Letrozole

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 a 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 a 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 a 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.

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 ) 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 )].

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 ) 2.1 Recommended Dose The recommended dose of letrozole tablet 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 post approval 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 tablet 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 )] .

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 )] 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 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 and tamoxifen. Certain adverse reactions were prospectively specified for analysis (see Table 1), based on the known pharmacologic properties and side effect profiles of the two drugs. Adverse reactions were analyzed irrespective of whether a symptom was present or absent at baseline. Most adverse reactions reported (approximately 75% of patients who reported AEs) were Grade 1 or Grade 2 applying the Common Toxicity Criteria (CTC) Version 2.0/ Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0. Table 1 describes adverse reactions (Grades 1-4 and Grades 3-4) irrespective of relationship to study treatment in the adjuvant trial for the monotherapy arms analysis (safety population). Table 1: Patients with Adverse Reactions (CTC Grades 1-4) in the Adjuvant Study – Monotherapy Arms Analysis (Median Follow-up 96 Months; Median Treatment 60 Months) Grades 1-4 Grades 3-4 Adverse Reactions Letrozole Tablets N=2448 n (%) Tamoxifen N=2447 n (%) Letrozole Tablets N=2448 n (%) Tamoxifen N=2447 n (%) Patients with any adverse reaction 2309 (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 1 361 (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 **2 249 (10.2) 175 ( 7.2) - - - - Fatigue (lethargy, malaise, asthenia) **2 235 ( 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) 66 ( 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 1 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 **1 11 (0.4) 72 (2.9) - - - - Endometrial hyperplasia/ Cancer **3 6/1909 ( 0.3) 57/1943 (2.9) - - - - Other endometrial disorders ** 2 (<0.1) 3 ( 0.1) 0 - 0 - Myocardial infarction **2 24 ( 1.0) 12 ( 0.5) - - - - Myocardial ischemia 6 ( 0.2) 9 ( 0.4) - - - - Cerebrovascular accident/TIA **1 74 (3.0) 68 (2.8) - - - - Cerebrovascular accident/TIA **2 51 ( 2.1) 47 ( 1.9) - - - - Angina requiring surgery **1 35 ( 1.4) 33 ( 1.3) - - - - Angina requiring surgery **2 25 ( 1.0) 25 ( 1.0) - - - - Thromboembolic event **1 79 ( 3.2) 113 ( 4.6) - - - - Thromboembolic event **2 51 ( 2.1) 89 ( 3.6) - - - - Cardiac failure 1 39 (1.6) 34 (1.4) - - - - Cardiac failure 2 27 (1.1) 15 (0.6) - - - - Hypertension 1 160 (6.5) 175 (7.2) - - - - Hypertension 2 138 (5.6) 139 (5.7) - - - - Other cardiovascular **1 172 (7.0) 174 (7.1) - - - - Other cardiovascular 2 120 (4.9) 119 (4.9) - - - - Second primary malignancy 1 129 (5.3) 150 (6.1) - - - - Second primary malignancy 2 54 ( 2.2) 79 ( 3.2) - - - - * Target events pre-specified for analys

7 DRUG INTERACTIONS Tamoxifen Coadministration of letrozole 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 therapy is not impaired if letrozole is 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 in combination with other anticancer agents.