فيمابنت 2.5مجم 14 قرص

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.

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 (DFS) in patients treated with letrozole tablets for a median of 60 months [see Clinical Studies ( 14.2 , 14.3 )] . 1.3 First and Second-Line Treatment of Advanced Breast Cancer Letrozole tablets are indicated for first-line treatment of postmenopausal women with hormone receptor positive or unknown, locally advanced or metastatic breast cancer. Letrozole tablets are also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy [see Clinical Studies ( 14.4 , 14.5 )].

Letrozole tablets are taken orally without regard to meals ( 2 ): Recommended dose: 2.5.mg once daily ( 2.1 ) Patients with cirrhosis or severe hepatic impairment: 2.5 mg every other day ( 2.5 , 5.3 ) 2.1 Recommended Dose The recommended dose of letrozole 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 percent (71%) 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 ( 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 )] .

The following are discussed in greater detail in other sections of the labeling. Bone effects [see ( 5.1 )] Increases in cholesterol [see ( 5.2 )] Fatigue and Dizziness [see ( 5.4 )] The most common (greater than 20%) were hot flashes, arthralgia; flushing, asthenia, edema, arthralgia, headache, dizziness, hypercholesterolemia, sweating increased, bone pain and musculoskeletal ( 6 ). To report SUSPECTED , 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, 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 to 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 were prospectively specified for analysis (see Table 1), based on the known pharmacologic properties and side effect profiles of the two drugs. were analyzed irrespective of whether a symptom was present or absent at baseline. Most 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 (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 (CTC Grades 1 to 4) in the Adjuvant Study – Monotherapy Arms Analysis (Median Follow-up 96 Months; Median Treatment 60 Months) Grades 1 to 4 Grades 3 to 4 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....

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