TabletsN=2448n (%)TamoxifenN=2447n (%)Letrozole TabletsN=2448n (%)TamoxifenN=2447n (%)Patients with any adverse reaction2309(93.4)2212(90.4)636(26.0)606(24.8)Hypercholesterolemia 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 361(14.7)280(11.4)----Night sweats 356(14.6)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 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 decrease140( 5.7)129( 5.3)8( 0.3)5( 0.2)Osteoporosis 126( 5.1)66( 2.7)10( 0.4)5( 0.2)Back Pain125( 5.1)136( 5.6)7( 0.3)11( 0.4)Bone pain123( 5.0)109( 4.5)6( 0.2)4( 0.2)Depression119( 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 extremity103( 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)Alopecia83( 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 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 ischemia6( 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)----Target events pre-specified for analysis Events pre-printed on CRF 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 2At 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) 3Excluding 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 to and were not individually gradedWhen considering all grades during study treatment, higher incidence of events was seen for letrozole regarding fractures (10.1% vs. 7.1%), myocardial infarctions (1.0% vs. 0.5%), and arthralgia (25.2% vs. 20.4%) (letrozole vs. tamoxifen respectively). 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 vs. tamoxifen respectively).At median follow up of 96 months, higher incidence of events was seen for letrozole (14.7%) than for tamoxifen (11.4%) regarding fractures. higher incidence was seen for tamoxifen compared to letrozole regarding thromboembolic events (4.6% vs. 3.2%), and endometrial hyperplasia or cancer (2.9% vs. 0.4%) (tamoxifen vs. letrozole, respectively). Bone Study: Results of 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 median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to median increase of 0.3% in the tamoxifen arm (difference 4.4%) P<0.0001). No patients with normal BMD at baseline became osteoporotic over the years and only 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 year period, fractures were reported by of 103 patients (4%) in the letrozole arm, and of 97 patients (6%) in the tamoxifen arm. Lipid Study: In 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 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 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 ReactionsLetrozole = 2049 (%) Anastrozole = 2062 (%) Grade 3/4 (%) All grades (%) Grade 3/4 (%) All grades (%) Patients with at least one AR628 (30.6)2049 (100.0)591 (28.7)2062 (100.0)Arthralgia80 (3.9)987 (48.2)69 (3.3)987 (47.9)Hot flush17 (0.8)666 (32.5)9 (0.4)666 (32.3)Fatigue8 (0.4)345 (16.8)10 (0.5)343 (16.6)Osteoporosis5 (0.2)223 (10.9)11 (0.5)225 (10.9)Myalgia16 (0.8)233 (11.4)15 (0.7)212 (10.3)Back pain11 (0.5)212 (10.3)17 (0.8)193 (9.4)Osteopenia4 (0.2)203 (9.9)1 (0.0)173 (8.4)Pain in extremity9 (0.4)168 (8.2)3 (0.1)174 (8.4)Lymphoedema5 (0.2)159 (7.8)2 (0.1)179 (8.7)Insomnia7 (0.3)160 (7.8)3 (0.1)149 (7.2)Hypercholesterolaemia2 (0.1)155 (7.6)1 (0.0)151 (7.3)25 (1.2)156 (7.6)20 (1.0)149 (7.2)Depression16 (0.8)147 (7.2)13 (0.6)137 (6.6)Bone pain10 (0.5)138 (6.7)9 (0.4)122 (5.9)Nausea6 (0.3)137 (6.7)5 (0.2)152 (7.4)Headache3 (0.1)130 (6.3)5 (0.2)168 (8.1)Alopecia2 (0.1)127 (6.2)0 (0.0)134 (6.5)Musculoskeletal pain6 (0.3)123 (6.0)9 (0.4)147 (7.1)Radiation skin injury11 (0.5)120 (5.9)6 (0.3)88 (4.3)Dyspnoea16 (0.8)118 (5.8)10 (0.5)96 (4.7)Cough1 (0.0)106 (5.2)1 (0.0)120 (5.8)Musculoskeletal stiffness2 (0.1)102 (5.0)2 (0.1)84 (4.1)Dizziness2 (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 MonthsIn 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 describes the adverse reactions occurring at frequency of at least 5% in any treatment group during treatment. Most adverse reactions reported were Grade and Grade 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 ArmNumber (%) of Patients with Grade 1-4 Adverse ReactionsNumber (%) of Patients with Grade 3-4 Adverse ReactionsLetrozole TabletsPlaceboLetrozole TabletsPlaceboN=2563N=2573N=2563N=2573Any Adverse Reaction2232 (87.1)2174 (84.5)419 (16.3)389 (15.1)Vascular Disorders1375 (53.6)1230 (47.8)59 (2.3)74 (2.9)Flushing1273 (49.7)1114 (43.3)3 (0.1)0 -General Disorders 1154 (45)1090 (42.4)30 (1.2)28 (1.1)Asthenia862 (33.6)826 (32.1)16 (0.6)7 (0.3)Edema NOS471 (18.4)416 (16.2)4 (0.2)3 (0.1)Musculoskeletal Disorders978 (38.2)836 (32.5)71 (2.8)50 (1.9)Arthralgia565 (22)465 (18.1)25 (1)20 (0.8)Arthritis NOS173 (6.7)124 (4.8)10 (0.4)5 (0.2)Myalgia171 (6.7)122 (4.7)8 (0.3)6 (0.2)Back Pain129 (5)112 (4.4)8 (0.3)7 (0.3)Nervous System Disorders863 (33.7)819 (31.8)65 (2.5)58 (2.3)Headache516 (20.1)508 (19.7)18 (0.7)17 (0.7)Dizziness363 (14.2)342 (13.3)9 (0.4)6 (0.2)Skin Disorders830 (32.4)787 (30.6)17 (0.7)16 (0.6)Sweating Increased619 (24.2)577 (22.4)1 (<0.1)0 -Gastrointestinal Disorders725 (28.3)731 (28.4)43 (1.7)42 (1.6)Constipation290 (11.3)304 (11.8)6 (0.2)2 (<0.1)Nausea221 (8.6)212 (8.2)3 (0.1)10 (0.4)Diarrhea NOS128 (5)143 (5.6)12 (0.5)8 (0.3)Metabolic Disorders551 (21.5)537 (20.9)24 (0.9)32 (1.2)Hypercholesterolemia401 (15.6)398 (15.5)2 (<0.1)5 (0.2)Reproductive Disorders303 (11.8)357 (13.9)9 (0.4)8 (0.3)Vaginal Hemorrhage123 (4.8)171 (6.6)2 (<0.1)5 (0.2)Vulvovaginal Dryness137 (5.3)127 (4.9)0 -0 -Psychiatric Disorders320 (12.5)276 (10.7)21 (0.8)16 (0.6)Insomnia149 (5.8)120 (4.7)2 (<0.1)2 (<0.1)Respiratory Disorders279 (10.9)260 (10.1)30 (1.2)28 (1.1)Dyspnea140 (5.5)137 (5.3)21 (0.8)18 (0.7)Investigations184 (7.2)147 (5.7)13 (0.5)13 (0.5)Infections and Infestations166 (6.5)163 (6.3)40 (1.6)33 (1.3)Renal Disorders130 (5.1)100 (3.9)12 (0.5)6 (0.2)Based on median follow-up of patients for 28 months,the incidence of clinical fractures from the core randomized study in patients who received letrozole was 5.9% (152) and placebo was 5.5% (142). The incidence of self-reported osteoporosis was higher in patients who received letrozole 6.9% (176) than in patients who received placebo 5.5% (141). Bisphosphonates were administered to 21.1% of the patients who received letrozole 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 6.8% (175) and placebo 6.5% (167). patient-reported measure that captures treatment impact on important symptoms associated with estrogen deficiency demonstrated 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 median duration of follow-up of 62 months, there was no significant difference between letrozole and placebo in total cholesterol or in any lipid fraction at any time over 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 MonthsThe 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 median treatment duration of 24 months. During treatment or within 30 days of stopping treatment (median duration of treatment 60 months) higher rate of fractures was observed for letrozole (10.4%) compared to placebo (5.8%), as also higher rate of osteoporosis (letrozole 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 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 median duration of follow-up of 62 months, there was no significant difference between letrozole and placebo in total cholesterol or in any lipid fraction over 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 CancerIn study P025 total of 455 patients were treated for median time of exposure of 11 months in the letrozole arm (median months in the tamoxifen arm). The incidence of adverse reactions was similar for letrozole 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 and in 15/455 (3%) of patients on tamoxifen.Adverse reactions that were reported in at least 5% of the patients treated with letrozole 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 ArmAdverseLetrozoleTamoxifenReactions2.5 mg20 mg(N=455)(N=455)%%General DisordersFatigue1313Chest Pain89Edema Peripheral56Pain NOS57Weakness64InvestigationsWeight Decreased75Vascular DisordersHot Flushes1916Hypertension84Gastrointestinal DisordersNausea1717Constipation1011Diarrhea84Vomiting78Infections/InfestationsInfluenza64Urinary Tract Infection NOS63Injury, Poisoning and Procedural ComplicationsPost-Mastectomy Lymphedema77Metabolism and Nutrition DisordersAnorexia46Musculoskeletal and Connective Tissue DisordersBone Pain2221Back Pain1819Arthralgia1615Pain in Limb108Nervous System DisordersHeadache NOS87Psychiatric DisordersInsomnia74Reproductive System and Breast DisordersBreast Pain77Respiratory, Thoracic and Mediastinal DisordersDyspnea1817Cough1313Chest Wall Pain66Other 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 CancerStudy discontinuations in the megestrol acetate comparison study (AR/BC2) for adverse reactions other than progression of tumor were 5/188 (2.7%) on letrozole 0.5 mg, in 4/174 (2.3%) on letrozole 2.5 mg, and in 15/190 (7.9%) on megestrol acetate. There were fewer thromboembolic events at both letrozole 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 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, 7/185 (3.8%) on 2.5 mg letrozole, 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 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 patients 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 0.5 mg, letrozole 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 Frequency of at Least 5% of Patients in Either Treatment ArmAdversePooledPooledmegestrolReactionsLetrozoleLetrozoleacetateaminoglutethimide2.5 mg0.5 mg160 mg500 mg(N=359)(N=380)(N=189)(N=178)%%%%Body as WholeChest Pain6373Peripheral Edema 5583Asthenia4545Weight Increase2293CardiovascularHypertension5756Digestive SystemNausea1315914Vomiting7759Constipation6797Diarrhea6534Pain-Abdominal6598Anorexia5355Dyspepsia3465Infections/InfestationsViral Infection6563Lab AbnormalityHypercholesterolemia3306Musculoskeletal SystemMusculoskeletal 21223014Arthralgia8883Nervous SystemHeadache91297Somnolence3229Dizziness3573Respiratory SystemDyspnea79165Coughing6575Skin and AppendagesHot Flushes6543Rash 54312Pruritus12531Includes peripheral edema, leg edema, dependent edema, edema 2Includes musculoskeletal pain, skeletal pain, back pain, arm pain, leg pain 3Includes rash, erythematous rash, maculopapular rash, psoriasiform rash, vesicular rash Other less frequent (less than 5%) adverse reactions considered consequential and reported in at least patients treated with letrozole, included hypercalcemia, fracture, depression, anxiety, pleural effusion, alopecia, increased sweating and vertigo.First and Second-Line Treatment of Advanced Breast CancerIn 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. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Eye Disorders: blurred visionHepatobiliary Disorders: increased hepatic enzymes, hepatitisImmune System Disorders: anaphylactic reactions, hypersensitivity reactionsNervous System Disorders: carpal tunnel syndrome, trigger fingerPregnancy: spontaneous abortions, congenital birth defectsSkin and subcutaneous disorders: angioedema, toxic epidermal necrolysis, erythema multiforme.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. conventional carcinogenesis study in mice at doses of 0.6 to 60 mg/kg/day (about to 100 times the daily maximum recommended human dose on mg/m basis) administered by oral gavage for up to years revealed dose-related increase in the incidence of benign ovarian stromal tumors. The incidence of combined hepatocellular adenoma and carcinoma showed significant trend in females when the high dose group was excluded due to low survival. In separate study, plasma AUC 0-12hr levels in mice at 60 mg/kg/day were 55 times higher than the AUC 0-24hr level in breast cancer patients at the recommended dose. The carcinogenicity study in rats at oral doses of 0.1 to 10 mg/kg/day (about 0.4 to 40 times the daily maximum recommended human dose on mg/m basis) for up to years also produced an increase in the incidence of benign ovarian stromal tumors at 10 mg/kg/day. Ovarian hyperplasia was observed in females at doses equal to or greater than 0.1 mg/kg/day. At 10 mg/kg/day, plasma AUC 0-24hr levels in rats were 80 times higher than the level in breast cancer patients at the recommended dose.The benign ovarian stromal tumors observed in mice and rats were considered to be related to the pharmacological inhibition of estrogen synthesis and may be due to increased luteinizing hormone resulting from the decrease in circulating estrogen. Letrozole was not mutagenic in in vitro tests (Ames and E.coli bacterial tests) but was observed to be potential clastogen in in vitro assays (CHO K1 and CCL 61 Chinese hamster ovary cells). Letrozole was not clastogenic in vivo (micronucleus test in rats). In fertility and early embryonic development toxicity study in female rats, oral administration of letrozole starting weeks before mating until pregnancy day resulted in an increase in pre-implantation loss at doses >= 0.03 mg/kg/day (approximately 0.1 times the maximum recommended human dose on mg/m basis). In repeat-dose toxicity studies, administration of letrozole caused sexual inactivity in females and atrophy of the reproductive tract in males and females at doses of 0.6, 0.1 and 0.03 mg/kg in mice, rats and dogs, respectively (approximately 1, 0.4 and 0.4 times the daily maximum recommended human dose on mg/m basis, respectively).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The growth of some cancers of the breast is stimulated or maintained by estrogens. Treatment of breast cancer thought to be hormonally responsive (i.e., estrogen and/or progesterone receptor positive or receptor unknown) has included variety of efforts to decrease estrogen levels (ovariectomy, adrenalectomy, hypophysectomy) or inhibit estrogen effects (antiestrogens and progestational agents). These interventions lead to decreased tumor mass or delayed progression of tumor growth in some women. In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.Letrozole is nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor- and tumor-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH, and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in reduction of estrogen biosynthesis in all tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticosteroid synthesis, aldosterone synthesis, or synthesis of thyroid hormones.. 12.2 >Pharmacodynamics. In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to mg letrozole suppress plasma concentrations of estradiol, estrone, and estrone sulfate by 75% to 95% from baseline with maximal suppression achieved within two-three days. Suppression is dose-related, with doses of 0.5 mg and higher giving many values of estrone and estrone sulfate that were below the limit of detection in the assays. Estrogen suppression was maintained throughout treatment in all patients treated at 0.5 mg or higher.Letrozole is highly specific in inhibiting aromatase activity. There is no impairment of adrenal steroidogenesis. No clinically-relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH or in plasma renin activity among postmenopausal patients treated with daily dose of letrozole 0.1 mg to mg. The ACTH stimulation test performed after and 12 weeks of treatment with daily doses of 0.1, 0.25, 0.5, 1, 2.5, and mg did not indicate any attenuation of aldosterone or cortisol production. Glucocorticoid or mineralocorticoid supplementation is, therefore, not necessary.No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1, 0.5, and 2.5 mg single doses of letrozole or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 mg to mg. This indicates that the blockade of estrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH were not affected by letrozole in patients, nor was thyroid function as evaluated by TSH levels, T3 uptake, and T4 levels.. 12.3 Pharmacokinetics. Absorption and Distribution: Letrozole is rapidly and completely absorbed from the gastrointestinal tract and absorption is not affected by food. It is metabolized slowly to an inactive metabolite whose glucuronide conjugate is excreted renally, representing the major clearance pathway. About 90% of radiolabeled letrozole is recovered in urine. Letrozoles terminal elimination half-life is about days and steady-state plasma concentration after daily 2.5 mg dosing is reached in to weeks. Plasma concentrations at steady state are 1.5 to times higher than predicted from the concentrations measured after single dose, indicating slight non-linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. These steady-state levels are maintained over extended periods, however, and continuous accumulation of letrozole does not occur. Letrozole is weakly protein bound and has large volume of distribution (approximately 1.9 L/kg). EliminationMetabolism and Excretion: Metabolism to pharmacologically-inactive carbinol metabolite (4,4-methanol-bisbenzonitrile) and renal excretion of the glucuronide conjugate of this metabolite is the major pathway of letrozole clearance. Of the radiolabel recovered in urine, at least 75% was the glucuronide of the carbinol metabolite, about 9% was two unidentified metabolites, and 6% was unchanged letrozole. In human microsomes with specific CYP isozyme activity, CYP3A4 metabolized letrozole to the carbinol metabolite while CYP2A6 formed both this metabolite and its ketone analog. In human liver microsomes, letrozole inhibited CYP2A6 and CYP2C19, however, the clinical significance of these findings is unknown.Specific PopulationsPediatric, Geriatric and Race: In the study populations (adults ranging in age from 35 to greater than 80 years), no change in pharmacokinetic parameters was observed with increasing age. Differences in letrozole pharmacokinetics between adult and pediatric populations have not been studied. Differences in letrozole pharmacokinetics due to race have not been studied. Renal Impairment: In study of volunteers with varying renal function (24-hour creatinine clearance: to 116 mL/min), no effect of renal function on the pharmacokinetics of single doses of 2.5 mg of letrozole was found. In addition, in study (AR/BC2) of 347 patients with advanced breast cancer, about half of whom received 2.5 mg letrozole and half 0.5 mg letrozole, renal impairment (calculated creatinine clearance: 20 to 50 mL/min) did not affect steady-state plasma letrozole concentrations. HepaticImpairment: In study of subjects with mild to moderate non-metastatic hepatic dysfunction (e.g., cirrhosis, Child-Pugh classification and B), the mean area under curve (AUC) values of the volunteers with moderate hepatic impairment were 37% higher than in normal subjects, but still within the range seen in subjects without impaired function. In pharmacokinetic study, subjects with liver cirrhosis and severe hepatic impairment (Child-Pugh classification C, which included bilirubins about to 11 times ULN with minimal to severe ascites) had two-fold increase in exposure (AUC) and 47% reduction in systemic clearance. Breast cancer patients with severe hepatic impairment are thus expected to be exposed to higher levels of letrozole than patients with normal liver function receiving similar doses of this drug. [see Dosage and Administration 2.5)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Updated Adjuvant Treatment of Early Breast Cancer. In multicenter study (BIG 1-98, NCT00004205) enrolling over 8,000 postmenopausal women with resected, receptor-positive early breast cancer, one of the following treatments was randomized in double-blind manner: Option 1:tamoxifen for years Letrozole for years tamoxifen for years followed by letrozole for years Letrozole for years followed by tamoxifen for yearsOption 2:tamoxifen for years Letrozole for yearsThe study in the adjuvant setting, BIG 1-98 was designed to answer two primary questions: whether letrozole for years was superior to Tamoxifen for years (Primary Core Analysis) and whether switching endocrine treatments at years was superior to continuing the same agent for total of years (Sequential Treatments Analysis). Selected baseline characteristics for the study population are shown in Table 6.The primary endpoint of this trial was disease-free survival (DFS) (i.e., interval between randomization and earliest occurrence of local, regional, or distant recurrence, or invasive contralateral breast cancer, or death from any cause). The secondary endpoints were overall survival (OS), systemic disease-free survival (SDFS), invasive contralateral breast cancer, time to breast cancer recurrence (TBR) and time to distant metastasis (TDM).The Primary Core Analysis (PCA) included all patients and all follow-up in the monotherapy arms in both randomization options, but follow-up in the two sequential treatments arms was truncated 30 days after switching treatments. The PCA was conducted at median treatment duration of 24 months and median follow-up of 26 months. Letrozole was superior to tamoxifen in all endpoints except overall survival and contralateral breast cancer [e.g., DFS: hazard ratio, HR 0.79; 95% CI (0.68, 0.92); P=0.002; SDFS: HR 0.83; 95% CI (0.70, 0.97); TDM: HR 0.73; 95% CI (0.60, 0.88); OS: HR 0.86; 95% CI (0.70, 1.06). In 2005, based on recommendations by the independent Data Monitoring Committee, the tamoxifen arms were unblinded and patients were allowed to complete initial adjuvant therapy with letrozole (if they had received tamoxifen for at least years) or to start extended adjuvant treatment with letrozole (if they had received tamoxifen for at least 4.5 years) if they remained alive and disease-free. In total, 632 patients crossed to letrozole or another aromatase inhibitor. Approximately 70% (448) of these 632 patients crossed to letrozole to complete initial adjuvant therapy and most of these crossed in years to 4. All of these patients were in Option 1. total of 184 patients started extended adjuvant therapy with letrozole (172 patients) or with another aromatase inhibitor (12 patients). To explore the impact of this selective crossover, results from analyses censoring follow-up at the date of the selective crossover (in the tamoxifen arm) are presented for the MAA.The PCA allowed the results of letrozole for years compared with tamoxifen for years to be reported in 2005 after median follow-up of only 26 months. The design of the PCA is not optimal to evaluate the effect of letrozole after longer time (because follow-up was truncated in two arms at around 25 months). The MAA (ignoring the two sequential treatment arms) provided follow-up equally as long in each treatment and did not over-emphasize early recurrences as the PCA did. The MAA thus provides the clinically appropriate updated efficacy results in answer to the first primary question, despite the confounding of the tamoxifen reference arm by the selective crossover to letrozole. The updated results for the MAA are summarized in Table 7. Median follow-up for this analysis is 73 months.The Sequential Treatments Analysis (STA) addresses the second primary question of the study. The primary analysis for the STA was from switch (or equivalent time-point in monotherapy arms) 30 days (STA-S) with two-sided test applied to each pair-wise comparison at the 2.5% level. Additional analyses were conducted from randomization (STA-R) but these comparisons (added in light of changing medical practice) were under-powered for efficacy.Table 6: Adjuvant Study Patient and Disease Characteristics (ITT Population)Primary Core Analysis (PCA)Monotherapy Arms Analysis (MAA)LetrozoleTamoxifenLetrozoleTamoxifenN=4003N=4007N=2463N=2459Characteristicn (%)n (%)n (%)n (%)Age (median, years)61616161Age range (years)38 to 8939 to 9038 to 8839 to 90Hormone receptor status (%)ER+ and/or PgR+99.799.799.799.7Both unknown0.30.30.30.3Nodal status (%)Node negative52525052Node positive41414341Nodal status unknown7777Prior adjuvant chemotherapy (%)24242424Table 7: Updated Adjuvant Study Results Monotherapy Arms Analysis (Median Follow-up 73 Months)LetrozoleN=2463TamoxifenN=2459Hazard ratioEvents(%)5-year rateEvents(%)5-year rate(95% CI)PDisease-free survival ITT445 (18.1)87.4500 (20.3)84.70.87 (0.76, 0.99)0.03Censor44587.448384.20.84 (0.73, 0.95)0 positive nodesITT16592.218990.30.88 (0.72, 1.09)1 to positive nodesITT15185.616383.00.85 (0.68, 1.06)>=4 positive nodesITT12371.214262.60.81 (0.64, 1.03)Adjuvant chemotherapyITT11986.415080.60.77 (0.60, 0.98)No chemotherapyITT32687.835086.10.91 (0.78, 1.06)Systemic DFS ITT40188.544686.60.88 (0.77,1.01)Time to distant metastasis ITT25792.429890.10.85 (0.72, 1.00)Adjuvant chemotherapyITT84-109-0.75(0.56 to 1.00)No chemotherapyITT173-189-0.90 (0.73,1.11)Distant DFS ITT38589.043287.10.87 (0.76,1.00)Contralateral breast cancerITT3499.24498.60.76 (0.49, 1.19)Overall survivalITT30391.834390.90.87 (0.75, 1.02)Censor30391.833890.10.82 (0.70, 0.96)0 positive nodesITT10795.212194.80.90 (0.69,1.16)1 to positive nodesITT9990.811490.60.81 (0.62,1.06)>=4 positive nodesITT9280.210473.60.86 (0.65, 1.14)Adjuvant chemotherapyITT7691.59688.40.79 (0.58, 1.06)No chemotherapyITT22791.924791.80.91 (0.76, 1.08)Definition of: Disease-free survival: Interval from randomization to earliest event of invasive loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death without prior event Systemic disease-free survival: Interval from randomization to invasive regional recurrence, distant metastasis, or death without prior cancer event Time to distant metastasis: Interval from randomization to distant metastasis Distant disease-free survival: Interval from randomization to earlier event of relapse in distant site or death from any cause ITT analysis ignores selective crossover in tamoxifen arms Censored analysis censors follow-up at the date of selective crossover in 632 patients who crossed to letrozole or another aromatase inhibitor after the tamoxifen arms were unblinded in 2005Figure shows the Kaplan-Meier curves for Disease-Free Survival Monotherapy AnalysisDFS events defined as loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death from any cause (i.e., definition excludes second non-breast primary cancers).The medians of overall survival for both arms were not reached for the MAA. There was no statistically significant difference in overall survival. The hazard ratio for survival in the letrozole arm compared to the tamoxifen arm was 0.87, with 95% CI (0.75, 1.02) (see Table 7). There were no significant differences in DFS, OS, SDFS, and Distant DFS from switch in the Sequential Treatments Analysis with respect to either monotherapy (e.g., [tamoxifen years followed by] letrozole years versus tamoxifen beyond years, DFS HR 0.89; 97.5% CI 0.68, 1.15 and [letrozole years followed by] tamoxifen years versus letrozole beyond years, DFS HR 0.93; 97.5% CI 0.71, 1.22). There were no significant differences in DFS, OS, SDFS, and Distant DFS from randomization in the Sequential Treatments Analyses.. tamoxifen for years Letrozole for years tamoxifen for years followed by letrozole for years Letrozole for years followed by tamoxifen for years. tamoxifen for years Letrozole for years. Figure Disease-Free Survival (Median follow-up 73 months, ITT Approach). 14.2 Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months. double-blind, randomized, placebo-controlled trial (MA-17, NCT00003140) of letrozole was performed in over 5,100 postmenopausal women with receptor-positive or unknown primary breast cancer who were disease free after years of adjuvant treatment with tamoxifen.The planned duration of treatment for patients in the study was years, but the trial was terminated early because of an interim analysis showing favorable letrozole effect on time without recurrence or contralateral breast cancer. At the time of unblinding, women had been followed for median of 28 months, 30% of patients had completed or more years of follow-up and less than 1% of patients had completed years of follow-up.Selected baseline characteristics for the study population are shown in Table 8.Table 8: Selected Study Population Demographics (Modified ITT Population)Baseline StatusLetrozolePlaceboN=2582N=2586Hormone Receptor Status (%)ER+ and/or PgR+9898Both Unknown22Nodal Status (%)Node Negative5050Node Positive4646Nodal Status Unknown44Chemotherapy4646Table shows the study results. Disease-free survival was measured as the time from randomization to the earliest event of loco-regional or distant recurrence of the primary disease or development of contralateral breast cancer or death. DFS by hormone receptor status, nodal status and adjuvant chemotherapy were similar to the overall results. Data were premature for an analysis of survival.Table 9: Extended Adjuvant Study ResultsLetrozoleN 2582 PlaceboN 2586 Hazard Ratio(95% CI) P-ValueDisease Free Survival (DFS)1Events122 (4.7%)193 (7.5%)0.62 (0.49, 0.78) 0.00003Local Breast Recurrence922Local Chest Wall Recurrence28Regional Recurrence74Distant Recurrence55920.61 (0.44 to 0.84)0.003Contralateral Breast Cancer1929Deaths Without Recurrence or Contralateral Breast Cancer3038CI confidence interval for hazard ratio. Hazard ratio of less than 1.0 indicates difference in favor of letrozole (lesser risk of recurrence); hazard ratio greater than 1.0 indicates difference in favor of placebo (higher risk of recurrence with letrozole). First event of loco-regional recurrence, distant relapse, contralateral breast cancer or death from any cause Analysis stratified by receptor status, nodal status and prior adjuvant chemotherapy (stratification factors as at randomization). P-value based on stratified log-rank test. 14.3 Updated Analyses of Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 60 Months. Table 10: Update of Extended Adjuvant Study ResultsLetrozoleN 2582 (%)PlaceboN 2586 (%)Hazard Ratio1(95% CI) P-Value2Disease Free Survival (DFS) events3344 (13.3)402 (15.5)0.89 (0.77, 1.03)0.12Breast cancer recurrence(Protocol definition of DFS events 4) 2092860.75 (0.63, 0.89)0.001Local Breast Recurrence1544Local Chest Wall Recurrence614Regional Recurrence108Distant Recurrence140167Distant Recurrence (first or subsequent events) Contralateral Breast Cancer 142 37 169 53 0.88 (0.70,1.10)0.246Deaths Without Recurrence or Contralateral Breast Cancer1351161 Adjusted by receptor status, nodal status and prior chemotherapy Stratified log-rank test, stratified by receptor status, nodal status and prior chemotherapy DFS events defined as earliest of loco-regional recurrence, distant metastasis, contralateral breast cancer or death from any cause, and ignoring switches to letrozole in 60% of the placebo arm. Protocol definition does not include deaths from any cause Updated analyses were conducted at median follow-up of 62 months. In the letrozole arm, 71% of the patients were treated for least years and 58% of patients completed at least 4.5 years of extended adjuvant treatment. After the unblinding of the study at median follow-up of 28 months, approximately 60% of the selected patients in the placebo arm opted to switch to letrozole. In this updated analysis shown in Table 10 letrozole significantly reduced the risk of breast cancer recurrence or contralateral breast cancer compared with placebo (HR 0.75; 95% CI 0.63, 0.89; P=0.001). However, in the updated DFS analysis (interval between randomization and earliest event of loco-regional recurrence, distant metastasis, contralateral breast cancer, or death from any cause) the treatment difference was heavily diluted by 60% of the patients in the placebo arm switching to letrozole and accounting for 64% of the total placebo patient- years of follow-up. Ignoring these switches, the risk of DFS event was reduced by non-significant 11% (HR 0.89; 95% CI 0.77, 1.03). There was no significant difference in distant disease-free survival or overall survival. 14.4 First-Line Treatment of Advanced Breast Cancer. randomized, double-blind, multinational trial (P025) compared letrozole 2.5 mg with tamoxifen 20 mg in 916 postmenopausal patients with locally advanced (Stage IIIB or loco-regional recurrence not amenable to treatment with surgery or radiation) or metastatic breast cancer. Time to progression (TTP) was the primary endpoint of the trial. Selected baseline characteristics for this study are shown in Table 11.Table 11: Selected Study Population DemographicsBaseline StatusLetrozoleTamoxifenN=458N=458Stage of DiseaseIIIB6%7%IV93%92%Receptor StatusER and PgR Positive38%41%ER or PgR Positive26%26%Both Unknown34%33%ER or PgR -/Other Unknown <1%0Previous Antiestrogen TherapyAdjuvant19%18%None81%82%Dominant Site of DiseaseSoft Tissue25%25%Bone32%29%Viscera43%46%Letrozole was superior to tamoxifen in TTP and rate of objective tumor response (see Table 12).Table 12 summarizes the results of the trial, with total median follow-up of approximately 32 months. (All analyses are unadjusted and use 2-sided P-values.) Table 12: Results of First-Line Treatment of Advanced Breast Cancer LetrozoleTamoxifenHazard or Odds2.5 mg20 mgRatio (95% CI)N=453N=454P-Value (2-Sided)Median Time to Progression9.4 months6.0 months0.72 (0.62, 0.83) P<0.0001 Objective Response Rate(CR PR)145 (32%)95 (21%)1.77 (1.31, 2.39) P=0.0002 (CR)42 (9%)15 (3%)2.99 (1.63, 5.47) P=0.0004 Duration of Objective ResponseMedian18 months 16 months (N=145)(N=95)Overall Survival35 months 32 months(N=458)(N=458)P=0.5136 31 Hazard ratio Odds ratio Overall log-rank test Figure shows the Kaplan-Meier curves for TTP.Table 13 shows results in the subgroup of women who had received prior antiestrogen adjuvant therapy, Table 14 results by disease site and Table 15, the results by receptor status.Table 13: Efficacy in Patients Who Received Prior Antiestrogen TherapyVariableLetrozole Tamoxifen2.5 mg20 mgN=84N=83Median Time to Progression (95% CI) 8.9 months (6.2, 12.5) 5.9 months (3.2, 6.2)Hazard Ratio for TTP (95% CI) 0.60 (0.43, 0.84)Objective Response Rate(CR PR)22 (26%)7 (8%)Odds Ratio for Response (95% CI)3.85 (1.50, 9.60)Hazard ratio less than or odds ratio greater than favors letrozole; hazard ratio greater than or odds ratio less than favors tamoxifen.Table 14: Efficacy by Disease SiteLetrozoleTamoxifen2.5 mg20 mgDominant Disease SiteSoft Tissue:N=113N=115Median TTP12.1 months6.4 monthsObjective Response Rate50%34%Bone:N=145N=131Median TTP9.5 months6.3 monthsObjective Response Rate23%15%Viscera:N=195N=208Median TTP8.3 months4.6 monthsObjective Response Rate28%17%Table 15: Efficacy by Receptor StatusVariableLetrozoleTamoxifen2.5 mg20 mgReceptor PositiveN=294N=305Median Time to Progression (95% CI)9.4 months (8.9, 11.8)6.0 months (5.1, 8.5)Hazard Ratio for TTP (95% CI)0.69 (0.58, 0.83)Objective Response Rate (CR+PR)97 (33%)66 (22%)Odds Ratio for Response 95% CI)1.78 (1.20, 2.60)Receptor UnknownN=159N=149Median Time to Progression (95% CI)9.2 months (6.1, 12.3)6.0 months (4.1, 6.4)Hazard Ratio for TTP (95% CI) 0.77 (0.60, 0.99)Objective Response Rate (CR+PR)48 (30%)29 (20%)Odds Ratio for Response (95% CI)1.79 (1.10, 3.00)Hazard ratio less than or odds ratio greater than favors letrozole; hazard ratio greater than or odds ratio less than favors tamoxifen.Figure 3: shows the Kaplan-Meier curves for survival.Legend: Randomized letrozole: n=458, events 57%, median overall survival 35 months (95% CI 32 to 38 months) Randomized tamoxifen: n=458, events 57%, median overall survival 32 months (95% CI 28 to 37 months)Overall log-rank P=0.5136 (i.e., there was no significant difference between treatment arms in overall survival). The median overall survival was 35 months for the letrozole group and 32 months for the tamoxifen group, with P-value 0.5136. Study design allowed patients to cross over upon progression to the other therapy. Approximately 50% of patients crossed over to the opposite treatment arm and almost all patients who crossed over had done so by 36 months. The median time to crossover was 17 months (letrozole to tamoxifen) and 13 months (tamoxifen to letrozole). In patients who did not cross over to the opposite treatment arm, median survival was 35 months with letrozole (n=219, 95% Cl 29 to 43 months) vs. 20 months with tamoxifen (n=229, 95% Cl 16 to 26 months). Figure Kaplan-Meier Estimates of Time to Progression (Tamoxifen Study). Figure Survival by Randomized Treatment Arm. 14.5 Second-Line Treatment of Advanced Breast Cancer. Letrozole was initially studied at doses of 0.1 mg to 5.0 mg daily in six noncomparative trials (AR/BC1, P01, AR/ST1, AR/PS1, AR/ES1 and NJO-03) in 181 postmenopausal estrogen/progesterone receptor positive or unknown advanced breast cancer patients previously treated with at least antiestrogen therapy. Patients had received other hormonal therapies and also may have received cytotoxic therapy. Eight (20%) of forty patients treated with letrozole 2.5 mg daily in trials achieved an objective tumor response (complete or partial response).Two large randomized, controlled, multinational (predominantly European) trials (AR/BC2, AR/BC3) were conducted in patients with advanced breast cancer who had progressed despite antiestrogen therapy. Patients were randomized to letrozole 0.5 mg daily, letrozole 2.5 mg daily, or comparator [megestrol acetate 160 mg daily in one study (AR/BC2); and aminoglutethimide 250 mg twice day with corticosteroid supplementation in the other study (AR/BC3)]. In each study over 60% of the patients had received therapeutic antiestrogens, and about one-fifth of these patients had an objective response. The megestrol acetate controlled study was double-blind; the other study was open label. Selected baseline characteristics for each study are shown in Table 16.Table 16:Selected Study Population DemographicsParametermegestrol acetateaminoglutethimidestudystudyNo. of Participants552557Receptor StatusER/PR Positive57%56%ER/PR Unknown43%44%Previous TherapyAdjuvant Only33%38%Therapeutic +/- Adj.66%62%Sites of DiseaseSoft Tissue56%50%Bone50%55%Viscera40%44%Confirmed objective tumor response (complete response plus partial response) was the primary endpoint of the trials. Responses were measured according to the Union Internationale Contre le Cancer (UICC) criteria and verified by independent, blinded review. All responses were confirmed by second evaluation to 12 weeks after the documentation of the initial response.Table 17 shows the results for the first trial (AR/BC2), with minimum follow-up of 15 months, that compared letrozole 0.5 mg, letrozole 2.5 mg, and megestrol acetate 160 mg daily. (All analyses are unadjusted.)Table 17: Megestrol Acetate Study ResultsLetrozole Letrozolemegestrol0.5 mg2.5 mgacetateN=188N=174N=190Objective Response (CR PR)22 (11.7%)41 (23.6%)31 (16.3%)Median Duration of Response552 days(Not reached)561 daysMedian Time to Progression154 days170 days168 daysMedian Survival 633 days730 days659 daysOdds Ratio for Responseletrozole 2.5 mg: letrozole 0.5 mg=2.33letrozole 2.5 mg: megestrol=1.58(95% CI: 1.32, 4.17); P=0.004 (95% CI: 0.94, 2.66); P=0.08 Relative Risk of Progressionletrozole 2.5 mg: letrozole 0.5 mg=0.81letrozole 2.5 mg megestrol=0.77(95% CI: 0.63, 1.03); P=0.09 (95% CI: 0.60, 0.98); P=0.03 Two-sided P-value The Kaplan-Meier curves for progression for the megestrol acetate study are shown in Figure 4.The results for the study comparing letrozole to aminoglutethimide (AR/BC3), with minimum follow-up of months, are shown in Table 18. (Unadjusted analyses are used).Table 18: Aminoglutethimide Study ResultsLetrozoleLetrozole0.5 mg2.5 mgaminoglutethimideN=193N=185N=179Objective Response (CR+PR)34 (17.6%)34 (18.4%)22 (12.3%)Median Duration of Response619 days706 days450 daysMedian Time to Progression103 days123 days112 daysMedian Survival 636 days792 days592 daysOdds Ratio for Responseletrozole 2.5 mg: letrozole 2.5 mg: letrozole 0.5 mg=1.05aminoglutethimide=1.61(95% CI: 0.62, 1.79); P=0.85 (95% CI: 0.90, 2.87); P=0.11 Relative Risk of Progressionletrozole 2.5 mg: letrozole 2.5 mg: letrozole 0.5 mg=0.86aminoglutethimide=0.74(95% CI: 0.68, 1.11); P=0.25 (95% CI: 0.57, 0.94); P=0.02 Two-sided P-value The Kaplan-Meier curves for progression for the aminoglutethimide study is shown in Figure 5.. Figure Kaplan-Meier Estimates of Time to Progression (Megestrol Acetate Study). Figure Kaplan-Meier Estimates of Time to Progression (Aminoglutethimide Study).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. 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)] 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)] 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: 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)] 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)] 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) Pregnancy 4) Known hypersensitivity to the active substance, or to any of the excipients 4).

DESCRIPTION SECTION.

11 DESCRIPTION. Letrozole tablet USP for oral administration contains 2.5 mg of letrozole, 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 isLetrozole is white to yellowish crystalline powder, practically odorless, freely soluble in dichloromethane, slightly soluble in ethanol, and practically insoluble in water. It has molecular weight of 285.31, empirical formula 17H 11N 5, and melting range of 184C to 185C. Letrozole is available as 2.5 mg tablets for oral administration.InactiveIngredients: Colloidal anhydrous silica, hypromellose, iron oxide yellow lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, starch (corn), talc, and titanium dioxide. Letrozole structural formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. 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) 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 tablet is one 2.5 mg tablet administered once 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 post approval adjuvant study, median treatment duration was 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 tablet is not known. The planned duration of treatment in the study was years. In the final updated analysis, conducted at 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 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)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. 2.5 mg tablets: yellow round, biconvex, film coated tablets imprinted with LT on one side and plain on other side. 2.5 mg tablets 3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. TamoxifenCoadministration of letrozole and tamoxifen 20 mg daily resulted in 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 therapy is not impaired if letrozole is administered immediately after tamoxifen. CimetidineA pharmacokinetic interaction study with cimetidine (study P004) showed no clinically significant effect on letrozole pharmacokinetics. WarfarinAn interaction study (P017) with warfarin showed no clinically significant effect of letrozole on warfarin pharmacokinetics.Other anticancer agentsThere is no clinical experience to date on the use of letrozole in combination with other anticancer agents.

GERIATRIC USE SECTION.

8.5 Geriatric Use. The median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was 64 to 65 years. About 1/3 of the patients were greater than or equal to 70 years old. In the first-line study, patients greater than or equal to 70 years of age experienced longer time to tumor progression and higher response rates than patients less than 70.For the extended adjuvant setting (MA-17), more than 5,100 postmenopausal women were enrolled in the clinical study. In total, 41% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. In the extended adjuvant setting, no overall differences in safety or efficacy were observed between these older patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.In the adjuvant setting (BIG 1-98), more than 8,000 postmenopausal women were enrolled in the clinical study. In total, 36 of patients were aged 65 years or older at enrollment, while 12% were 75 or older. More adverse reactions were generally reported in elderly patients irrespective of study treatment allocation. However, in comparison to tamoxifen, no overall differences with regards to the safety and efficacy profiles were observed between elderly patients and younger patients.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Packaged in HDPE bottles and unit dose blister package.2.5 mg tablets yellow round, biconvex, film coated tablets imprinted with LT on one side and plain on other side.NDC 68071-5264-3 BOTTLES OF 30Store at 25C (77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Letrozole tablet is 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) 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 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 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)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Embryo-Fetal ToxicityAdvise females of reproductive potential of the potential risk to fetus and to use effective contraception during letrozole therapy and for at least weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with letrozole tablets [see Warnings and Precautions 5.6), and Use in Specific Populations 8.1), 8.3)] LactationAdvise women not to breastfeed during letrozole tablets treatment and for at least weeks after the last dose [see Use in Specific Populations 8.2) InfertilityAdvise females and males of reproductive potential of the potential for reduced fertility from letrozole tablets [see Use in Specific Populations 8.3) Fatigue and DizzinessSince fatigue and dizziness have been observed with the use of letrozole tablets and somnolence was uncommonly reported, caution is advised when driving or using machinery.Bone Effects Consideration should be given to monitoring bone mineral density. Manufactured For: Accord Healthcare, Inc., 1009 Slater Road, Suite 210-B, Durham, NC 27703, USA. Manufactured By:Intas Pharmaceuticals Limited, Plot No. 457, 458, Village Matoda, Bavla Road, Ta.- Sanand, Dist.- Ahmedabad 382 210. India. 10 2293 697339Issued May 2019.

LACTATION SECTION.

8.2 Lactation. Risk SummaryIt is not known if letrozole is present in human milk. There are no data on the effects of letrozole on the breastfed infant or milk production. Exposure of lactating rats to letrozole was associated with impaired reproductive performance of the male offspring (see Data). Because of the potential for serious adverse reactions in breastfed infants from letrozole tablets, advise lactating women not to breastfeed while taking letrozole tablets and for at least weeks after the last dose.DataAnimal DataIn postnatal developmental toxicity study in lactating rats, letrozole was administered orally at doses of 1, 0.003, 0.03 or 0.3 mg/kg/day on day through day 20 of lactation. The reproductive performance of the male offspring was impaired at letrozole dose as low as 0.003 mg/kg/day (approximately 0.01 times the maximum recommended human dose on mg/m basis), as reflected by decreased mating and pregnancy ratios. There were no effects on the reproductive performance of female offspring.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The growth of some cancers of the breast is stimulated or maintained by estrogens. Treatment of breast cancer thought to be hormonally responsive (i.e., estrogen and/or progesterone receptor positive or receptor unknown) has included variety of efforts to decrease estrogen levels (ovariectomy, adrenalectomy, hypophysectomy) or inhibit estrogen effects (antiestrogens and progestational agents). These interventions lead to decreased tumor mass or delayed progression of tumor growth in some women. In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.Letrozole is nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor- and tumor-bearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum LH, and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum FSH. Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in reduction of estrogen biosynthesis in all tissues. Treatment of women with letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to significantly affect adrenal corticosteroid synthesis, aldosterone synthesis, or synthesis of thyroid hormones.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. conventional carcinogenesis study in mice at doses of 0.6 to 60 mg/kg/day (about to 100 times the daily maximum recommended human dose on mg/m basis) administered by oral gavage for up to years revealed dose-related increase in the incidence of benign ovarian stromal tumors. The incidence of combined hepatocellular adenoma and carcinoma showed significant trend in females when the high dose group was excluded due to low survival. In separate study, plasma AUC 0-12hr levels in mice at 60 mg/kg/day were 55 times higher than the AUC 0-24hr level in breast cancer patients at the recommended dose. The carcinogenicity study in rats at oral doses of 0.1 to 10 mg/kg/day (about 0.4 to 40 times the daily maximum recommended human dose on mg/m basis) for up to years also produced an increase in the incidence of benign ovarian stromal tumors at 10 mg/kg/day. Ovarian hyperplasia was observed in females at doses equal to or greater than 0.1 mg/kg/day. At 10 mg/kg/day, plasma AUC 0-24hr levels in rats were 80 times higher than the level in breast cancer patients at the recommended dose.The benign ovarian stromal tumors observed in mice and rats were considered to be related to the pharmacological inhibition of estrogen synthesis and may be due to increased luteinizing hormone resulting from the decrease in circulating estrogen. Letrozole was not mutagenic in in vitro tests (Ames and E.coli bacterial tests) but was observed to be potential clastogen in in vitro assays (CHO K1 and CCL 61 Chinese hamster ovary cells). Letrozole was not clastogenic in vivo (micronucleus test in rats). In fertility and early embryonic development toxicity study in female rats, oral administration of letrozole starting weeks before mating until pregnancy day resulted in an increase in pre-implantation loss at doses >= 0.03 mg/kg/day (approximately 0.1 times the maximum recommended human dose on mg/m basis). In repeat-dose toxicity studies, administration of letrozole caused sexual inactivity in females and atrophy of the reproductive tract in males and females at doses of 0.6, 0.1 and 0.03 mg/kg in mice, rats and dogs, respectively (approximately 1, 0.4 and 0.4 times the daily maximum recommended human dose on mg/m basis, respectively).

OVERDOSAGE SECTION.

10 OVERDOSAGE. Isolated cases of letrozole overdose have been reported. In these instances, the highest single dose ingested was 62.5 mg or 25 tablets. While no serious adverse reactions were reported in these cases, because of the limited data available, no firm recommendations for treatment can be made. However, emesis could be induced if the patient is alert. In general, supportive care and frequent monitoring of vital signs are also appropriate. In single-dose studies, the highest dose used was 30 mg, which was well tolerated; in multiple-dose trials, the largest dose of 10 mg was well tolerated. Lethality was observed in mice and rats following single oral doses that were equal to or greater than 2,000 mg/kg (about 4,000 to 8,000 times the daily maximum recommended human dose on mg/m basis); death was associated with reduced motor activity, ataxia and dyspnea. Lethality was observed in cats following single IV doses that were equal to or greater than 10 mg/kg (about 50 times the daily maximum recommended human dose on mg/m basis); death was preceded by depressed blood pressure and arrhythmias.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness in pediatric patients have not been established.Letrozole administration to young (postnatal day 7) rats for 12 weeks duration at 0.003, 0.03, 0.3 mg/kg/day by oral gavage resulted in adverse skeletal/growth effects (bone maturation, bone mineral density) and neuroendocrine and reproductive developmental perturbations of the hypothalamic-pituitary axis. Administration of 0.3 mg/kg/day resulted in AUC values that were similar to the AUC in adult patients receiving the recommended dose of 2.5 mg/day. Decreased fertility was accompanied by hypertrophy of the hypophysis and testicular changes that included degeneration of the seminiferous tubular epithelium and atrophy of the female reproductive tract. Young rats in this study were allowed to recover following discontinuation of letrozole treatment for 42 days. Histopathological changes were not reversible at clinically relevant exposures.

PHARMACODYNAMICS SECTION.

12.2 >Pharmacodynamics. In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to mg letrozole suppress plasma concentrations of estradiol, estrone, and estrone sulfate by 75% to 95% from baseline with maximal suppression achieved within two-three days. Suppression is dose-related, with doses of 0.5 mg and higher giving many values of estrone and estrone sulfate that were below the limit of detection in the assays. Estrogen suppression was maintained throughout treatment in all patients treated at 0.5 mg or higher.Letrozole is highly specific in inhibiting aromatase activity. There is no impairment of adrenal steroidogenesis. No clinically-relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, ACTH or in plasma renin activity among postmenopausal patients treated with daily dose of letrozole 0.1 mg to mg. The ACTH stimulation test performed after and 12 weeks of treatment with daily doses of 0.1, 0.25, 0.5, 1, 2.5, and mg did not indicate any attenuation of aldosterone or cortisol production. Glucocorticoid or mineralocorticoid supplementation is, therefore, not necessary.No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among healthy postmenopausal women after 0.1, 0.5, and 2.5 mg single doses of letrozole or in plasma concentrations of androstenedione among postmenopausal patients treated with daily doses of 0.1 mg to mg. This indicates that the blockade of estrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma levels of LH and FSH were not affected by letrozole in patients, nor was thyroid function as evaluated by TSH levels, T3 uptake, and T4 levels.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption and Distribution: Letrozole is rapidly and completely absorbed from the gastrointestinal tract and absorption is not affected by food. It is metabolized slowly to an inactive metabolite whose glucuronide conjugate is excreted renally, representing the major clearance pathway. About 90% of radiolabeled letrozole is recovered in urine. Letrozoles terminal elimination half-life is about days and steady-state plasma concentration after daily 2.5 mg dosing is reached in to weeks. Plasma concentrations at steady state are 1.5 to times higher than predicted from the concentrations measured after single dose, indicating slight non-linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. These steady-state levels are maintained over extended periods, however, and continuous accumulation of letrozole does not occur. Letrozole is weakly protein bound and has large volume of distribution (approximately 1.9 L/kg). EliminationMetabolism and Excretion: Metabolism to pharmacologically-inactive carbinol metabolite (4,4-methanol-bisbenzonitrile) and renal excretion of the glucuronide conjugate of this metabolite is the major pathway of letrozole clearance. Of the radiolabel recovered in urine, at least 75% was the glucuronide of the carbinol metabolite, about 9% was two unidentified metabolites, and 6% was unchanged letrozole. In human microsomes with specific CYP isozyme activity, CYP3A4 metabolized letrozole to the carbinol metabolite while CYP2A6 formed both this metabolite and its ketone analog. In human liver microsomes, letrozole inhibited CYP2A6 and CYP2C19, however, the clinical significance of these findings is unknown.Specific PopulationsPediatric, Geriatric and Race: In the study populations (adults ranging in age from 35 to greater than 80 years), no change in pharmacokinetic parameters was observed with increasing age. Differences in letrozole pharmacokinetics between adult and pediatric populations have not been studied. Differences in letrozole pharmacokinetics due to race have not been studied. Renal Impairment: In study of volunteers with varying renal function (24-hour creatinine clearance: to 116 mL/min), no effect of renal function on the pharmacokinetics of single doses of 2.5 mg of letrozole was found. In addition, in study (AR/BC2) of 347 patients with advanced breast cancer, about half of whom received 2.5 mg letrozole and half 0.5 mg letrozole, renal impairment (calculated creatinine clearance: 20 to 50 mL/min) did not affect steady-state plasma letrozole concentrations. HepaticImpairment: In study of subjects with mild to moderate non-metastatic hepatic dysfunction (e.g., cirrhosis, Child-Pugh classification and B), the mean area under curve (AUC) values of the volunteers with moderate hepatic impairment were 37% higher than in normal subjects, but still within the range seen in subjects without impaired function. In pharmacokinetic study, subjects with liver cirrhosis and severe hepatic impairment (Child-Pugh classification C, which included bilirubins about to 11 times ULN with minimal to severe ascites) had two-fold increase in exposure (AUC) and 47% reduction in systemic clearance. Breast cancer patients with severe hepatic impairment are thus expected to be exposed to higher levels of letrozole than patients with normal liver function receiving similar doses of this drug. [see Dosage and Administration 2.5)].

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary Based on postmarketing reports, findings from animal studies and the mechanism of action, letrozole can cause fetal harm and is contraindicated for use in pregnant women. In post-marketing reports, use of letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects; however, the data are insufficient to inform drug-associated risk [see Contraindications 4), Warnings and Precautions 5.6), Adverse Reactions 6.2) and Clinical Pharmacology 12.1)]. In animal reproduction studies, administration of letrozole to pregnant animals during organogenesis resulted in increased post-implantation pregnancy loss and resorption, fewer live fetuses, and fetal malformation affecting the renal and skeletal systems in rats and rabbits at doses approximately 0.1 times the daily maximum recommended human dose (MRHD) on mg/m basis (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. DataAnimal DataIn fertility and early embryonic development toxicity study in female rats, oral administration of letrozole starting weeks before mating until pregnancy day resulted in an increase in pre-implantation loss at doses >= 0.003 mg/kg/day (approximately 0.01 times the maximum recommended human dose on mg/m basis). In an embryo-fetal developmental toxicity study in rats, daily administration of oral letrozole during the period of organogenesis at doses >= 0.003 mg/kg (approximately 0.01 time the maximum recommended human dose on mg/m basis) resulted in embryo-fetal toxicity including intrauterine mortality, increased resorptions and postimplantation loss, decreased numbers of live fetuses and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. Letrozole was teratogenic to rats at dose of 0.03 mg/kg (approximately 0.01 times the maximum recommended human dose on mg/m basis) and caused fetal domed head and cervical/centrum vertebral fusion. In the embryo-fetal development toxicity study in rabbits, daily administration of oral letrozole during the period of organogenesis at doses >= 0.002 mg/kg (approximately 0.01 times the maximum recommended human dose on mg/m basis) resulted in embryo-fetal toxicity including intrauterine mortality, increased resorption, increased postimplantation loss and decreased numbers of live fetuses. Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs.

SPL UNCLASSIFIED SECTION.

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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. 8.2) Lactation: Advise not to breastfeed. 8.2) 8.1 Pregnancy. Risk Summary Based on postmarketing reports, findings from animal studies and the mechanism of action, letrozole can cause fetal harm and is contraindicated for use in pregnant women. In post-marketing reports, use of letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects; however, the data are insufficient to inform drug-associated risk [see Contraindications 4), Warnings and Precautions 5.6), Adverse Reactions 6.2) and Clinical Pharmacology 12.1)]. In animal reproduction studies, administration of letrozole to pregnant animals during organogenesis resulted in increased post-implantation pregnancy loss and resorption, fewer live fetuses, and fetal malformation affecting the renal and skeletal systems in rats and rabbits at doses approximately 0.1 times the daily maximum recommended human dose (MRHD) on mg/m basis (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. DataAnimal DataIn fertility and early embryonic development toxicity study in female rats, oral administration of letrozole starting weeks before mating until pregnancy day resulted in an increase in pre-implantation loss at doses >= 0.003 mg/kg/day (approximately 0.01 times the maximum recommended human dose on mg/m basis). In an embryo-fetal developmental toxicity study in rats, daily administration of oral letrozole during the period of organogenesis at doses >= 0.003 mg/kg (approximately 0.01 time the maximum recommended human dose on mg/m basis) resulted in embryo-fetal toxicity including intrauterine mortality, increased resorptions and postimplantation loss, decreased numbers of live fetuses and fetal anomalies including absence and shortening of renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. Letrozole was teratogenic to rats at dose of 0.03 mg/kg (approximately 0.01 times the maximum recommended human dose on mg/m basis) and caused fetal domed head and cervical/centrum vertebral fusion. In the embryo-fetal development toxicity study in rabbits, daily administration of oral letrozole during the period of organogenesis at doses >= 0.002 mg/kg (approximately 0.01 times the maximum recommended human dose on mg/m basis) resulted in embryo-fetal toxicity including intrauterine mortality, increased resorption, increased postimplantation loss and decreased numbers of live fetuses. Fetal anomalies included incomplete ossification of the skull, sternebrae, and fore- and hind legs. 8.2 Lactation. Risk SummaryIt is not known if letrozole is present in human milk. There are no data on the effects of letrozole on the breastfed infant or milk production. Exposure of lactating rats to letrozole was associated with impaired reproductive performance of the male offspring (see Data). Because of the potential for serious adverse reactions in breastfed infants from letrozole tablets, advise lactating women not to breastfeed while taking letrozole tablets and for at least weeks after the last dose.DataAnimal DataIn postnatal developmental toxicity study in lactating rats, letrozole was administered orally at doses of 1, 0.003, 0.03 or 0.3 mg/kg/day on day through day 20 of lactation. The reproductive performance of the male offspring was impaired at letrozole dose as low as 0.003 mg/kg/day (approximately 0.01 times the maximum recommended human dose on mg/m basis), as reflected by decreased mating and pregnancy ratios. There were no effects on the reproductive performance of female offspring. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingBased on animal studies, letrozole can cause fetal harm when administered to pregnant woman [see Use in Specific Populations 8.1)]. Females of reproductive potential should have pregnancy test prior to starting treatment with letrozole. ContraceptionFemalesBased on animal studies, letrozole tablets can cause fetal harm when administered to pregnant woman [see Use in Specific Populations 8.1)]. Advise females of reproductive potential to use effective contraception during treatment with letrozole tablets and for at least weeks after the last dose. InfertilityFemalesBased on studies in female animals, letrozole tablets may impair fertility in females of reproductive potential [see Nonclinical Toxicology 13.1)]. MalesBased on studies in male animals, letrozole tablets may impair fertility in males of reproductive potential [see Nonclinical Toxicology 13.1)]. 8.4 Pediatric Use. The safety and effectiveness in pediatric patients have not been established.Letrozole administration to young (postnatal day 7) rats for 12 weeks duration at 0.003, 0.03, 0.3 mg/kg/day by oral gavage resulted in adverse skeletal/growth effects (bone maturation, bone mineral density) and neuroendocrine and reproductive developmental perturbations of the hypothalamic-pituitary axis. Administration of 0.3 mg/kg/day resulted in AUC values that were similar to the AUC in adult patients receiving the recommended dose of 2.5 mg/day. Decreased fertility was accompanied by hypertrophy of the hypophysis and testicular changes that included degeneration of the seminiferous tubular epithelium and atrophy of the female reproductive tract. Young rats in this study were allowed to recover following discontinuation of letrozole treatment for 42 days. Histopathological changes were not reversible at clinically relevant exposures.. 8.5 Geriatric Use. The median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was 64 to 65 years. About 1/3 of the patients were greater than or equal to 70 years old. In the first-line study, patients greater than or equal to 70 years of age experienced longer time to tumor progression and higher response rates than patients less than 70.For the extended adjuvant setting (MA-17), more than 5,100 postmenopausal women were enrolled in the clinical study. In total, 41% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. In the extended adjuvant setting, no overall differences in safety or efficacy were observed between these older patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.In the adjuvant setting (BIG 1-98), more than 8,000 postmenopausal women were enrolled in the clinical study. In total, 36 of patients were aged 65 years or older at enrollment, while 12% were 75 or older. More adverse reactions were generally reported in elderly patients irrespective of study treatment allocation. However, in comparison to tamoxifen, no overall differences with regards to the safety and efficacy profiles were observed between elderly patients and younger patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Decreases in bone mineral density may occur. Consider bone mineral density monitoring 5.1) Increases in total cholesterol may occur. Consider cholesterol monitoring. 5.2) Fatigue, dizziness and somnolence may occur. Exercise caution when operating machinery 5.4) Embryo-Fetal toxicity: Can cause fetal harm when administered to pregnant women. Obtain pregnancy test in females of reproductive potential. Advise females of reproductive potential to use effective contraception 5.6, 8.1, 8.3) Decreases in bone mineral density may occur. Consider bone mineral density monitoring 5.1) Increases in total cholesterol may occur. Consider cholesterol monitoring. 5.2) Fatigue, dizziness and somnolence may occur. Exercise caution when operating machinery 5.4) Embryo-Fetal toxicity: Can cause fetal harm when administered to pregnant women. Obtain pregnancy test in females of reproductive potential. Advise females of reproductive potential to use effective contraception 5.6, 8.1, 8.3) 5.1 Bone Effects. Use of letrozole may cause decreases in bone mineral density (BMD). Consideration should be given to monitoring BMD. Results of safety study to evaluate safety 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 median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to median increase of 0.3% in the tamoxifen arm (difference 4.4%) P<0.0001) [see Adverse Reactions 6)] Updated results from the BMD substudy (MA-17B) in the extended adjuvant setting demonstrated that at years patients receiving letrozole had median decrease from baseline of 3.8% in hip BMD compared to median decrease of 2.0% in the placebo group. The changes from baseline in lumbar spine BMD in letrozole and placebo treated groups were not significantly different [see Adverse Reactions 6)]. In the adjuvant trial (BIG 1-98) the incidence of bone fractures at any time after randomization was 14.7% for letrozole and 11.4% for tamoxifen at median follow-up of 96 months. The incidence of osteoporosis was 5.1% for letrozole and 2.7% for tamoxifen [see Adverse Reactions 6)] In the extended adjuvant trial (MA-17), the incidence of bone fractures at any time after randomization was 13.3% for letrozole and 7.8% for placebo at median follow-up of 62 months. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo [see Adverse Reactions 6)]. 5.2 Cholesterol. Consideration should be given to monitoring serum cholesterol. In the adjuvant trial (BIG 1-98), hypercholesterolemia was reported in 52.3% of letrozole patients and 28.6% of tamoxifen patients. Grade to hypercholesterolemia was reported in 0.4% of letrozole patients and 0.1% of tamoxifen patients. Also in the adjuvant setting, an increase of greater than or equal to 1.5 upper limit of normal (ULN) in total cholesterol (generally nonfasting) was observed in patients on monotherapy who had baseline total serum cholesterol within the normal range (i.e., less than=1.5 ULN) in 155/1843 (8.4%) patients on letrozole vs 71/1840 (3.9%) patients on tamoxifen. Lipid lowering medications were required for 29% of patients on letrozole and 20% on tamoxifen [see Adverse Reactions 6)]. 5.3 Hepatic Impairment. Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of letrozole experienced approximately twice the exposure to letrozole as healthy volunteers with normal liver function [see Clinical Pharmacology 12.3)] Therefore, dose reduction is recommended for this patient population. The effect of hepatic impairment on letrozole exposure in cancer patients with elevated bilirubin levels has not been determined [see Dosage and Administration 2.5)]. 5.4 Fatigue and Dizziness. Because fatigue, dizziness, and somnolence have been reported with the use of letrozole, caution is advised when driving or using machinery until it is known how the patient reacts to letrozole use. 5.5 Laboratory Test Abnormalities. No dose-related effect of letrozole on any hematologic or clinical chemistry parameter was evident. Moderate decreases in lymphocyte counts, of uncertain clinical significance, were observed in some patients receiving letrozole 2.5 mg. This depression was transient in about half of those affected. Two patients on letrozole developed thrombocytopenia; relationship to the study drug was unclear. Patient withdrawal due to laboratory abnormalities, whether related to study treatment or not was infrequent. 5.6 Embryo-Fetal Toxicity. Based on post-marketing reports, findings from animal studies and the mechanism of action, letrozole can cause fetal harm and is contraindicated for use in pregnant women. In post-marketing reports, use of letrozole during pregnancy resulted in cases of spontaneous abortions and congenital birth defects. Letrozole caused embryo-fetal toxicities in rats and rabbits at maternal exposures that were below the maximum recommended human dose (MHRD) on mg/m basis. Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during therapy with letrozole and for at least weeks after the last dose [see Adverse Reactions 6.2), Use in Specific Populations 8.1, 8.3) and Clinical Pharmacology 12.1)].